Contributors

Endocrinology, Diabetes and Metabolism Unit

Internal Medicine Department
Mansoura University

• Prof. Mohammed Ragheb Refaey • Prof. Mohammed Ghoneem

• Prof. Nader Abo Elenen • Prof. Mohammed Helaly
• Prof. Nabil Lamoon • Prof. Hala Abdulhafez
• Prof. Megahed Abuelmagd • Prof. Amany Mousa
• Prof. Mammdoh Elnahas • Dr. Alaa Wafa
• Prof. Nagy Shaaban • Dr. Mervat Elashmawy
• Prof. Elhadidy Mohammed • Dr. Eman Eladawy
Elhadidy • Dr. Mohammed Shereif
• Prof. Omayma Saleh • Dr. Enas Taher
• Prof. Ataa Mahfouz Bakr • Dr. Maha Elshafey
• Prof. Hanan Gawish • Dr. Mohammed Mosaad
• Prof. Mohammed Elsayed • Dr. Mohammed Gameel
Abdulhamed • Dr. Amr Elsehrawy
• Prof. Manal Tarshoby • Dr. Amr Abdel hamed Elsayed
• Prof. Mohammed Yaqoot • Dr. Fady Azmy Kerlis
• Prof. Elsayed Hatata • Dr. Ibrahim Elbadawy
• Prof. Omnia State
Table of Contents
Chapter Diabetes Mellitus
1 1- 45

Chapter Hypothalamus and pituitary

gland
2 46 - 74

Chapter Thirst Axis

3 75 - 80

Chapter Thyroid Disorders

4 81 -115

Chapter Adrenal Glands

5 116 - 134

Chapter Reproduction
6 135 – 148
Chapter Calcium bone
7 149 – 168

Chapter Obesity and Metabolic

8 169 – 175

Chapter Hyperlipidaemia
9 176 – 182

Chapter Nutritional Deficiency

10 183 – 185
CHAPTER

Diabetes
Mellitus
 Diabetes Mellitus

Definition:
1
• It is a clinical syndrome Characterized by:
▪ Chronic persistent hyperglycemia.
▪ Disturbed metabolism of Ptn, Fat, CHO & Electrolyte.
▪ Microangiopathy esp. in Retina, Glomeruli, &
peripheral nerves.
• It is caused by: ( absolute or relative lack of insulin )

Classification of DM
1. Type I diabetes
A. Immune mediated B. Idiopathic
2. Type 2 diabetes
3. Gestational DM
4. Other specific types:
- Genetic defects of B-cell function
- Genetic defects in insulin action
- Exocrine pancreatic causes
• Congenital cystic fibrosis
• Chronic pancreatitis, Hemochromatosis
• Fibrocalculus pancreatopathy (tropical DM - tropical
malnutrition)
- Endocrinal causes
• Acromegaly, Pheochromocytoma
• Cushing syndrome, Conn's syndrome
• Somatostatinoma, Glucagonoma,
• Thyrotoxicosis
- Infections:
• congenital rubella
• cytomegallovirus
- Drugs: interferon, Corticosteroids, CCP

N.B:** (MODY type): Mature Onset Diabetes in the Young:

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 2 Diabetes Mellitus

- Represent 15 % of cases, autosomal dominant, in young obese people

-Treated by oral antidiabetics, less liable for microangiopathy
** (LADA): (Late onset Autoimmune Diabetes of Adult)

Pathophysiology of type1 DM:

• Type1 DM is the result of destruction of insulin-secreting beta
cells of the islets of Langerhans more than 75%,
• Currently, autoimmunity is considered the major factor in the
pathophysiology of type 1 DM.
• Approximately 85% of type 1 DM patients have circulating
islet cell antibodies, and the majority also has detectable anti-
insulin antibodies before receiving insulin therapy.
• The most commonly found islet cell antibodies are those
Chapter 1

directed against glutamic acid decarboxylase (GAD), an

enzyme found within pancreatic beta cells.

Etiology:
Genetic predisposition and an environmental component.
- From 90% to 95% of young children with type 1 DM carry
HLA-DR3 or HLA-DR4.
- Potential triggers for immunologically mediated destruction of
the beta cells include viruses (eg, enterovirus, mumps, rubella,
and coxsackievirus B4), toxic chemicals, and exposure to
cow’s milk in infancy, and cytotoxins.

Pathophysiology of type 2 DM:

• A combination of peripheral insulin resistance and inadequate
insulin secretion by pancreatic beta cells.
• A role for excess glucagon cannot be underestimated;

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 Diabetic Mellitus 3

Chapter 1
Scheme for type 2 DM pathophysiology

Etiology
Complex interactions between environmental and genetic factors.
• The genetics of type 2 diabetes are complex and not
completely understood. Evidence supports the involvement
of multiple genes in pancreatic beta-cell failure and insulin
resistance.
The major risk factors for type 2 diabetes mellitus are the
following:
• Age greater than 45 years (though, as noted above, type 2
diabetes mellitus is occurring with increasing frequency in
young individuals)
• Weight greater than 120% of desirable body weight
• Family history of type 2 diabetes in a first-degree relative (eg,
parent or sibling)
• History of previous impaired glucose tolerance (IGT) or
impaired fasting glucose (IFG) or A1C >5.7.
• Hypertension (>140/90 mm Hg) or dyslipidemia (HDL
cholesterol level < 35 mg/dL or triglyceride level >250
mg/dL)
• History of gestational diabetes mellitus or of delivering a
baby with a birth weight of over 9 lb
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 4 Diabetes Mellitus

• Polycystic ovarian syndrome (which results from insulin

resistance)
Diagnosis of DM
 Clinical Picture
A. Asvmptomatic: in 1/3 of cases
B. Classic symptoms:
1. Polyuria : with nocturia
2. Polydypsia
3. Polyphagia with weight loss
4. Pruritis especially of vulva
5. Pains & paresthesia
6. Premature loosening of teeth
7. Blurred vision : due to osmotic swelling of lens
Chapter 1

C. Symptoms of complications: acute, chronic.

Complication of DM

Acute complications Chronic

Complication
1. Diabetic comas - Neurological compl.
2. Infections - Ocular Complication.
3. Complication related to systems - CVS complication.
• RF -Pul. complication
• AMI - GIT complication.
• Acute neuropathy - Renal complication
- Genital complication.
- Skin complication.
- Diabetic Foot.

Rheumatological comp
- Infection
- Psychiatric complication
- comp. of therapy

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 Diabetic Mellitus 5

Differential Diagnosis

A) D.D. of reducing substance in urine

1. Glucosuria
1. Renal glucosuria due to Low renal threshold:
 Pregnancy
 De-Toni Fanconi syndrome
2. Alimetary glycosuria: Gastrectomy, liver cirrhosis
3. Cerebral glucosuria: Sub arachinoid hge, Meningitis
2. Other Sugar in urine : Fructosuria , galactosuria, pentosuria
3. Other Reducing substances in urine : Vit.C , salicylates

Chapter 1
B). D.D. of symptomatology
1. loss of weight inspite of good appetite:
- Malabsorption syndrome
- Parasitic infestation
- Thyrotoxicosis
2. Other causes of Polyuria

C) 1ry from 2rv DM: (e g Cushing disease)

D). Type 1 DM from Type 2 DM:

Type I DM = Type 2=
(IDDM) (NIDDM)

Incidence 5-15% 85%

Subtypes Type I A : 80 % Type 2-obese: 80

immune Type 2-non obese
Type I B : 20 % : 20
idiopathic

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 6 Diabetes Mellitus

Genetic Chromosome 6 - Chromosome 11 -

locus recessive multifactorial
HALA DR3, absent
DR4,B8,B15,
Pathogenesis See before See before

Age of onset < 30 years > 30 years

onset acute Gradual

symptoms Severe, including May be no

coma symptoms
Chapter 1

Complication Ketoresistant
Ketolabile
(DKA)
Investigation

- Abnormal
- ↑↑ insulin
Insulin Low or absent resistance

High and High and resistant

Glucagon suppressed by to insulin
insulin
ICA, ICSA, Anti- Absent
Auto Ab
GAD

C-peptide deficient increased

Treatment -Diet - OHD ±

Insulin is a must
insulin

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 Diabetic Mellitus 7

Investigations
A- To diagnose DM

Normal (mg/dl) Prediabetes diabetes

Fasting 70 to less than100 100-125 (IFG) > 126

2 hr. PP <140 140 -199 (IGT) > 200

HbA1C <5.7 5.7-6.4 >6.5

Chapter 1
 IFG: "Impaired fasting glucose"
100 - 125 mg
 IGT: "Impaired glucose tolerance"- 2h. P.P. 140 -199 mg
IGT Personnel: (rule of third)
1/3 remain IGT
1/3 develop frank DM,
1/3 return to normal plasma glucose

C- To monitor diabetic complications

 Retinopathy: Fundus Exam.
 Nephropathy: urine analysis for microalbuminuria
 ECG
 Lipid profile
D- To monitor diabetic patients
 BLOOD:
1. Glycosylated proteins
a- Hb A1c:

Target in diabetics: < 7%

 Formed due to non-enzymatic glycosylation of amino acid
valine & lysine in β chain of HbA

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 8 Diabetes Mellitus

 Its % gives an estimate of diabetic control for the preceding

3 months.
 The Normal level 4 - 6 % of total Hb

b- Other glycosylated proteins: fructosamine (glycosylated albumin)

Factors interfering with measurement of A1c.
a. False high values: uremia, high concentrations of fetal
hemoglobin (HbF), high aspirin doses (usually>10 g/day), or
high concentrations of ethanol.
b. False low values: hemogloinopathies, hemorrhage and hemolytic
disorders.
Chapter 1

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 Diabetic Mellitus 9

Complication of diabetes

1- Neurologic complications:
Brain comp.
Cerebral Atheroscelerosis
Diabetic Coma
• DKA coma
• HHNK coma
• Hypoglycemic coma
• Lactic Acid coma
Spinal cord
1. Pyramidal tract affection : diabetic lateral sclerosis
2. Anterior spinal artery occlusion

Chapter 1
3. Diabetic pseudotabes
Nerve
• Peripheral neuropathy
• Autonomic neuropathy

Hypoglycemia

Definition:
1. In Patients with diabetes
Hypoglycemia is defined as all episodes of an abnormally low plasma
glucose concentration (with or without symptoms) that expose the
individual to harm,
(at a self-monitored blood glucose (SMBG) level ≤70 mg/dL)

2. In Patients without diabetes

Whipple's triad:
• Patient's symptoms of hypoglycemia.
• Documented low patient's plasma glucose when the
symptoms are present.
• The symptoms can be relieved by administration of glucose.

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 10 Diabetes Mellitus

Hpoglycemia mechanisms

1. Insulin secretion declines as the glucose declines to low-

normal levels, around 80 mg/dl in venous blood.
Low insulin levels stimulate increases in hepatic and renal
glucose production

2. Epinephrine is released by the adrenal medullae at mild levels

of hypoglycemia (65–70 mg/dl). , And stimulates hepatic and
renal glucose production and decreases glucose utilization by
peripheral tissues

3. Glucagon release:
Chapter 1

At glucose (65–70 mg/dl) Increases hepatic glucose production

via glycogenolysis and gluconeogenesis.

4. Cortisol and growth hormone release

Contribute only if the hypoglycemia persists for several hours.

5. Neuroglycopenic symptoms
Develop if glucose levels to decline into the mid-50 mg/dl range.

Symptoms:
1. neurogenic (autonomic)

(Warning symptoms) Caused by sympathetic neural response to blood

glucose <65

• Sweating
• Weakness
• Palpitations
• Tremor
• Nervousness
• Hunger
• Paresthesias

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 Diabetic Mellitus 11

2. neuroglycopenia
• Confusion., Loss-of-consciousness.
• Cognitive impairment.
• Seizure.
• Focal neurologic deficits.
• Visual disturbances.
Signs:

• Diaphoresis and pallor.

• Heart rates and systolic blood pressures are raised.
• Neuroglycopenic manifestations.

Outcome and complications:

Chapter 1
• The vast majority of episodes are reversed after the glucose level
is raised to normal.
• Prolonged untreated hypoglycemia can lead to:

1- Transient neurological deficits, but Permanent neurological

damage is rare.
2- Death

CAUSES OF HYPOGLYCEMIA

Drugs are the most common cause

A- In diabetes
Exogenous insulin and insulin secretagogue (sulfonylureas)

NB: Insulin sensitizers (metformin, thiazolidinediones), glucosidase

inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and
dipeptidyl peptidase IV inhibitors are much less common causes
hypoglycemia.

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 12 Diabetes Mellitus

B- Hypoglycemia in patients without diabetes

1- Drugs: Insulin, sulfonylureas, quinolones, pentamidine, quinine,

angiotensin-converting enzyme inhibitors,IGF-1,alcohol, and
salicylates
2- Endocrine causes of hypoglycaemia
- Hypopituitarism.
- Addison’s disease.
3- Endogenous hyperinsulinism
- A beta cell secretagogue, such as a sulfonylurea
- Insulinoma diagnosed by Whipple’s triad, plus insulin
levels,. C-peptide during a spontaneous episode of
hypoglycaemia.
Chapter 1

- Insulin autoimmune hypoglycemia

4- Tumours
Mesenchymal tumors, fibromas, carcinoid, myelomas,
lymphomas, hepatocellular, and colorectal carcinomas.
5- Critical illness
6- Sepsis Because of cytokine induced inhibition of
gluconeogenesis in the setting of glycogen depletion.
7- Chronic kidney disease
Impaired gluconeogenesis, reduced renal clearance of insulin,
and reduced renal glucose production.
8- In fulminant liver failure,
Gluconeogenesis is also impaired.
9- Malnourishment
As a result of substrate limitation of gluconeogenesis and
glycogenolysis in the setting of glycogen depletion.

• Postprandial hypoglycaemia
occurs within four hours after meals (after gastric surgery).

• Factitious hypoglycemia: surreptitious use of drugs that cause

hypoglycemia

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 Diabetic Mellitus 13

Special types of hypoglycemia:

1- Nocturnal hypoglycemia
Can lead to disruption of sleep and delays in correction of the
hypoglycemia.
If high morning sugars preceded by an episode of nocturnal
hypoglycemia (Somogyi effect).

2- Hypoglycemia Unawareness
Occurs in longstanding diabetes, especially type 1 diabetes.
It is due to hypoglycemia-associated autonomic [Link] will
develop neuroglycopenic symptoms, without warnings symptoms of
hypoglycemia.

Chapter 1
Treatment of hypoglycemia

Treatment of acute hypoglycemia

If the patient is conscious and able to drink and swallow, administer
a rapidly-absorbed oral carbohydrate as If the patient has altered
mental status, is unable to swallow, give an IV bolus of 12.5 to 25
gm of glucose (25 percent dextrose).

If glucose cannot be given by parenteral or oral routes, give

glucagon 1 mg IM or SC.

Treatment of the underlying cause

• Adjust dose of antidiabetics
• Surgical removal of the insulinoma is the Non islet tumours
• oral glucocorticoids, diazoxide and octreotide, glucagon.
• Replacement therapy for addison disease.

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 14 Diabetes Mellitus

Diabetic ketoacidosis “DKA”

• Occurs in type 1 DM or less frequently type 2DM

Causes:
• Missed insulin
• Relative insulin deficiency
▪ stress, steroid ttt, infection
▪ Tissue damage : trauma, operation, burns, shock, stroke, MI
▪ Pregnancy, labor & lactation
• ↑ ketone bodies Formation : as in Starvation, severe exertion
or excess fat intake
Pathogenesis:
• Glucose can't enter cells in absence of insulin 
Chapter 1

Hyperglycemia & glucosuria. Fat are mobilized for energy

production excess production of KB.
• (acetone, acetoacetic acid & B- hydroxyl Butyric acids)
 ketosis,
 ketonemia
 ketonuria.
• Shift of K outside cells (in absence of insulin) which is then
lost in urine.

Clinical Picture:
• Symptoms of uncontrolled DM for 2 - 3 days
• Respiration :
▪ Kussmaul respiration deep rapid
▪ Acetone breath
• CVS : shock, peripheral VD, dysrhythmias
• Dehydration
• Kidney : ketonuria + glucosuria  severe polyuria, polydypsia
&dehydration (dry inelastic skin, sunken eye, thirst, low BP &
low temp)
• GIT :
▪ Acute abdomen (epigastric pain),
▪ Nausea, vomiting, constipation & hematemesis

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 Diabetic Mellitus 15

• Muscles: generalized weakness & ms pain .

▪ End stage : coma ( due to acidosis, ketosis, dehydration &
electrolyte imbalance )
Complications:
• ARDS, (adult respiratory disorders syndrome)
• DIC, arterial and venous thrombosis,
• Pancreatitis,
• Brain edema

Investigations:
• Blood
o Hyperglycemia, ketonemia
o Acidosis (T plasma HCO3)

Chapter 1
▪ Dehydration  ↑ PCV, ↑ serum creatinine c-T FFA
& TG
o Serum K : normal or high despite depletion of body K due
to extracellular shift
o leucocytosis and ↑ serum amylase
• Urine : glucosuria , ketonuria, polyuria
• ECG, chest X-ray

D_D: from other types of comas in diabetics

Hypoglycemia DKA
History excess ttt - ↓ttt - stress ,
missed meal infection
-Onset of rapid + irritable slow + silent
coma
- normal subnormal
Temperature
-Respiration normal - Kuassmal (air
hunger)
CIP - acetone odour
-Pulse strong weak & rapid

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 16 Diabetes Mellitus

BP ↑ systolic low
-Skin wet dry & cold
-Tongue moist dry
-Eyes normal sunken
-Pupils dilated normal
Urine normal sugar & acetone
Investigation Blood Hypoglycemia Hyperglycemia
-ve Ketonemia
-ve Acidosis

Treatment Oral sugar Fluid + insulin

Chapter 1

Treatment
Aim:
• confirm diagnosis
• Search for and treat any ppt cause
• assess hydration and give fluid
• give insulin
• Monitor clinical signs and biochemistry

Lines of therapy:
1- Hospitalization better in ICU
2- Fluid replacement:
• Amount :
▪ Guided by CVP (10cm H2O)
▪ 1 L / hour till HR & BP return normal
• Type :
▪ At 1st: isotonic saline
▪ Then: glucose 5% when blood glucose drops < 250 mg (to
avoid hypoglycemia).
▪ Hypotonic saline with hypernatremia
3-Insulin
• Type : short acting

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 Diabetic Mellitus 17

▪ Dose: low dose regimen 0.1 U/ kg/h. continuous infusion

or deep IM
▪ Follow up: by blood sugar every hour & give further
insulin accordingly
4- ttt of acid base and electrolyte disturbances
• Metabolic acidosis: + NaHCO3
Indication: in severe case
Lab.: pH < 7.1 & HC03 <10 mEq
Dose: 1 L of 1/6 molar NaHC03 IV (till PH > 7.2 not reach 7.4
to avoid over correction  Alkalosis)
Correct plasma K+ level: K from the start
Hypo K+ : occurs with insulin ttt due to intracellular shift
Dose:

Chapter 1
Add 10 ml KCL (20 mEq) to each 1 L of fluid given.
Oral r given after recovery

Phosphate: as K
5- Care of comatosed Pt.: (see neurology)
6- ttt cause & ppt factors
7-Monitoring:
• State of hydration, urine output, conscious level, plasma
glucose, K and ABG
8-Others
• Prophylactic antibiotic
• Nasogastric tube : to aspirate gastric content
• Heparin IV in old & dehydrated patients to guard against DIC -
Frusemide IV in oliguric patients
• O2 if P02 < 80mmHg
9-Insulin therapy: convential after control DKA
10- Prevention of recurrence:
• Avoid reduction of insulin dose during intercurrent illness.

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 18 Diabetes Mellitus

Hyperglycemic hyperosmolar non-ketotic state (HHONK)

Causes: occurs in old type 2 DM due to
• Absence of fat reserve or fat mobilization (relative lack
of GH or cortisol)
• Insensitive thirst center in old age lead to dehydration
aggravated by use of diuretics
• PPt factors : infection, infarction
C/P:
• Severe polyuria, polydypsia & dehydration (main
symp.)
• No or little ketosis
• Prerenal uremia may occur due to dehydration
• Neurologic symptoms: convulsions, coma,
Chapter 1

hemiparesis, stupor
Investigations:
• Blood :
▪ severe hyperglycemia often > 1000mg.
▪ ↑ PCV, ↑ Na, ↑ plasma osmolality (N. 290
mosm/L)
▪ Urine: glucose without ketone bodies

Treatment: as DKA without bicarbonate

• Fluids
▪ Type : 1/2 normal saline (1/2 molar)
▪ Amount : IL / hour not faster to avoid cerebral
edema
▪ Insulin : smaller amount than ketoacidosis
▪ Heparin : since there is ↑ incidence of DIC

Diabetic lactic acidosis

Cause:
• Tissue hypoxia : pneumonia, myocardial infarction
• Diabetics taking biguanides

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 Diabetic Mellitus 19

CIP: of acidosis
• Kussmaul respiration
• Late CNS, CVS inhibition

Investigations
Wide anion gap.
• ↓pH & bicarbonate
• ↑ plasma lactate

Treatment
• Correct hypoxia
• NaHCO3 -Insulin-glucose combination
• Dialysis may be needed

Chapter 1
• High fatality rate.

Macrovascular Complication of DM

Diabetes is a risk factor in the development of atherosclerosis.

Meanwhile, diabetic risk factors of macrovascular complication are:
• Duration of diabetes
• Increasing age
• Hypertension
• obesity and syndrome X (metabolic syndrome)
• Hyperlipidaemia, particularly hypertriglyceridaemia/low
HDL
• Proteinuria (including microalbuminuria)

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 20 Diabetes Mellitus

Atheromatous lesion in diabetes:

• Atheromatous lesion tend to be more sever, extensive and run
Chapter 1

more aggressive in diabetes than non-diabetic people

• Pathogenesis :
a. Hyperglycemia ,hyperlipidemia ,smoking etc. leads to
monocyte and /or platelet adhesion
b. Monocyte migrate into the artery wall between the
endothelial cells ,become macrophage and accumulate
lipid to form "foam cells"
c. Release of growth factors and cytokines leads to
migration and proliferation of smooth muscle cells
which produce large amount of connective tissue in the
atherosclerotic plaque
1- Coronary heart disease:
• Myocardial infarction is three to five times more among
diabetic people
• Women with diabetes lose their premenopausal protection
from coronary artery disease.
• Painless angina and myocardial infarction may be due to
neuropathic damage to the autonomic nerves serving the
myocardium.
• Atypical presentation of angina and myocardial infarction
(malaise, sweating, dyspnea and syncope which may be
confused with hypoglycemia.

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 Diabetic Mellitus 21

• Long term mortality from MI are increased in diabetes may

be due to increased risk of HF in diabetes
• Management of MI is similar to non- diabetic population
with more caution with usage of thrombolytic therapy
because of the risk of intraocular haemorrhage in the patient
with retinopathy.
2- Cardiomyopathy:
• Diabetes can cause a cardiomyopathy even without
coronary artery atheroma
• Left ventricular contractility abnormalities detected by
echocardiography is the main subclinical feature
3- Hypertension:
• Hypertension is twice more in diabetics than non- diabetic

Chapter 1
• Hypertension is closely associated with metabolic
syndrome X, Insulin resistance or hyper insulinaemia.
4- Cardiac autonomic neuropathy:
• May lead to fixed heart rates, and orthostatic hypotension

Investigation:
Hypertensive diabetic patients should be investigated for:
1- Secondary hypertension (Cushing’s, Conn's disease and
Pheochromocytoma).
2- Renal damage (protienuria or microalbinuria, urine microscopy,
serum creatinine and electrolytes).
3- CV damage (ECG, chest x-ray for left ventricular hypertrophy.
4- Other CV risk factors eg. hyperlipidaemia, poor glycemic
control.
Treatment:
• ACE inhibitors are the first choice due to:
1- It delay the progression of diabetic retinopathy and
reduce microalbminuria.
2- It has no adverse effect in lipid profile or glycemic
control.
• A thiazide should be used at low dose to avoid worsening
of glycemic control and aggravation of dyslipidemia.

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 22 Diabetes Mellitus

• Beta-adrenoceptors can aggravate hyperglycemia,

dyslipidemia and impotence.

Peripheral arterial disease PAD:

Symptoms:
1. Asymptomatic
2. Intermittent claudication calf pain on walking
3. Buttock pain may occur if iliac vessels is affected
4. Decreasing claudication distance and rest pain denote critical
ischemia
5. Unhealed skin wound
Signs:
1. Absence of pedal pulse ( 8%dorsalis pedis 2% posterior
Chapter 1

tibialis)
2. Cold extremities
3. Pale or bluish colour of the skin
4. thin ,shiny skin with scanty hair
5. dystrophic toenail
Investigation:
1. Doppler US
2. Ankle Brachial Index (ABI) : normal value 0.98 - 1.31
3. Angiography
Prevention of macrovascular complication:
1. Early control of blood glucose.
2. Strict control of hypertension.
3. Stop smoking
4. Treatment of lipid abnormalities : to the lowest achievable
level
5. ACE inhibitors/angiotensin II receptor antagonists : 25–35%
lowering of the risk of heart attack, stroke, overt nephropathy
or cardiovascular death
6. Low dose aspirin: can reduce macrovascular risk, but is
associated with a morbidity and mortality from bleeding.

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 Diabetic Mellitus 23

Cerebral stroke:
• Stroke is twice higher in diabetic population than non-
diabetics
• Mortality and disability from stroke are also worse in the
diabetic person

Microvascular Complications of Diabetes Mellitus

Microvascular disease is specific to diabetes. Small blood vessels

throughout the body are affected but the disease process is of particular
danger in three sites: Retina, Renal glomerulus and Nerves.

Pathophysiology of Microvascular Complications

Chapter 1
Chronic Hyperglycemia leads to:
 Non-enzymatic glycosylation of a wide variety of proteins, e.g.
hemoglobin, collagen, LDL. This leads to an accumulation of
advanced glycosylated end-products causing injury and
inflammation via stimulation of pro-inflammatory factors, e.g.
complement, cytokines.
 Polyol pathway: The metabolism of glucose by increased
intracellular aldose reductase leads to accumulation of sorbitol
and fructose. This causes changes in vascular permeability,
cell proliferation and capillary structure via stimulation of
protein kinase C and TGF-B.
 Abnormal microvascular blood flow impairs supply of
nutrients and oxygen. Microvascular occlusion is due to
vasoconstrictors, e.g. endothelins and thrombogenesis, and
leads to endothelial damage.
 Other factors include the formation of reactive oxygen species
and growth factors stimulation (TGF-B) and vascular
endothelial growth factor (VEGF). These growth factors are
released by ischaemic tissues and cause endothelial cells to
proliferate.
 Haemodynamic changes, e.g. in kidney.

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 24 Diabetes Mellitus

Diabetic Neuropathies
Classifications:
A- Focal and multifocal neuropthies e.g. mononeuropathy,
amyotrophy, radiculopathy, entrapment neuropathy,
mononeuritis multiplex.
B- Symmetrical neuropathies e.g. diabetic peripheral
neuropathy and autonomic Neuropathy.

Mononeuropathies: Affect peroneal, median or ulnar nerves. It tends

to occur at sites of entrapment or external compression. Peroneal nerve
palsy is characterized by weakness or paralysis of foot and toe
dorsiflexors, foot drop and foot eversion. Impaired sensation over the
dorsum of the foot and the lower anterior aspect of the leg. The ankle
Chapter 1

reflex is preserved as is foot inversion.

Cranial nerve palsies: Often affect III, VI, IV and rarely VII nerves. III
nerve palsy is characterized by: acute onset and Intact papillary
reactions: pupilloconstrictor fibres located peripherally so they are
affected in lesions that produce compression e.g. aneurysm.

Entrapment Neuropathies
1- Carpal tunnel syndrome: found in 5.8 % of diabetic patients.
It has a less favorable outcome after surgical decompression,
as diabetes slows nerve regeneration.
2- Ulnar neuropathy at the elbow affects 2.1% of diabetic
patients
3- Peroneal neuropathy at the fibular head affects 1.4–13% of
diabetic patients.
4- Lateral cutaneous nerve of the thigh (meralgia paresthetica)
affect 0–1.0% of diabetic patients.

Autonomic Neuropathies:
The most common effect of autonomic neuropathy is erectile
dysfunction, which affects 40% of males with diabetes. Only a small
number develop severe GI and bladder dysfunction.

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 Diabetic Mellitus 25

Clinical features
• Impotence
• Postural hypotension, giving dizziness and syncope in up to 12%
• Resting tachycardia or fixed heart rate/loss of sinus arrhythmia
in up to 20%
• Gustatory sweating—sweating after tasting food
• Dysphagia with delayed gastric emptying, nausea/vomiting
• Constipation or diarrhea
• Urinary retention or overflow incontinence
• Anhydrosis—absent sweating on the feet is especially
problematic as it increases the risk of ulceration
• Abnormal pupillary reflexes

Chapter 1
Assessment
At least annually check the following:
• Lying and standing BP (measure systolic BP 2 minutes after
standing; normal is <10 mmHg drop, >30 mmHg is abnormal)
• Pupillary responses to light

Peripheral neuropathy
The presence of symptoms and/or signs of peripheral nerve dysfunction
in people with diabetes after exclusion of other causes of peripheral
neuropathy.
It affects 25-35% of diabetic patients, had gradual onset and progressive
course with predominant sensory manifestations. Diagnosis depends on
loss of perception of pain, touch, vibration and pressures in glove and
stocking pattern.

Manifestation of peripheral neuropathy:

Usually insidious onset with numbness or paresthesia, often found on
screening rather than as a presenting problem
• Starts in the toes and on the soles of the feet, and then spreads up
to mid-shin level, mostly in a symmetrical fashion. Less often, it
also involves the fingers and hands.

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 26 Diabetes Mellitus

• Affects all sensory modalities and results in reduced vibration

perception thresholds, pinprick, fine touch, and temperature
sensations.
• Decreased vibration sensation and absent ankle reflexes are often
the first features found.
• Less often, the skin is tender or sensitive to touch (hyperesthesia),
or frank pain can occur.
• Painful neuropathy affects up to 5% of a general clinic
population.
• This pain may be sharp, stabbing, or burning in nature and at
times very severe.
• There may also be some wasting of the intrinsic muscles of the
foot with clawing of the toes.
Chapter 1

Management of peripheral neuropathy: Tight glycemic control.

Alpha Lipoic Acid and Benfotiamine can help to improve nerve
functions. Drugs that reduce pain e.g. tricyclic antidepressants,
gabapentin, pregabalin and serotonin noradrenaline reuptake inhibitors.
Protect a foot that lost its natural protective mechanisms is essential to
prevent progression of neuropathy into a more advanced foot
pathology.

Diabetic eye diseases

Diabetic eye diseases include:

1. Diabetic retinopathy
2. Cataract which develops earlier in diabetes than in the general
population. However with high levels of blood sugar often
associated with a degree of ketosis an acute cataract may
develop (snowflake cataract) which comes on very rapidly
and does not clear.
3. Error of refraction due to fluctuations in blood sugar leading
to osmotic changes within the lens.
4. Ocular Nerve palsies: The sixth and the third nerve are the
most commonly affected. These nerve palsies usually recover
spontaneously within a period of 3–6 months.
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 Diabetic Mellitus 27

Diabetic retinopathy: Diabetic retinopathy is the commonest cause

of blindness worldwide. Diabetic retinopathy increases with the
duration of diabetes. Progression of retinopathy often accelerated
with poor control of diabetes and blood pressure. Diabetic
retinopathy is asymptomatic until become advanced, so fundus
examination should be routinely done at least annually. It can be
either background (Nonproliferative) or Proliferative. Diabetic
Maculopathy: If the oedema extends into the macula then the retina
becomes thickened, visual function deteriorates and there is loss of
central vision.

Renal affection in Diabetes

Chapter 1
Renal affection in Diabetes leads to increased risk of:
• Renal artery atherosclerosis
• Urinary tract infections, papillary necrosis
• Glomerular lesions, e.g. from basement membrane thickening
and glomerulosclerosis (Diabetic nephropathy).

Diabetic nephropathy: Approximately 40% of patients with type 1 and

20% with type 2 diabetes develop nephropathy. Diabetic nephropathy
is the most common cause of chronic kidney failure and end-stage
kidney disease worldwide.

Stages of Diabetic nephropathy

1. Elevated glomerular filtration rate with enlarged kidneys
2. Intermittent Microalbuminuria
3. Microalbuminuria
4. Proteinuria and Nephrotic syndrome.
5. ESRD
Clinical features are usually absent until advanced chronic kidney
disease develops. Therefore, we should evaluate urinary albumin
excretion (microalbuminuria) annually in all subjects with diabetes.

Management of Diabetic Nephropathies:

• Optimal control of blood glucose and blood pressure.

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 28 Diabetes Mellitus

• Avoid high protein intake.

• ACE inhibitors should be started and titrated to full dose in all
patients with confirmed nephropathy (including those with
microalbuminuria alone).
• If ACE inhibitors are not tolerated, angiotensin ll receptor
antagonists should be substituted.
• Avoid taking Contrast agents containing Iodine and NSAIDs.

Diabetic Foot complications

The term diabetic foot indicates any foot pathology that results directly
from diabetes or its long-term complications.
Diabetic gangrene is usually preceded by advanced foot pathology e.g.
Chapter 1

Diabetic Foot ulcers, diabetic foot Infections, critical limb ischemia and
Charcot foot.
The high risk foot is the foot that has developed one or more of the
following risk factors:
• Peripheral Neuropathy
• Peripheral arterial disease
• Foot Deformity
• Trauma
• Callus
• Skin and Nail pathology
For prevention of foot problems the diabetic patients should:
1- Achieve tight control of blood glucose levels
2- Annual foot screening
3- Report any changes in his or her feet immediately to healthcare
professional.
4- Engage in a simple daily foot care routine by washing and drying
between toes, moisturizing and checking for abnormalities.

DM & other systems affected

1-Infections and diabetes

1.1- Why diabetes increases risk of infections?

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 Diabetic Mellitus 29

Due to abnormalities in cell mediated immunity and phagocytic

function, hyperglycemia, diminished vascularity and autonomic
dysfunction.
1.2- Effects of infections on diabetes:
A. Increasing insulin resistance leading to bad glycemic
control.
B. Precipitation of diabetic ketoacidosis.
1.3- Common infections in diabetes:
A. Skin: staphylococcal infections (boils, abscesses, carbuncles)
and mucocutaneous candidiasis.
B. Gastrointestinal: periodontal disease and cholecystitis
(including emphysematous cholecystitis).
C. Urinary tract: cystitis, pyelonephritis (including

Chapter 1
emphysematous pyelonephritis) and perinephric abscess.
D. Lung: pneumonia and tuberculosis.
E. Bone: osteomyelitis.
F. ENT: rhino-cerebral mucormycosis and malignant otitis
externa.
1.4- Prevention of diabetic infections:
Good glycemic control, good hygiene and vaccination with
pneumococcal and influenza vaccines.
1.4- Treatment of diabetic infections:
A. Proper diagnosis and early start of antimicrobial.
B. Use insulin during infection period if patient is on oral
treatment.

2- Gastrointestinal complications of diabetes

2.1- Mouth: periodontal disease with looseness of the teeth and gum
inflammation.
2.2- Esophagus: gastroesophageal reflux disease (GERD) caused
by autonomic neuropathy with decreased lower esophageal
sphincter (LES) pressure or delayed gastric emptying.
2.3- Gastroparesis:
• Clinical symptoms that suggest gastroparesis include early
satiety, nausea, vomiting, bloating, and postprandial

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 30 Diabetes Mellitus

abdominal fullness in addition to unexplained poor glycemic

control despite strong therapeutic efforts.
• The presence of residual food in the stomach after an
overnight fast during upper gastrointestinal endoscopy
supports the diagnosis.
• The traditional "gold standard" to establish the diagnosis of
gastroparesis is scintigraphic measurement of gastric
emptying.
• Treatment: small meals, avoid fatty meals, use of prokinetics
eg metoclopramide and avoid use of GLP-1 based therapies
in treatment of diabetes.
2.4- Diabetic enteropathy:
Presented by diarrhea which is watery and painless, occurs at night,
Chapter 1

and may be associated with fecal incontinence. Bouts of diarrhea can

be episodic with intermittent normal bowel habits or even
alternating with periods of constipation in addition steatorrhea can
occur due to bacterial overgrowth.
2.4.1- Management:
• Exclude other causes of diarrhea especially infectious one.
• Correction of water and electrolyte imbalances, tight control
of blood glucose, and restoration of possible nutritional
deficiencies.
• Symptomatic therapy: antidiarrheal agents such as
loperamide.
2.5- Liver: Non alcoholic fatty liver (NAFLD) including non-
alcoholic steato-hepatitis (NASH).
2.6- Gall bladder: cholecystitis including emphysematous
cholecystitis.

3- Skin and diabetes

3.1- Acanthosis negricans: Velvety hyperpigmented plaques in
neck, back and body folds.
3.2- Necrobiosis lipoidica diabeticorum: Painful violaceous
plaque with central yellowish area surrounded by brownish border
usually on chin of the leg. Central ulceration may occur.

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 Diabetic Mellitus 31

3.3- Diabetic dermopathy: Painless reddish papules usually on the

shin of the tibia heal leaving atrophic scarred hyperpigmented
macules.
3.4- Bullosis diabeticorum: Non-inflamed bullae with sterile fluid
heal within 2-3 weeks without residual scarring.
3.5- Granuloma annulare: Ring shaped papules with depressed
centers usually on dorsum of the hand and arm.
3.6- Diabetic thick skin:
• Fingers and hands ( Duputyren,s contracture) inability to do
non islamic praying.
• Scleroderma diabeticorum: marked thickening of the skin in
posterior aspect of the neck and upper back.
3.7- Caroteinoderma: Yellow skin and nails.

Chapter 1
3.8- Skin ulcers: Vascular and neuropathic ulcers.
3.9- Hyperlipidemia:
• Eruptive xanthoma: yellow papules or nodules usually on
extensor surfaces.
• Xanthelasma: yellow plaques that usually appear on the
medial aspects of the eyelids.
3.10- Skin infections:
• Fungal: Candidal intertrigo and paronychia, dermatophytes
causing powdery white lesions especially between fingers.
• Bacterial: Carbuncles, furuncles, abscesses, cellulitis,
erysipelas.
3.11- Skin and anti-diabetic medications:
• Insulin: Lipoatrophy and lipohypertrophy.
• Sulphonylurea: Drug eruptions.

Diabetes and pregnancy

Classification:
Pregestational diabetes either type 1 or type 2diabetes.
Gestational diabetes: carbohydrate intolerance that begin in pregnancy.

Risk factors for developing gestational diabetes:

* Family history of diabetes * Past history of gestational diabetes.
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 32 Diabetes Mellitus

* Age >25 years. * Previous delivery of a baby > 4 kg.

* Polycystic ovary syndrome * Current use of glucocorticoids.
* Certain ethnic groups eg, African-American, South or East Asian.
* Prepregnancy body mass index >30 kg/m2.

Effects of pregnancy on diabetic state:

• Hyperinsulinemia and increased insulin resistance due
placental secretion of diabetogenic hormones eg corticotropin
releasing hormone, placental lactogen, and progesterone, as
well as decreased exercise.
• Diabetic retinopathy worsens.
• Diabetic nephropathy: Pregnancy is not associated with
permanent worsening of renal function in the majority of
Chapter 1

diabetic women in the absence of uncontrolled hypertension

or baseline serum creatinine concentration above 1.5 mg/dL.
• Pregnancy does not affect the course of somatic or autonomic
neuropathy.

Effects of diabetes on pregnancy:

Fetal and neonatal complications:
• Congenital malformations: eg congenital heart defects, caudal
dysgenesis and neural tube defects.
• Macrosomia with associated shoulder dystocia and increasing
likelihood of cesarean delivery.
• Neonatal: Hypoglycemia, erythrocytosis, hyperbilirubinemia,
prematurity with respiratory problems.
Maternal complications:
* Spontaneous abortion. * Hypertension/preeclampsia.
* Polyhydramnios. * Infections: eg urinary tract infections.
* Recurrence of gestational diabetes in subsequent pregnancies.
* Gestational diabetes increases risk of developing type 2 diabetes.

Screening and diagnosis:

Whom to screen: Universal screening for all pregnant women is better
than screening women who have at least one risk factor for development
of gestational diabetes.
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 Diabetic Mellitus 33

Whom and how to screen:

* First prenatal visit: Fasting plasma glucose or HbA1c to exclude
overt diabetes (Fasting plasma glucose ≥ 126 mg/dL, or A1C ≥6.5
percent).
* 24 to 28 weeks of gestation:
A. One step approach: 75 gram two hour oral glucose tolerance
test, a diagnosis of gestational diabetes can be made in women
who meet either of the following criteria (fasting plasma
glucose ≥92 mg/dL but <126 mg/dL or one hour ≥180 mg/dL
or two hour ≥153 mg/dL).
B. Two step approach: if one hour plasma glucose after a 50
gram oral glucose ≥130 mg/dL go to 75 gram two hour oral
glucose tolerance test.

Chapter 1
Management:
Target blood glucose:
• Fasting glucose concentrations ≤ 95 mg/dL.
• Preprandial glucose concentrations ≤ 100 mg/dL.
• One-hour postprandial glucose concentrations ≤ 140 mg/dL.
• Two-hour postprandial glucose concentrations ≤ 120 mg/dL.
• Glucose levels should not decrease to less than 60 mg/dL.

4.6.2- Diet:
• Weight loss in pregnancy is not generally recommended, so
the aim of diet is to prevent excessive weight gain.
• For women who are at ideal body weight during pregnancy,
the caloric requirement is 30 kcal/kg/day; for women who are
overweight and obese, the caloric requirement is 22 to 25
kcal/kg/day; and for morbidly obese women, the caloric
requirement is 12 to 14 kcal/kg/day.
Insulin: regular insulin, NPH insulin, insulin aspart, insulin lispro
and insulin detemir have acceptable safety profiles, while insulin
glargine has not been studied extensively in pregnancy.
Oral medications:
• Glyburide and metformin can be given if patient refuse taking
insulin.
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 34 Diabetes Mellitus

• Women with polycystic ovary syndrome who get pregnant and

taking metformin can continue it during pregnancy.

Management of DM

1. Life style modification(including medically assisted weight

loss)
2. Oral anti-diabetic agents
3. Insulin

Therapeutic Lifestyle Changes

• Weight loss (for overweight and obese patients): Reduce by
5% to 10%
Chapter 1

• Physical activity: 150 min/week of moderate-intensity

exercise (eg, brisk walking) plus flexibility and strength
training.
• Diet:
▪ Eat regular meals and snacks; avoid fasting to lose
weight
▪ Consume plant-based diet (high in fiber, low
calories/glycemic index, and high in
phytochemicals/antioxidants)
▪ Understand Nutrition Facts Label information
▪ Incorporate beliefs and culture into discussions
▪ Use mild cooking techniques instead of high-heat
cooking.
• Healthful Eating Recommendations:

▪ Carbohydrate:
▪ Specify healthful carbohydrates (fresh fruits and
vegetables, legumes, whole grains); target 7-10
servings per day
▪ Preferentially consume lower-glycemic index
foods (glycemic index score <55 out of 100:
multigrain bread, pumpernickel bread, whole

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 Diabetic Mellitus 35

oats, legumes, apple, lentils, chickpeas, mango,

yams, brown rice)
▪ Fat
▪ Specify healthful fats; containing poly-
unsaturated fatty acids (nuts, avocado, certain
plant oils, fish)
▪ Limit saturated fats (butter, fatty red meats,
tropical plant oils, fast foods) and trans fat;
choose fat-free or low-fat dairy products.
▪ Protein:
▪ Consume protein in foods with low saturated fats
(fish, egg whites, beans); there is no need to avoid
animal protein

Chapter 1
▪ Avoid or limit processed meats
▪ Micronutrients
▪ Routine supplementation is not necessary; a
healthful eating meal plan can generally provide
sufficient micronutrients
▪ Chromium; vanadium; magnesium; vitamins A,
C, and E; and CoQ10 are not recommended for
glycemic control
▪ Vitamin supplements should be recommended to
patients at risk of insufficiency or deficiency.

Insulin

Insulin therapy is appropriate for patients with type (1) and type
(2) diabetes.
The absolute insulin deficiency of established type (1) diabetes
can only be treated effectively with multiple daily insulin injections.

Indications of insulin therapy in type (2) diabetes:

1- Patients unable to adequately control their blood glucose
levels with maximum dose combinations of oral glucose
lowering medications.
2- Patients undergoing surgery

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 36 Diabetes Mellitus

3- Patients with renal or hepatic disease.

4- Women who are planning pregnancy or who are already
pregnant.
5- Critically ill hospitalized patients.

Insulin therapy is often instituted early for type (2) diabetes patients
who:
• Can’t control their diabetes with diet and exercise
• Are highly symptomatic with marked catabolic state.
• Are newly diagnosed with very high glucose level

The first step in choosing an insulin regimen is to establish

glycemic goals for most patients; this means that one half of SHBG
Chapter 1

results of all within the following ranges:

Preprandial 90-130 mg/dl

Bedtime 100-140 mg/dl
Postprandial (1-2h) <180mg/dl

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 Diabetic Mellitus 37

Insulin by comparative action table:

Chapter 1

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 38 Diabetes Mellitus

(ADA) recommendations:
• It is Very important to individualize the patient’s age, health
states, and history of significant hypoglycemia, life styles and
personal goals.
• For example, it would be reasonable to modify preprandial goal
to 100-140mg/dl or higher for a type (1) diabetes patients with
severe or hypoglycemia unawareness.
• Pregnant women with either type(1) or type (2) diabetes require
meticulous glycemic control, whole blood goals should be
modified to <95mg/dl fasting , <140 mg/dl postprandial
(1h),<120 mg/dl (2h) postprandial.

Insulin regimen:
Chapter 1

2 injections /day
Advantages: Two Injections /day
Disadvantages: NPH given at supper peaks during the night
And often not last overnight until breakfast
Leading to nocturnal
hypoglycemia and/or
And high breakfast
glucose levels.
1) Inflexibility in dealing
with midday glucose levels.

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 Diabetic Mellitus 39

3 Injections / Day
-Using NPH and short or
rapid acting analog before
breakfast and short or rapid
acting insulin at supper and
NPH at bed time.
-Advantages: Better
overnight glucose control
-Disadvantages: still
injectable at midday.

4 injections/day
Using short or rapid acting insulin and long acting.

Chapter 1
Advantages: allows meal to
meal adjustment.

Determining total insulin

dose:
About one-half to two-thirds of
the total-daily insulin dose is
given to cover basal-needs and
should be longer acting insulin.
The other one-third to one-half
of the total daily insulin dose
should be rapid or short acting
insulin given before each meal
to control postprandial
glycemia,

When initiating insulin therapy, base line total daily dose is often
calculated as 0.6 X body weight in kilograms.

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 40 Diabetes Mellitus

Correction insulin dose:

Adjusting insulin dose:

If glucose are out of target at Adjust this insulin component

Postbreakfast/ prelunch Prebreakfast rapid/ short insulin
postlunch/ presupper Prelunch rapid/ short insulin and /or
morning NPH
Midafternoon Morning NPH or long-acting insulin
analog
Postsupper/ bedtime Presupper rapid/ short insulin
Early morning Every NPH or long-acting insulin
analog
Chapter 1

1500 =X (correction factor)

BW
Current Blood Sugar – Target Blood Sugar=Correction Insulin
Dose
Correction Factor (X)
Example:
80-kg patient who is 60 mg/dl above target glucose level would require
3-unit supplement based on equation:
1500/80kg=18.72
(200-140mg/dl)/18.75=~3units

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 Diabetic Mellitus 41

Initial insulin dose type-1 diabetes patient:

Dose
patient
(unit/kg/day)
0.5 Conditioned athletes
0.6 Motivated exercisers or women in follicular phase of
menses
0.7 Women in last week luteal phase of menses or in 1 st
trimester of pregnancy, child starting puberty, adult
ill with a virus
0.8 Women in 2nd trimester of pregnancy, child in mid-
puberty, adult with a severe or localized viral
infection

Chapter 1
0.9 Women in 3rd trimester of pregnancy, adult ill with
bacterial infection
1.0 Women at term pregnancy, adult with a severe
bacterial infection or illness, child at peak pubescence
1.5-2.0 Child at peak pubescence who is ill

Oral Hypoglycemic Agents:

- Insulin sensitizers
▪ Metformin
▪ Thiazolidinedione
- Insulin secretagogues.
▪ Sulphonylureas and glinides.
▪ Dpp4 inhibitors.
Classes:
▪ Biguanides eg metformin.
▪ Sulphonylureas e.g gliclazide ,glimepride.
▪ Meglitinides eg repaglinide.
▪ Thiazolidinediones eg pioglitazone.
▪ Dipeptidylpeptidase 4 inhibitors e.g. sitagliptin,
vildagliptin.
▪ Alpha glucosidase inhibitors e.g. Acarbose.

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 42 Diabetes Mellitus

1. Biguanides
MOA: -act directly against insulin resistance and reduce hepatic
glucose output.
It is considered as the corner stone in treatment of type 2 diabetes in
all guidelines.
Advantages:
▪ Cheap
▪ No weight gain
▪ No or minimal episodes of hypoglycemia.
▪ Beneficial cardiovascular outcomes.
Side effects: Gastro-intestinal like flatulencies and diarrhea.

2. Sulphonylureas:
Chapter 1

MOA: triggering insulin release by inhibiting KATP channels of the

pancreatic B-cells.
Typical reduction in A1C values for SU is 1.0-2.0 %.
First Generation:
1) Tolbutamide
2) Acetohexamide
3) Chlorpromide
Second or new generation:
1) Glipizide
2) Glyburide (glibenclamide)
3) Glimipride (amaryl)
4) Gliclazide (diamicron)
5) Gliquidone (glurinorm)
Side effects:
1) Hypoglycemia
2) Weight gain
Advantages:
1) Effective reduction of A1C
2) Not Expensive.
Contraindications:
1) Pregnancy
2) Type (1) diabetes.
3) Patients with acute or end-stage liver disease

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 Diabetic Mellitus 43

4) Patients with end-stage renal diseases.

3. Non-sulphonylurea secretagouges
Meglitindes
Short acting secretagouges
Act on the same potassium channels of [Link] insulin
secretion.
Examples:
1- Repaglinide
2- Natiglinide.
3- Mitiglinides
-They are called prandial glucose regulators as these drugs
act mainly on the postprandial glucose excursions

Chapter 1
-Typical reduction in A1C 0.5-1.0%.
Side-effects:
1) Hypoglycemia
2) Weight gain.

4. Thiazolidinediones:
E.g. pioglitazone dose (15-45mg/day)
binds to PPAR¥ nuclear receptors lead to transcription of genes
regulating glucose and fat metabolism
Typical reduction in A1C (1.0-1.5%)
Advantages: no or minimal hypoglycemia.
Disadvantages:
1. Weight gain
2. Oedema both L.L
3. Osteoporosis especially in postmenopausal females.
Contra-indications:
1. Pregnancy
2. Advanced heart failure
3. Hepatic cell failure
4. Acute liver injury

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 44 Diabetes Mellitus

5. Dipeptidyl peptidase-4 inhibitors (DPP4I)

Inhibits destruction of endogenous GLP-1 (glucagon like
polypeptide 1) and cause increase in incretin level which stimulates
insulin release from pancreatic B-cells in a glucose dependant
manner
E.g.
1) Sitagliptin
2) linagliptin
3) alogliptin.
4) saxagliptin.
5) vildagliptin.

Advantages:
Chapter 1

1. No hypoglycemia
2. No weight gain
3. Well tolerated drugs.

Disadvantages: Costly.
Side effects: Minimal like nasopharyngitis, headache and nausea.

6. Alpha-glucosidase inhibitors:
E.g. Acarbose : inhibits the upper gastrointestinal enzymes that
convert dietary starch and other complexes into simple sugar
which can be absorbed.
It causes mild to moderate reduction in postprandial glucose.
Advantages:
1. no hypoglycemia
2. no weight gain
Side effects:
Usually cause flatulence and diarrhea.

7. Sodium –Glucose co transporter inhibitors: (SGLT2I)

Inhibits glucose re-absorption from proximal convoluted tubules
of the kidney
E.g. 1) Canagliflozin
2) Dapagliflozin

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 Diabetic Mellitus 45

Advantages:
1. No hypoglycemia
2. Mild reduction in systolic blood pressure
3. Decrease body weight

Disadvantages:
1. Expensive drugs
2. with mild to moderate reduction in A1C

Side effects:
1. Urinary-tract infections
2. Ketoacidosis

Chapter 1

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CHAPTER

Hypothalamus
and pituitary
gland
Hypothalamus and pituitary
gland
2
1- Anatomy:
• The hypothalamus is located at the base of the brain, below the
third ventricle and just above the optic chiasm and pituitary
gland.
• The pituitary gland is situated in the sella turcica within the
sphenoid bone covered by diaphragma sellae. It is connected with
the hypothalamus by the pituitary stalk which carries
hypophyseal pituitary portal blood supply.
• The pituitary gland has two portions: anterior pituitary
(adenohypophysis) and posterior pituitary (neurohypophysis).

1.1-Relations of the pituitary gland:

• Superior: optic chiasma, hypothalamus and third ventricle.
• Inferior: sphenoidal air sinus
• Lateral: cavernous sinus

1.2- Blood supply:

Arterial supply from superior and inferior hypophyseal arteries,
branches of internal carotid arteries and venous drainage into the
petrosal sinuses and then into the peripheral circulation via the internal
jugular veins except posterior pituitary which drains into inferior
hypophyseal veins.

2- Functions (table 1):

Hypothalamus controls thirst sensation, appetite, thermal
regulation. It also secretes hormones that control release of pituitary
hormones. Most of pituitary and hypothalamic hormones are secreted
in a pulsatile manner.

The majority of anterior pituitary hormones are under

predominant positive control of hypothalamic hormones except
prolactin which is under tonic inhibition by dopamine.
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 Hypothalamus and Pituitary Gland 47

Table 1: Hypothalamic pituitary hormonal axis:

Hormone Function
Hypothalamic Stimulates release of GH from pituitary gland
hormones Inhibits release of GH from pituitary gland
GHRH Inhibits release of prolactin from pituitary gland
GHRIH Stimulates release of ACTH from pituitary gland
(somatostatin) Stimulates release of TSH from pituitary gland
PIF (dopamine) Stimulates release of FSH and LH from pituitary
CRH gland
TRH
GnRH
Anterior pituitary
hormones Stimulates body growth

Chapter 2
GH Stimulates milk secretion and inhibits gonadal
Prolactin activity
ACTH Stimulates secretion of cortisol and androgens
TSH from supra-renal gland
Stimulates secretion of thyroid hormones
FSH Stimulates ovarian follicular development and
release of inhibin in females and stimulates
sertoli cells of the testes to produce mature
sperms and inhibin in males
LH
Stimulates luteinization of ovarian follicle in
females and testosterone production from leydig
cells of the testes in males
Posterior pituitary
hormones
ADH Stimulates water reabsorption in collecting
Oxytocin tubules of the kidney leading to concentration
of the urine
Stimulates milk ejection and uterine
contractions during labor
GH, growth hormone. GHRH, growth hormone releasing hormone.
GHRIH, growth hormone release inhibitory hormone. PIF, prolactin
inhibitory factor. CRH, corticotrophin releasing hormone. ACTH,
adrenocoticotrophic hormone. TRH, thyrotrophin releasing hormone.

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 48 Hypothalamus and Pituitary Gland

TSH, thyroid stimulating hormone. GnRH, gonadotrophin releasing

hormone. FSH, follicle stimulating hormone. LH, luteinizing hormone.
ADH, antidiuretic hormone.

3.1-Assessment of excess pituitary function (table 2):

Biochemical
Hormone Clinical aspect assessment
GH Acromegaly and gigantism IGF-1, basal and
suppressed growth
hormone
Prolactin Gynaecomastia, galactorrhoea, Basal prolactin level
hypogonadism and subfertility
ACTH Cushing disease 24 hour urinary free
Chapter 2

cortisol and
dexamethasone
suppression tests
TSH Thyrotoxicosis TSH, free T4, free T3
FSH and Primary excess is uncommon
LH
ADH SIADH Hyponatremia, low
plasma osmolarity,
high urine osmolarity
GH, growth hormone. ACTH, adrenocoticotrophic [Link],
thyroid stimulating hormone. FSH, follicle stimulating hormone. LH,
luteinizing hormone. ADH, antidiuretic hormone.

3.2-Assessment of pituitary insufficiency (table 3):

Biochemical
Hormone Clinical aspect assessment
GH Short stature IGF-1, basal and
provacated growth
hormone
ACTH Secondary adrenal Morning serum
insufficiency cortisol and ACTH
stimulation tests
TSH Hypothyroidism TSH, free T4, free T3
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 Hypothalamus and Pituitary Gland 49

FSH and Delayed puberty and Testosterone in males

LH hypogonadism and estradiol in
females. In both FSH,
LH.
ADH Diabetes insipidus Water deprivation test
GH, growth hormone. ACTH, adrenocoticotrophic [Link],
thyroid stimulating hormone. FSH, follicle stimulating hormone.
LH, luteinizing hormone. ADH, antidiuretic hormone.

4- Pituitary tumors

4.1- Classification:
1. Pituitary adenomas: lactotroph adenomas, nonfunctioning

Chapter 2
adenomas, somatotroph adenomas and corticotroph adenomas.
2. Other benign tumors: craniopharyngioma, meningioma and
pituicytoma.
3. Malignant tumors: primary eg germ cell tumors and lymphoma
or secondary to breast cancer and lung cancer.

4.2- Clinical picture:

A. Pressure symptoms:
• Superior: bitemporal hemianopia with suprasellar
extension.
• Inferior: Cerebrospinal fluid rhinorrhea, uncommon
presentation.
• Lateral: cranial nerves in cavernous sinus: III, IV, V and
VI cranial nerves.
• Headache caused by expansion of the sella.
B. Deficiency of one or more of pituitary gland hormones.
C. Excess secretion of pituitary hormones: either primary from
tumor itself e.g. acromegaly in somatotroph adenomas or
secondary due to pituitary stalk interruption leading to
hyperprolactinemia.

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 50 Hypothalamus and Pituitary Gland

4.3- Diagnosis:
Pituitary tumors can be discovered during evaluation of
neurologic symptoms, such as visual impairment or headache or as an
incidental finding on magnetic resonance imaging (MRI) performed for
some other reason or during evaluation of pituitary hormonal
abnormalities.

A. Radiologic procedures: MRI brain (better than CT scan in

evaluating pituitary tumors): lesions less than 1 cm in diameter
called microadenoma while lesions more than 1 cm called
macroadenoma.
B. Pituitary hormonal evaluation.
Chapter 2

4.4- Differential diagnosis:

From other causes of sellar masses:
A. Pituitary hyperplasia eg Lactotroph hyperplasia during
pregnancy.
B. Cysts eg Rathke's cleft.
C. Hypophysitis eg lymphocytic hypophysitis.
D. Infiltration: sarcoidosis, and Langerhans cell histiocytosis.

4.5- Management:
Three lines of treatment:
A. Surgery: through trans-sphenoidal or subfrontal approach.
B. Radiotherapy: conventional or gamma knife technique.
C. Medical: somatostatin analogues and or dopamine agonists.

The choice between these 3 lines is according to type, size of the tumor
and according to pituitary hormonal status.

Hypopituitarism

Ι- Hypopituitarism in children
1. Pituitary Dwarfism:
1ry deficiency of GH in childhood

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 Hypothalamus and Pituitary Gland 51

Causes:
1. Deficiency of GH-RH from hypothalamus
2. Deficiency of GH from pituitary:
3. End organ unresponsiveness (Levi-Laron syndrome)

Clinical features:
1. Proportionate dwarfism.
2. Pseudo-super-intelligence.
3. Protein induced hypoglycemia
(normally:protein a.a Insulin secretion hypoglycemia but this corrected
by G.H)
4. Premature senility.
5. Infantilism: hypopituitarism + hypogonadism.

Chapter 2
Investigations:
1. Fasting level of GH: low (+ low IGF-l)
2. Growth hormone stimulation test: negative
3. Insulin induced hypoglycemia: normally ↓ blood sugar to 50mg
→↑ GH level.

Treatment:

Recombinant GH.
2- Froehlich's Syndrome:

Causes:
• Hypothalamo-pituitary tumor (as craniopharyngioma).

Clinical picture:
Hypothalamic lesion
• Diabetes insipidus
• Dwarfism
• Infantilism = dwarfism + hypogonadism
• Polyphagia + samboxa shape obesity + genu valgum
• Polyuria &hypersomnia,
• ± Autonomic disturbance, mental retardation, visual disturbance
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 52 Hypothalamus and Pituitary Gland

N.B: Samboxa shape obesity, fat is deposited in the face. Shoulder,

trunk, hips but sparing the extremities

3- Laurence-Moon-Bidel Syndrome:
• Rare congenital AR disease

Clinical picture:
1- Features of Froehlich's syndrome
2- Polydactyly
3- Skull deformations, mental retardation
4- Retinitis pigmentosa

D.D of hypopituitrism in children:

Chapter 2

1- Dawarfism.
2- Infantilism = Short stature & hypogonadism

II- Hypopituitsrism in adults

1- Isolated hormone deficiency:
1- ↓ TSH: 2nry hypothyroidism
2- ↓ ACTH: 2nry hypocorticism
3- ↓Gonadotrophins: (2ndry hypogonadism) Kaliman’s
syndrome (anosmia, midline fascial deformities,renal
abnornialties & colour blindness)

2- Panhypopituitarism: (Simmond’s disease)

Etiology:
1- Infarction:
- Sheehan syndrome: pituitary infarction following severe
post partum hge 2nry to vascular spasm & slow
circulation.
- Pituitary apoplexy: infarction or hemorrhage in pituitary
tumour, it may present with severe headache & collapse.
2- Infective: basal meningitis, encephalitis
3- Neoplastic: Pituitary tumor
4- Infiltration-by: TB - gumma - sarcoidosis - histiocytosis
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 Hypothalamus and Pituitary Gland 53

5- Iatrogenic: hypophysectomy or pituitary irradiation

6- Immunological: pituitary antibodies
7- Traumatic: fracture base of skull
8- Others: empty sella syndrome

Clinical Features:
Insidious onset with weakness & apathy
1- Manifestation of underlying cause:
e.g.: Pressure manifestation in pituitary tumor
2- Manifestations of sex hormone & prolactin deficiency:
First presentation is 2ndry hypogonadism

a. ↓ FSH/LH:

Chapter 2
- Amenorrhea, impotence, loss of libido,
- Atrophy of breast & genitalia,
- Loss of pubic and axillary hair
b. ↓ prolactin: failure to establish lactation after delivery

3- Thyroid deficiency -↓ - TSH:

a. Hypothyroidism: puffy lids - dry skin - coldness, apathy
b. Hypothermic coma may occur on exposure to cold

4- Adrenocortical insufficiency - ↓ ACTH:

a. Hypoglycemia, infection
b. NO
- Hyperpigmentation “absent ACTH” there is pallor
& depigmented area (absent MSH & anemia).
- Marked hypotension: normal secretion of
aldosteronc.
- Diarrhea: as hypothyroidism cause constipation
5- Deficiency of GH: early (the 1st to be affected)
- Atrophy of viscera - skin wrinkling - weakness –
wasting.
- Hypoglycemia, premature CVS disease, reduce
muscular mass.

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 54 Hypothalamus and Pituitary Gland

6- Hypopituitary crisis: on exposure to stress

- Present with acute abdomen like picture due to
lack ACTH & cortisone
7- Manifestation of ADH deficiency: D.I
8- Coma may occur terminally due to:
- Hypoglycemia
- Hypothermia
- Pressure by tumor pressure on brain stem reticular
formation

Investigations:

I- For function:
Chapter 2

1. Basal hormone level:

a- FSH, LH, sex hormones, TSH, T3, T4, ACTH &
corticosteroids: low
b- Hyperprolactinemia: in pituitary stalk lesion
2. Combined Pituitary stimulation test:
Insulin +TSH-RH + Gonadotrophic releasing hormones (FSH-
RH + LH-RH)
a. Normally: Level of all hormones should increase 3 folds
b. Failure to do so indicates hypopituitarism
3. Others:
- Water deprivation for D.I.
- Anemia, hypoglycemia.

II: For etiology:

1. X-ray sella tursica:
a- Intrasellar tumor:
- Ballooning of sella.
b- Suprasellar tumor: saucerisation of sella.
2- CT scan & MRI: the best.
3- Visual field examination.

Differential diagnosis:
1- 1ry hypogonadism:

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 Hypothalamus and Pituitary Gland 55

- Thyroid & adrenal function are normal

- Features of hypogonadism
- High FSH / LH
- Disproportionate gigantism if condition starts in childhood
2- 1ry hypothyroidism (thyroid myxedema)
- Adrenal & gonadal function are normal
- Features of hypothyroidism
- ↑ TSH and TSH stimulation shows no elevation of T3 &
T4
- Body weight is markedly increase
3- 1ry "Adrenal" hypocorticism (Addison disease)
- Thyroid & gonadal function are normal
- Features of hypocorticism

Chapter 2
- ↑ ACTH and ACTH stimulation shows no elevation of
cortisol
- Skin pigmentation due to high ACTH
- Marked hypotension
4- Anorexia nervosa:
- Thyroid & adrenal function are normal
- More common in young female with psychiatric
disturbance.
- Very active & aggressive attitude
- Marked anorexia, weight loss.
- Body hair and breast are normal
5- Pernicious anemia:
- Blood picture & serum B 12

Treatment of hypopituitarism:
a. ttt of cause: if possible.
b. Replacement therapy:
1- Hydrocortisone: 25-75 mg/day- Mineralocorticoids are
not required.
2- Gonadal hormones.
▪ If fertility is required: gonadotrophines should be
given.
▪ If fertility is not required → sex hormones are given:

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 56 Hypothalamus and Pituitary Gland

▪ In males: methyl testosterone 25-50 mg/day.

▪ In females:
▪ Estrogen therapy on days 1-21
▪ Progesterone on days 14-21
3- Thyroxin:
▪ Should be started in a gradual increasing dose [0.1
mg - 0.2 mg/d].
▪ Should follow cortisol to avoid adrenal failure
(since T4 ↑ the need for cortisol in the body.
4- Purified pituitary hormone or hypothalamic RH
5- DDAVP for DI.
▪ 100-200 ug three times/d by nasal spray or oral
6- For pituitary crisis:
Chapter 2

▪ Hydrocortisone.
▪ Volume expansion
▪ Hypertonic saline.

Short Stature
Definition:
Short stature is a term applied to a child whose height is 2
standard deviations (SD) or more below the mean for children of that
sex and chronologic age (and ideally of the same racial-ethnic group).
This corresponds to a height that is below the 3rd percentile. Short
stature may be either a variant of normal growth or caused by a disease.

Causes of Short Stature:

• Proportionate Short Stature:
▪ Normal Variants: (Table 1)
• Familial
• Constitutional delay in growth and puberty.
▪ Prenatal Causes:
• Intrauterine growth restriction (placental, infections or teratogen)
• Genetic disorders (chromosomal and metabolic disorders).
▪ Postnatal Causes:
• Under nutrition
• Chronic systemic illness
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 Hypothalamus and Pituitary Gland 57

• Psychosocial short stature (emotional deprivation)

• Endocrine causes
▪ Growth hormone deficiency/insensitivity
▪ Juvenile diabetes mellitus
▪ Cushing’s syndrome
▪ Pseudohypoparathyroidism
▪ Precocious puberty.

• Disproportionate Short Stature:

• With Short Limbs:
• Achondroplasia, hypochondroplasia, osteogenesis
imperfecta, refractory rickets.
- Cretinism and juvenile hypothyroidism.

Chapter 2
• With Short trunk:
- Spondyloepiphyseal dysplasia, mucolipidosis,
mucopolysaccharidosis

Table 1: comparison between familial and constitutional short stature:

Features Familial short stature Constitutional delay in
growth
Sex Both equally affected More common in boys
Length at birth Normal Normal
(starts falling < 5th centile
in 1st 3
years of life)
Family history Short stature Delayed puberty
Parents stature Short (one or both) Average
Height velocity Normal Normal
Puberty Normal Delayed
Bone age (BA) BA = CA CA > BA
&chronological
age (CA)
Final height Short, but normal for Normal
target height

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 58 Hypothalamus and Pituitary Gland

Prenatal Causes
• Intrauterine Growth Restriction.
• Placental, infections or teratogen.
• Genetic Syndromes:

Turner's syndrome of 45, XO (gonadal dysgenesis), other syndromes,

e.g. Down syndrome, Noonan syndrome and Prader-Willi syndrome.

Postnatal Causes
- Chronic Systemic Illness:

Chronic illnesses that may lead to growth retardation are:

Chapter 2

• Chronic infections
• Malabsorption with small bowel disorders, [Link] disease.
• Birth defects: Congenital heart defect (CHD), urinary tract and
nervous system anomalies.
• Miscellaneous: Cirrhosis of liver, bronchiectasis, acquired heart
diseases, cardiomyopathies.

- Endocrine Causes:
Growth Hormone Deficiency: Classic GH deficiency, either
alone or in conjunction with other pituitary hormone deficiencies.
Laron’s Syndrome: Conditions of GH insensitivity, characterized by
growth failure, high serum GH levels, and very low serum IGF-1 levels.
Type-1 Diabetes Mellitus: Growth failure can occur in diabetic children
with long-standing poor glycemic control.
Cushing’s syndrome: Glucocorticoid excess impairs skeletal growth,
interferes with normal bone metabolism by inhibiting osteoblastic
activity, and enhances bone resorption.

- Congenital and juvenile hypothyroidism:

Untreated congenital and juvenile hypothyroidism results in
profound growth failure. Skeletal maturation is delayed and body
proportion is immature, with an increased upper-to-lower body segment
ratio.
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 Hypothalamus and Pituitary Gland 59

- Psychosocial Short Stature:

An extreme form of failure to thrive is termed psychosocial
dwarfism or emotional deprivation dwarfism.

- Skeletal Dysplasias:
The osteochondrodysplasias encompass a heterogeneous group
of disorders characterized by intrinsic abnormalities of cartilage and
bone.

Assessment of A Child With Short Stature:

A detailed history and physical examination (Tables 2 and 3) are the
cornerstones for the etiological diagnosis of short stature.

Chapter 2
TABLE 2 │ Clues to etiology short stature from history:
History Etiology
History of delay of puberty in Constitutional delay of growth
parents
Low birth weight SGA (small for gestational age)
Neonatal hypoglycemia, GH deficiency
jaundice, micropenis
Dietary intake Undernutrition

Headache, vomiting, visual Pituitary/hypothalamic lesion

problem
Lethargy, constipation, weight Hypothyroidism
gain
Polyuria CRF, RTA
Social history Psychosocial dwarfism
Diarrhea, greasy stools Malabsorption

TABLE 3 │ Clues to etiology short stature from examination :

Examination findings Etiology
Disproportion Skeletal dysplasia, rickets,
congenital and juvenile
hypothyroidism
Dysmorphism Congenital syndromes
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 60 Hypothalamus and Pituitary Gland

Hypertension Chronic renal failure

Goiter, coarse skin Hypothyroidism
Central obesity, striae Cushing’s syndrome

• The key issues which help in deciding the cause are:

1. Accurate Height Measurement
2. Assessment of Body Proportion
- Upper segment: Lower segment ratio, comparison of arm
span with height.
3. Assessment of Height Velocity
4. Comparison with Population Norms
Height plotted on appropriate growth charts (Figure 1) and
expressed as centile or SD score.
Chapter 2

5. Comparison with Child’s Own Genetic Potential

- Mid-parental height for boys = (Mother's height + father's
height)/2 + 6.5 cm ± 8 cm
- Mid-parental height for girls = (Mother's height + father's
height)/2 – 6.5 cm ± 8 cm.
-

Figure1 (Growth chart)

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 Hypothalamus and Pituitary Gland 61

6. Bone Age
Bone age assessment should be done in all children with short
stature.

Investigations:
• Complete hemogram with erythrocyte sedimentation rate (ESR)
• Urine analysis (microscopy, pH, osmolality)
• Stool (parasites, steatorrhea, occult blood)
• Blood (renal function test, calcium, phosphate, alkaline
phosphatase, venous gas, fasting sugar, albumin, transaminases).
• Serum thyroxine, thyroid-stimulating hormone (TSH)
• Karyotype to rule out Turner’s syndrome in girls
• Coeliac serology (anti-endomysial or anti-tissue

Chapter 2
transglutaminase antibodies), duodenal biopsy.
• Growth hormone stimulation test with glucagon or insulin,

Serum IGF-1 levels.

Management:
• Counseling of parents (for psychosocial causes).
• Dietary advice ([undernutrition, celiac disease).
• Limb lengthening procedure (Skeletal dysplasia).
• Levothyroxine (in hypothyroidism) .
• Growth hormone subcutaneous injections (GH deficiency).
• Monitoring with regular and accurate recording of height is
mandatory for a good outcome in any form of therapy.

Gigantism & Acromegaly

Gigantism

Definition:
Gigantism refers to growth hormone (GH) excess that occurs before
fusion of the epiphyseal growth plates. In this setting, elevated level

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 62 Hypothalamus and Pituitary Gland

of serum GH and IGF-I lead to rapid, excessive linear growth &

extremely tall stature.

Causes:
1. Pituitary GH-secreting adenoma
2. Hypothalamic GH-releasing hormone excess
3. Ectopic GH or GHRH secretion [rare].

Clinical Presentation
[Link]
• Dramatic linear growth acceleration: tall stature.
[Link] signs and symptoms
• Symptoms of tumor compression eg. Headache, visual
Chapter 2

disturbance, pituitary hypofunction.

• Amenorrhea with or without galactorrhea in adolescents with
GH-secreting adenomas.
• Type 2 diabetes has been reported in adolescents with
pituitary gigantism.
• Cardiovascular disease: hypertension, left ventricular
hypertrophy, cardiomyopathy, heart failure.

Other Etiologeis Of Rapid Linear Growth (Should Be Carefully

Excluded)
1. Familial and Genetic tall stature
2. Cerebral gigantism
3. Kleinfelter syndrome
4. Precocious puberty
5. Hyperthyroidism
6. Marfan syndrome
7. Neurofibromatosis.

Investigations
1. Biochemical studies:
A. GH-related studies
a. GH suppression test (OGTT), the gold standard for making a
definitive diagnosis.

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 Hypothalamus and Pituitary Gland 63

b. Serum IGF-I, IGFBP-3,

c. Prolactin (usually is elevated in children with GH excess)
d. GHRH is elevated in suggested ectopic GHRH secretion
B. Other tests
a. Bone age
b. Thyroid function tests
c. Sex steroid hormone
d. karyotype
2. Radiographic imaging
• Radiographic imaging of the hypothalamus and
pituitary gland is undertaken once biochemical
evidence of pituitary gigantism is confirmed.
• MRI with contrast is the study of choice because it has

Chapter 2
the ability to detect subtle abnormalities in the size and
structure of the hypothalamic-pituitary region.

Treatment

The 3 therapeutic modalities used to treat pituitary gigantism are

surgery, radiation, and pharmacologic therapy.
1. Surgery — Transsphenoidal surgery is the treatment of
choice for discrete pituitary adenomas. This technique is safe
in children, although complication and recurrence rates tend
to be higher than in adults.
2. Pharmacologic treatment:
Medical therapy is indicated in patients whose GH excess is
incompletely controlled by surgery or in whom surgery is not an
option.
a. Somostatin analog
b. Dopamine analog
c. GH receptor antagonist: in cases unresponsiveness to other
pharmacologic agents.
3. Radiation:
• Cranial radiation may provide useful adjunctive therapy
in some settings,

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 64 Hypothalamus and Pituitary Gland

• Disadvantages: delayed efficacy and panhypopituitarism ,

and should be avoided if possible.
Chapter 2

Gigantism
Acromegaly:

Definition:
• Acromegaly is the clinical syndrome that results from persistent
hypersecretion of growth hormone (GH) & hence IGF-1 in
adults.
• GH secretion remains episodic but the number, duration &
amplitude of secretory episodes are increased.

Incidence:
• Its annual incidence is 3: 4/ million people.
• The mean age at diagnosis is 40: 45 years.

Causes:
1. GH hormone- secreting pituitary adenoma [the most common
cause~ 95%].

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 Hypothalamus and Pituitary Gland 65

2. Other causes [all are very rare]:

A. Excess secretion of GHRH by hypothalamic tumors.
B. Ectopic GHRH secretion by neuroendocrine tumors such
as carcinoid tumors or small-cell lung cancers.
C. Ectopic secretion of GH by neuroendocrine tumors.

Clinical Manifestations
1. Somatic effects
2. Metabolic effects
3. Direct effects of tumor.

1. Somatic effects
A. Soft tissue and skin overgrowth

Chapter 2
FACE: The facial features become coarse, with enlargement
of the nose, lips, tongue and frontal bones as well as the jaw
(macrognathia), and the teeth become spread apart.
• enlargement of hands and feet with spade hands and
sausage like fingers & toes, which result in increasing shoe
and glove size and the need to enlarge rings.
• paresthesias of the hands (eg, carpal tunnel syndrome in
20%).
• Deepening of the voice: Macroglossia and enlargement of
the soft tissues of the pharynx and larynx which also lead
to obstructive sleep apnea in about 50% of patients.
• The skin: skin thickens, skin tags, hyperhidrosis is
common, hair growth increases, and some women have
hirsutism
B. Bone and joints
• Hypertrophic arthropathy: due to synovial tissue and
cartilage enlargement
• Kyphosis
• Bone density may be increased in both the spine and hip
early in the disease.
• Osteoporosis later on caused by concurrent gonadal
insufficiency due to the enlarging pituitary tumor → back
pain.
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 66 Hypothalamus and Pituitary Gland

C. Visceral enlargement
Many visceral organs are enlarged in acromegaly, including the
thyroid, heart, liver, lungs, and kidneys.
D. Cardiovascular disease
Hypertension, left ventricular hypertrophy, cardiomyopathy, Heart
failure.

2. Metabolic effects
• Hyperinsulinism, insulin resistance, overt diabetes in 10 to
15% of cases, and IGT in a further 50%
• Hypertriglyceridemia
• Hypercalciuria.
• Hyperphosphatemia: it is due to direct stimulation of renal
Chapter 2

tubular phosphate reabsorption by IGF-I.

3. Direct effects of tumor

• Headache
• Visual field defects (classically bitemporal hemianopsia)
• Cranial nerve palsies
• Pituitary function impairment: due to size of pituitary
macroadenoma eg. Gonadotropins & TSH and ACTH
deficiency.

4. Other manifestations
• Fatigue and weakness; they may result from sleep apnea,
cardiovascular dysfunction, neuropathy, hypogonadism,
hyperglycemia, or some combination of these factors.
• Tumors: Colonic neoplasia; adenomatous colonic polyps.

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 Hypothalamus and Pituitary Gland 67

Chapter 2
Diagnosis
1. Documenting Excess Gh Secretion
A. Serum IGF-I concentration
Serum IGF-I concentrations are elevated in virtually all patients
with acromegaly and provide excellent discrimination from normal
individuals.

B. Oral glucose tolerance test (OGTT)

• OGTT is the most specific dynamic test for establishing the
diagnosis.
• In normal subjects, serum GH concentrations fall to 1 ng/mL
or less within 2 hours after ingestion of 75 g glucose.
• The criterion for the diagnosis is a GH concentration greater
than 1 ng/mL.
2. Determining the Source of Excess Gh
• MRI: once GH hypersecretion has been confirmed pituitary
tumors as small as 2 mm in diameter can be detected with this
technique.
• In about 75% of patients, the tumor is a macroadenoma
(tumor diameter 10 mm or more), and the tumor may extend
to the parasellar or suprasellar region.

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 68 Hypothalamus and Pituitary Gland

Other causes of acromegaly:

1. Abdominal and chest imaging should be performed in suspected
ectopic GH secretion.
2. GHRH secretion assessment: in suspected GHRH
hypersecretion.

Treatment
Lines of treatment:
1. Transsphenoidal surgery
2. Medical treatment [somatostatin analog, Dopamine agonist, GH
receptor antagonist]
3. Radiotherapy
Chapter 2

1. Transsphenoidal surgery

Indications:
A. Microadenoma, or macroadenoma that appears to be fully
resectable or,
B. Macroadenoma causing impairment of vision.
• For patients who have undergone transsphenoidal surgery with
normalization of serum IGF-1 concentration, no further therapy
is needed.

2. Medical treatment
Indication: Secondary therapy for patients who have undergone
transsphenoidal surgery without normalization of serum IGF-1
concentration.
• Long-acting somatostatin analog.
• Dopamine agonist: If somatostatin analogs are ineffective.
• GH receptor antagonist for controlling IGF-1 levels: If
somatostatin analogs, dopamine agonist, or a combination of
the two are ineffective.
• Radiotherapy or repeat surgery:
In patients who have a continued increase in adenoma size despite
medical therapy (ie, somatostatin analog + GH receptor antagonist)

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 Hypothalamus and Pituitary Gland 69

Long-acting somatostatin analog from the start in:

A. Patients whose adenoma does not appear to be fully respectable.
B. Patients whose risk of surgery is great.
C. Who choose not to have surgery.
A sustained-release formulation of a somatostatin analog, is another
available agent. This medication, administered IM every 2 to 4 weeks,
is safe and effective in treating adults with acromegaly.

Chapter 2

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 70 Hypothalamus and Pituitary Gland
Chapter 2

Hyperprolactinemia & Prolactinomas

Prolactin "PRL"
• Primary function: enhances breast development during
pregnancy and to induces Lactation
• Secretion of PRL: is pulsatile; where it increases with exercise
,sleep, stress, pregnancy, and chest wall stimulation or trauma
• PRL Secretion: is under tonic inhibitory control by dopamine
(PRL inhibiting factor -PIF)
• PRL production can be stimulated by the hypothalamic peptides,
“thyrotropine releasing hormone- TRH” and “vaso active
intestinal peptide -VIP” (PRL releasing factor -PRF)

Hyperprolactinemia
Elevation of serum PRL level above normal "women: 25 ng/mL,
men: 20 ng/mL
Causes of Hyperprolactinemia
A- Hypothalamic Dopamine Deficiency
• Diseases of the hypothalamus: Tumors
▪ Arterio-venous malformations
▪ Inflammatory processes

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 Hypothalamus and Pituitary Gland 71

• Drugs: Alpha-methyldopa & Reserpine

B-Defective Dopamine Transport Mechanisms

• Section of the pituitary stalk
• Pituitary or stalk tumors

C- Lactotroph Insensitivity to Dopamine

• Dopamine-receptor-blocking agents:
Phenothiazines (e.g. chlorpromazine)
Butyrophenones (haloperidol)
Benzamides (metoclopramide, sulpiride, and
domperidone)

Chapter 2
D- Direct Stimulation of Lactotrophs
• Hypothyroidism- increased TRH production (acts as a
PRF)
• Estrogens: stimulate lactotrophs
• Injury to the chest wall: abnormal stimulation of the reflex
associated with the rise in PRL that is seen normally in
lactating women during suckling

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 72 Hypothalamus and Pituitary Gland

Aetiologic Mechanisms of Hyperprolactinewmia

Clinical Features of Hyperprolactinemia/Prolactinoma:

Women:
1. Amenorrhea
2. Oligomenorrhea
3. Galactorrhea
4. loss of libido
5. breast heaviness
6. Infertility
Men:
1. Decreased libido
2. Sexual dysfunction (in both men and women)
Chapter 2

3. Erectile dysfunction
4. Infertility and gynaecomastia.

Disturbed menses and infertility lead to early diagnosis in

women(microprolactinoma) compared to men with delay in diagnosis
(macroprolactinoma).
Work up of Patient with Hyperprolactinemia
• In females, pregnancy must always be ruled out
• Assess TSH (hypothyroidism is another common cause of ↑PRL)
• Rule out medication effects (Drug history)
• Rule out other common causes including:
a. Non fasting sample
b. Nipple stimulation or sex
c. Excessive exercise
d. History of chest wall surgery or trauma
e. Renal failure
f. Cirrhosis

If no cause is determined, or a pituitary tumor suspected, consider

pituitary MRI, especially if high PRL levels (> 100 ng/mL) are
encountered.

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 Hypothalamus and Pituitary Gland 73

Prolactinomas

Most common functioning pituitary adenomas

25-30% of all pituitary adenomas
Some growth hormone (GH)–producing tumors also co-secrete PRL
Women with prolactinomas → 90% with microprolactinomas
Men with prolactinomas → 60% present with macroprolactinomas
Clinical Features of Prolactinomas:
As hyperprolactinemia in addition to the mass-effects manifestations
being a space occupying lesion within the pituitary leading to
manifestations of elevated intrasellar pressure and may be
hypopituitarim

Chapter 2
Treatment of hyperprolactinemia and Prolactinomas:

Pharmacotherapy
• Dopamine agonists are treatment of choice for most prolactin
micro-adenomamas
• Choices include Bromocriptine, Pergolide and Cabergoline

Side effects include: postural hypotension, dizziness, nasal stuffiness,

And GI Side Effects
Dopamine Agonists
Bromocriptine
start with low dose "1.25- 2.5 mg /d" at night, before increasing to "2.5
– 10 mg /d" in divided doses. Take with food to reduce side effects.

Cabergoline
• More Effective
• Fewer Side Effects than Bromocriptine
• More Expensive
• Given once or twice / week, with a starting dose of 0.25 mg 2 x
week

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 74 Hypothalamus and Pituitary Gland

Other lines for treatment of prolactinomas

1 - Pituitary Surgery
• Transsphenoidal approach:
• Endonasal submucosal trans-septal approach
• Septal Pushover/Direct Sphenoidotomy
• Endoscopic approach
Indications of surgery:
• Failure of medical or radiotherapy
• It provides prompt relief from excess hormone secretion
and mass effect.
• Indicated in pituitary apoplexy with compressive
symptoms
Chapter 2

2 - Radiation Therapy
• Conventional radiotherapy
• Gamma knife radiosurgery

Reserved for pts with larger tumors and/or Persistent hormonal

hyperfunction despite surgical intervention

Copyright © 2017 Internal Medicine Department. All rights reserved

CHAPTER

Thirst Axis
 Thirst Axis

Diabetes Insipidus
3
• Diabetes insipidus (DI) is caused by decreased secretion or
action of antidiutertic hormone (ADH), resulting in the
production of abnormally large volumes of dilute urine.
• Two subtypes are described:
• Neurohypophyseal DI is caused by deficient ADH secretion from
the neurohypophysis and/or hypothalamus. Also referred to as
central DI, cranial DI, or pituitary DI
• Nephrogenic DI is caused by defective ADH action on the renal
collecting tubules.

Etiology

Neurohypophyseal (central) DI
• Head trauma (closed and penetrating)
• Disorders associated with destruction of the hypothalamus
e.g.
▪ Neoplasms: Craniopharyngioma, glioma, metastasis,
lymphoma
▪ Granulomatous disorders: sarcoidosis, histocytosis
▪ Infections:T.B., menengitis
• Pituitary surgery: transfrontal, trans-sphenoidal
• After cranial radiotherapy
• Familial
• Idiopathic

Nephrogenic DI
• Drugs: Lithium, Amphotericin B, Aminoglycosides
• Metabolic: Hypercalcemia/hypercalciuria, Hypokalemia
• Renal diseases as renal tubular acidosis

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 76 Thirst-Axis

• Sickle-cell disease
• Genetic disorders: ADH receptor mutations
N.B Primary polydipsia: Psychiatric disorder due to excessive water
intake with resulting polyuria and low ADH.

Symptoms & Signs of DI

• Marked polyuria by day and night (5-20L/day)
• Nocturnal Enuresis in children
• Polydipsia
• Mild daytime fatigue/somnolence, as a consequence of
sleep disturbance.
• Signs of dehydration (rare). Only if fluid intake is
Chapter 3

impaired

Diagnostic Approach
• Measurement of 24-hour urine output and urine
osmolarity.
▪ Diagnosis of polyuria is confirmed if output is >
50 mL/kg daily (>3500 mL in a 70-kg man).
▪ Urine osmolarity < 300 mosmol/L indicates a
water diuresis and should be further evaluated with
fluid deprivation test. If urine osmolarity > 300
mosmol/L suggests that polyuria is due to a solute
diuresis and should be followed by evaluation for
test for diabetes mellitus or other cause of
excessive solute excretion.
• Fluid deprivation test
▪ Test differentiates patients with DI from patients
with primary polydipsia.
▪ Physiologic principle: Dehydration causes
elevation of plasma osmolality, which stimulates
ADH secretion, causing concentration of urine.
▪ Patients with primary polydipsia will concentrate
urine; patients with DI will not

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 Thirst-Axis 77

• Desmopressin (1-desamino-8-D-arginine vasopressin

[DDAVP]) challenge
▪ Test differentiates central DI from nephrogenic DI.
▪ Physiologic principle: DDAVP causes urine
concentration.
▪ Patients with neurohypophyseal DI will
concentrate urine after receiving DDAVP; patients
with nephrogenic DI will not.
• Imaging: The differential diagnosis of DI may also be
facilitated by MRI of the pituitary and hypothalamus.

Treatment

Chapter 3
Depends on the cause of DI:
• Central DI
▪ Treat primary disease
▪ Correct a fluid deficit
▪ Desmopressin: is the mainstay of therapy, it is the
synthetic analogue of ADH, acts selectively at V2
vasopressin receptors to increase urine concentration and
decrease urine flow in a dose-dependent manner, given
intravenous or subcutaneous injection, nasal inhalation,
or tablet.
• Nephrogenic DI
Initial therapy should be directed at correcting an
underlying disorder or discontinuing an offending
medication
• Thiazide diuretics diminish the degree of polyuria acting on
ADH receptors.
• Low-sodium diet can decrease net solute excretion, and thus
diminish urine output.
• Inhibitors of prostaglandin synthesis (e.g., indomethacin):
Decrease the action of renal prostaglandins that normally
inhibit the action of vasopressin in the kidney

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 78 Thirst-Axis

Differential diagnosis of polyuria and polydipsia

Polyuria is the passage of excessive quantity of urine and it
implies water or solute diuresis of at least 2.5–3 L/day or
urine volume of more than 40 mL/kg/day. Polyuria is usually
associated with polydipsia which is defined as water intake
of more than 100 mL/kg/day (6 L/day).
Syndrome of Inappropriate antidiuretic Hormone
(SIADH)
• SIADH is characterized by the non-physiologic release of
ADH, resulting in impaired water excretion with normal sodium
excretion
• SIADH is characterized by:
▪ Fluid retention
Chapter 3

▪ Serum hypo-osmolarity
▪ Dilutional hyponatraemia
▪ Hypochloremia
▪ Concentrated urine in the presence of normal or increased
intravascular volume
▪ Normal renal function

Pathophysiology
• Inappropriate ADH secretion occurs when there is
dysregulation of cells secreting ADH
• The posterior pituitary is not always the source of ADH
secretion
• A variety of ADH-secreting tumors has been associated with
SIADH, as well as various CNS disorders, pulmonary disorders
& drugs

Causes:
• Increased hypothalamic production of ADH:
• Infections: meningitis, encephalitis, abscess, HIV
• Vascular: subarachnoid or subdural hemorrhage
– Neoplasm
– Guillain-Barré syndrome, acute intermittent porphyria,
autonomic neuropathy, post–pituitary surgery, multiple
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 Thirst-Axis 79

sclerosis, psychosis, bone marrow transplantation or

Stem Cell Transplants
– Drugs
▪ Chemotherapeutic - Cyclophosphamide,
vincristine, vinblastine
▪ Antipsychotic - Thiothixene, thioridazine,
haloperidol
▪ Antidepressants - Monoamine oxidase inhibitors,
tricyclic antidepressants, serotonin reuptake
inhibitors
▪ Miscellaneous – Bromocriptine
– Pulmonary diseases
• Pneumonia, Tuberculosis, Acute respiratory failure,

Chapter 3
Positive pressure ventilation, Asthma & Atelectasis
– Idiopathic

Signs & symptoms

• Decreased urine output
• Symptoms of hyponatraemia
– Lethargy, apathy, disorientation, muscle cramps,
anorexia, agitation
• Symptoms of water toxicity
– nausea, vomiting, personality changes, confusion
• If Na < 110 mEq/L
– seizures, bulbar palsies, hypothermia, stupor, coma

Investigations
• Serum Na < 135 (Na is diluted by excessive free water re-
absorption)
• Serum osmolality low,
• Urine Na is inappropriately high, >20 mmol/L (actually losing
Na in urine instead of retaining it)
• Urine osmolality is inappropriately high, can range between
300-1400 mosm/l
• Central venous pressure "CVP" is normal, euvolemic state.

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 80 Thirst-Axis

• Chest radiographs may reveal an underlying cause (e.g.,

pulmonary disease)
• Brain CT: evidence of cerebral edema, brain tumor etc….

Clinical Management
• Treatment of underlying medical condition
• Normalize serum sodium (130 meq/l and above) over 24 -48
hours (Max correction of 15meq/day)
– Warning, if elevation of serum Na is too fast, there is a
risk for pontine myelinolysis
• Normalize serum osmolality
• Correct excess extravascular fluid volume
– Restrict fluids
Chapter 3

– 3% NaCl
– Loop diuretics

Drug therapy in SIADH:

• loop diuretics: impair urine concentrating mechanism.
• Vasopressin antagonists (Vaptans): iv (conivaptan) and oral
(tolvaptan) are approved for ttt of euvolemic hyponatremia
• Demeclocycline & lithium: anti ADH action.

Prognosis
• The prognosis of SIADH best correlates to the underlying cause

Copyright © 2017 Internal Medicine Department. All rights reserved

CHAPTER

Thyroid Disorders
 Thyroid Disorders

Thyroid Gland
4
• Anatomy:
The thyroid gland is located in the front of the neck attached to the lower
part of the larynx and to the upper part of the trachea, so it moves with
swallowing. It has two lobes. These lobes are connected by isthmus.
Each lobe is about 4 cm long and 1 to 2 cm wide.
• Histology:
The thyroid is composed of spherical follicles that selectively absorb
iodine from the blood for production of thyroid hormones, and also for
storage of iodine in thyroglobulin. Twenty-five percent of the body's
iodide ions are in the thyroid gland.

Figure 1: show secretion of thyroid hormones

• Actions of thyroxin hormone:

1. Increases cardiac output and increases heart rate
2. Increases ventilation rate and oxygen consumption

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 82 Thyroid Disorders

3. Increases basal metabolic rate

4. potentiates the effects of catecholamine (i.e. increases
sympathetic activity)
5. Potentiates brain development
6. Thickens endometrium in females
7. Increases metabolism of proteins (i.e. they have a catabolic
action).
8. Increases absorption and utilization of glucose
9. It lowers cholesterol.

Thyroid function tests

1- TSH: (TSH, thyrotropin) is elevated in hypothyroidism and

Chapter 4

secondary hyperthyroidism and decreased in hyperthyroidism and

secondary hypothyroidism. It is the most sensitive test for thyroid
hormone function.
2- Total T4: rarely measured now, having been largely superseded by
free thyroxin tests, generally elevated in hyperthyroidism and
decreased in hypothyroidism. It is usually slightly elevated in
pregnancy secondary to increased levels of thyroid binding globulin
(TBG).
3- Free T4: generally elevated in hyperthyroidism and decreased in
hypothyroidism. Reference ranges depend on the method of
analysis.
4- Estimation of T3: to diagnose T3 toxicosis.
5- T3 resin uptake: measures the free TBG, unoccupied sites of TBG.
Radioactive T3 added to patient serum, fixed to binding sites of
TBG, the remaining unabsorbed radioactive T3 is absorbed into a
resin & its radioactivity is measured. It decreased in hypothyroidism
and increased in hyperthyroidism.
6- Free thyroxine index: obtained by multiplying the total T4 with T3
resin uptake. FTI is considered to be a more reliable indicator of
thyroid status in the presence of abnormalities in plasma protein
binding.
7- TSH stimulation test: differentiate 1ry from 2ry hypothyroidism,
we give TSH to the patient;
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 Thyroid Disorders 83

-increase of thyroxin in 2ry hypothyroidism, but it will not be increased

in 1ry hypothyroidism.
8- Calcitonin: Increased in medullary carcinoma.
9- Thyroid sonar: differentiate cystic from solid nodules and detect
retrosternal extension.
10- Thyroid scan: using radioactive iodine or Technetium uptake.
High uptake in hyperthyroidism or Iodine deficiency. Low uptake
present in hypothyroidism or thyroiditis. Differentiate functioning
(hot) nodules from non-functioning (cold) nodules.

Chapter 4
11- Fine needle biopsy: for pathological assessment.
12- Immunologic tests:
▪ Antithyroglobulin and antimicrosomal antibodies in hashimoto
thyroiditis.
▪ Thyroid stimulating immunoglobulin (TSI) marker of Graves'
disease.
Goiter
Definition
• A goiter is an enlarged thyroid gland, and it may be diffuse or
nodular.
• Because of the anatomic relationship of the thyroid gland to the
trachea, larynx, superior and inferior laryngeal nerves, and
esophagus, abnormal growth may cause a variety of
compressive syndromes.

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 84 Thyroid Disorders

• Thyroid function may be normal (nontoxic goiter), overactive

(toxic goiter), or underactive (hypothyroid goiter).
Chapter 4

Figure 2: show development of goiter & subtypes

Pathogenesis:
• When diffuse enlargement of the thyroid occurs in the absence
of nodules and hyperthyroidism, it is referred to as a diffuse
nontoxic goiter. This is sometimes called simple goiter, due to
the absence of nodules, or colloid goiter, due to the presence of
uniform follicles that are filled with colloid.
• Worldwide, diffuse goiter is most commonly caused by iodine
deficiency and is termed endemic goiter when it affects >5% of
the population.

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 Thyroid Disorders 85

Chapter 4
Figure 3: show pathogenesis of goiter

• In non-endemic regions, sporadic goiter occurs, and the cause

is usually unknown.
• Thyroid enlargement in teenagers is sometimes referred to as
juvenile goiter. In general, goiter is more common in women
than men, In iodine-deficient areas, thyroid enlargement
reflects a compensatory effort to trap iodide and produce
sufficient hormone under conditions in which hormone
synthesis is relatively inefficient.
• Iodide appears to have direct actions on thyroid vasculature and
may indirectly affect growth through vasoactive substances
such as endothelins and nitric oxide.
• Endemic goiter is also caused by exposure to environmental
goitrogens such as cassava root, which contains a thiocyanate;
vegetables of the Cruciferae family (known as cruciferous
vegetables) (e.g., Brussels sprout, cabbage, and cauliflower)
• Though relatively rare, inherited defects in thyroid hormone
synthesis including abnormalities at each step in hormone

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 86 Thyroid Disorders

synthesis ( dyshormonongenesis), lead to a diffuse nontoxic

goiter.
• TSH-dependent hyperplasia→→autonomy may be due to
mutations that occur with cell division in the oncogen that
activate the G protein in the cell membrane (called GSP
oncogen).
• When a small group of thyroid cells, inflammatory cells, or
malignant cells metastatic to the thyroid is involved, a thyroid
nodule may develop.
• If nodule can concentrate iodine → hot nodule or cannot →
cold nodule
• If Can synthesize thyroglobulin→ colloid nodule…. If cannot→
Chapter 4

microfollicular nodules. Hemorrhage and necrosis → cyst

formation.
• Initially hyperplasia is TSH-dependent but later becomes
autonomous.

Types &causes of goiter

Typical Symptoms and

Type of Goiter Cause
Signs
Iodine deficiency Lack of sufficient dietary Thyroid gland
(endemic goiter) iodine intake enlargement (goiter)
Normal or underactive
thyroid
(hypothyroidism)
Graves disease Autoimmune stimulation Goiter
(diffuse toxic goiter) of the thyroid gland Hyperthyroidism
Autoimmune Persistent immune Goiter
thyroiditis (Hashimoto, system inflammation Hypothyroidism
chronic lymphocytic) of person's own thyroid
Subacute thyroiditis Viral infection Painful, tender and
(painful, de Quervain) swollen gland
Malaise, fever, chills,
and night sweats

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 Thyroid Disorders 87

Thyrotoxicosis, often
followed by
hypothyroidism
Toxic adenoma and Benign thyroid tumor(s) Nodular goiter
toxic multi-nodular Hyperthyroidism
goiter
Goiter and thyroid Malignant thyroid No symptoms
nodules suspicious for tumors Local neck symptoms
malignancy Symptoms of tumor
spread
Table1; shows most of types & causes of goiter

Causes
The different etiologic mechanisms that can cause a goiter include

Chapter 4
the following:
• Iodine deficiency
• Autoimmune thyroiditis - Hashimoto or postpartum thyroiditis
• Excess iodine (Wolff-Chaikoff effect) or lithium ingestion,
which decrease release of thyroid hormone
• Goitrogens
• Stimulation of TSH receptors by TSH from pituitary tumors,
pituitary thyroid hormone resistance, gonadotropins, and/or
thyroid-stimulating immunoglobulins
• Inborn errors of metabolism causing defects in biosynthesis of
thyroid hormones
• Exposure to radiation
• Deposition diseases
• Thyroid hormone resistance
• Subacute thyroiditis (de Quervain thyroiditis)
• Silent thyroiditis
• Riedel thyroiditis
• Infectious agents
• Acute suppurative - Bacterial
• Chronic - Mycobacteria, fungal, and parasitic
• Granulomatous disease
• Thyroid malignancy

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 88 Thyroid Disorders

• Low selenium levels: This may be associated with goiter

prevalence.

Non toxic goiter

Causes:
1. Iodine deficiency
2. Dietary goitrogens
3. Hashimotos Thyroiditis
4. Subacute Thyroiditis
5. Dyshormononogensis
6. Neoplasm : benign or malignant
Chapter 4

Iodine deficiency:
• Most common cause of endemic goiter.
• Daily allowance 150-300 ugm/day.

Dietary goitrogens:
• Rare cause of goiter.
1. Most common is iodide itself (especially in susceptible
individuals and hypothyroidism).
2. Lithium carbonate
3. Amiodarone
4. Some vegetable foodstuffs: goitrogens found in certain roots
and seeds Cyanogenic glycosides found in cassava and
cabbage→ release thiocyanates→goiter.

Compounds as phenols, phthalates, pyridines, polyaromatic

hydrocarbons found in industrial waste water… all these are
weakly goiterogenic (endocrine disruptors).

Hashimoto Thyroiditis:
• Most common cause of goiter in developed countries.
• Subacute Thyroiditis: causes goiter and exquisite tenderness.

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 Thyroid Disorders 89

Dyshormonogensis (familial goiter):

a) Complete form: cretin with goiter
b) Incomplete form: mild hypothyroidism with goiter.

C/P
• Mass.
• Pressure symptoms in the neck or thoracic inlet syndrome (with
retro sternal extension)
• Recurrent laryngeal nerve paralysis with vocal cord paralysis.
• Hypothyroid symptoms.

Lab. Findings:

Chapter 4
• Normal TSH, with low or normal free T4.
• Radio iodine uptake may be low, normal or high (depending on
Iodide pool and TSH derive)

Imaging study:
• Hot and cold nodules.
• U/S: solid and cystic changes.

DD:
• Mainly to rule out malignancy

Treatment:
• Suppressive thyroxine therapy.
Surgery: in suspicious, large with pressure symptoms, RSE

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 90 Thyroid Disorders

Thyrotoxicosis

Clinical syndrome that results when tissues are exposed to high

levels of circulating thyroid hormones.

Causes:
1. Diffuse toxic goiter (Graves disease)
2. Toxic adenoma (Plummer disease)
3. Toxic multi-nodular goiter
4. Subacute thyroiditis
5. Silent thyroiditis
6. Thyrotoxicosis factitia
7. Rare causes include: ovarian Struma, metastatic thyroid
Chapter 4

carcinoma, hydatiform mole, TSH-Producing pituitary tumor

Graves’ disease

• Most common cause of thyrotoxicosis

• Female to male incidence 5:1
• Peak incidence 20-40 years
• Consists of: thyrotoxicosis, goiter, ophthalmopathy, dermopathy.

Etiology
• Auto immune disease of unknown cause
• Strong familial predisposition.
• Environmental factors may trigger the process e.g. stress,
tobacco use, infection and iodine exposure.
• T-lymphocytes are sensitized to antigen within the thyroid gland
 stimulate B lymphocytes  thyroid stimulating antibody
(TSAB) or thyroid- stimulating immunoglobulin (TSI) 
stimulate thyroid growth and function.

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 Thyroid Disorders 91

Ophthalmopathy:
Cytotoxic lymphocytes and cytotoxic antibodies are sensitized to
antigens in orbital fibroblasts and muscles  ↑ cytokines 
proliferation of orbital fibroblasts and orbital tissue  ↑ amount of
orbital fat, glycosamino-glycans and inflammation of extraoccular
muscles  manifestations of ophthalmopathy.

Dermopathy (pretibial myxedema)

Similar process lead to activation of dermal fibroblasts in the
anterior aspect of the legs.

Clinical features of thyrotoxicosis

1. General features:

Chapter 4
• Weight loss associated with increased appetite
• Emotional lability
• Anxiety and difficult concentration
• Fatigue due to disturbed sleep

Associated autoimmune diseases:

Pernicious anemia, type I diabetes, RA, myasthenia gravis,
vitiligo, adrenal insufficiency

Thyroid:
Diffuse, painless and firm enlargement of the thyroid
2. Neurologic features
• Fine tremors in the hands
• Proximal muscle weakness  difficulty in climbing
stairs, reach the arm over the head, standing from the
sitting position.

3. Dermatologic features:
• ↑ sweating, skin is worm, soft and smooth
• Heat intolerance
• Fingernails are separated from the nail bed
(onycholysis)

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 92 Thyroid Disorders

• Pretibial myxedema occurs in a small subset of patients

with Graves's disease. It is characterized by lymphocyte
infiltration of the dermis, accumulation of
glycoaminoglycans, and edema. It occurs in the
anterolateral aspect of the shin. The skin is thickened,
indurated and non-pitting. It may be pruitic or painful
• Clubbing of fingers may occur (thyroid acropachy)

4. Ophthalmologic features
• Lid lag and stare look: due to ↑ sympath. tone 
contraction of the eyelid muscles (Muller muscle)
• Proptosis (exophthalmos): due to ↑ in volume of retro-
bulbar tissue
Chapter 4

• Diplopia and limitation of eye movements at one or

more gaze due to involvement of extraoccular muscles
• Dry or gritty sensation of the eye and corneal
ulceration due to inability to fully close the eye lids.
• Other complications include peri-orbital edema,
conjunctival edema and hyperemia and photophobia.

5- Cardiovascular
• ↑ in heart rate, wide pulse pressure
• Flow murmur over precordium
• Cardiac arrhythmia: atrial fibrillation, multiple premature
beats
• CHF
• Anginal attacks

6- Gastrointestinal:
• Hyperphagia associated with weight loss
• ↑ gut motility  frequent defecation and/or diarrhea
• Obstructive dysphagia when large goiter is present

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 Thyroid Disorders 93

7- Reproductive system:
• Menstrual irregularities specially oligomenorrhea.
• Gynecomastia and sexual dysfunction: ↑ SHBG which
has higher affinity to androgens  ↓ level of free
androgens relative to estrogens. Also there is ↑
aromatization of testosterone to estrogens in the
peripheral tissues.

8- Bone:
• ↑ Thyroid hormone  ↑ loss of cortical and trabecular
bone  ↑ risk of osteoporosis and bone fractures.

Lab findings:

Chapter 4
• ↓ TSH concentration
• ↑ free T4 and T3
• T3 level only may be ↑ in some cases (T3 toxicosis)
• ↑ in TSAb
• Hyperglycemia due to ↑ in catecholamine – induced
glycogenolysis.
• Hypercalcemia and ↑ in alkaline phosphatase due to ↑
bone resorption.

Thyroid scintigraphy:
• Use technetium or iodine 123
• It shows diffuse uptake of radioisotope by thyroid.

Treatment of Graves Disease

A- Anti-thyroid drugs:
• Methimazole, carbimazole and propylthiouracil (PTU)
• They inhibit thyroid hormone synthesis
• PTU also prevent peripheral conversion of T4 to T3.

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 94 Thyroid Disorders

Recommendation
1. Thyroid function should be checked every 4-6 weeks and
doses are adjusted to achieve and maintain euthyroid state
and avoid hypothyroidism.
2. Focus on free T3 and T4 level to assess thyroid state
because TSH may be suppressed for several months after
peripheral thyroid hormone levels are normalized.

Duration of therapy
• 1-2 years to offer a chance for remission of hyperthyroid
state.
• The chance of permanent remission after cassation of
therapy is 35%-50%.
Chapter 4

Dose and regimens:

• Start with large dose. When the patient becomes
eurthryoid after 4-12 weeks, maintenance therapy is
achieved with lower dose.
• For methimazole start with 10-20 mg/day and maintain
with 5-10 mg/day
• For PTU start with 300 – 400 mg/day and maintain with
50-200 mg/day.
• Another approach is to continue large loading dose and
add thyroid hormone (block and replace therapy)
Indications:
1. Mild disease and small goiter because they have high
chance of remission
2. Elderly or other comorbidities increasing surgical risk.
3. Limited life expectancy
4. previous operation or irradiation to the neck
5. Lack of high-volume thyroid surgeon
Side effects
1. Skin rash, arthralgia, GI problems
2. Agranulocytosis: Potentially lethal adverse effect presents
with fever, sore throat which progress to sepsis. Any
patient on thionamide therapy who present with fever and
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 Thyroid Disorders 95

sore throat should have complete blood picture to exclude

this condition.
3. Hepatic problems
• Methimazole may produce cholestasis
• PTU may produce hepatitis with elevated markers of
hepatocellular injury.
• Patients on thionamide therapy should have liver
function before starting therapy and during treatment
with antithyroid drugs.

B- Radio-active iodine
• Suitable for most patients with Graves' disease.
• It is effective, safe, and does not require hospitalzation.

Chapter 4
• Given orally in a single dose in a capsule or liquid form.
• Very few side effects as no other tissue absorb RAI.

Precautions:
Patients with severe hyperthyroidism, elderly patients or
patients with underlying heart disease should be pretreated
with anti-thyroid drugs and β-blockers to achieve an euthyroid
state prior to radio-active iodine.

Indication:
1. ↑ surgical risk due to associated comorbidities.
2. Previous operation or irradiation to the neck
3. Lack of access to high-volume thyroid surgeon
4. Contraindication for use of anti-thyroid drugs.

Disadvantages:
• Occurrence of permanent hypothyroidism
• Worsening of ophthalmopathy.

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 96 Thyroid Disorders

Contraindication:
• Pregnancy and lactation.
• Children
• Associated severe opthalmopathy

C- Thyroidectomy is indicated in:

• Failure of response to anti-thyroid drugs.
• Severe adverse reactions to anti-thyroid drugs.
• Patient refuses radioactive iodine treatment.
• Huge goiter which cause pressure symptoms.
• Suspected malignancy in thyroid gland.

Preoperative preparation:
Chapter 4

• Anti-thyroid drugs to reduce hyperfunction.

• β-blockers to control pulse rate below 80/min.
• Potassium iodide may be given for 2 weeks before surgery.
It reduce intraoperative blood loss.
Complications
A. Hypothyroidism.
B. Risk of hypoparathyroidsm.
C. Recurrent laryngeal nerve damage.
D. Complications of general anesthesia.

D-Adjuvant therapy (β-blockers)

Should be given to:
• All thyroid patients with resting heart rate >90/min.
• Elderly patients with symptomatic thyrotoxicosis.

Toxic multi-nodular goiter

Etiology:
• Occur in patients with long-standing multi-nodular goiter.
• There is constitutive activation of TSH receptors in thyroid
nodules due to mutation in TSH receptor gene.
Clinical picture:

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 Thyroid Disorders 97

• Nodular thyroid enlargement.

• Manifestations of thyrotoxicosis.
• No opthalmopathy or dermopathy

Thyroid scintigraphy:
Heterogenous pattern with areas of hyperactivity (hot areas)
interspersed with hypoactive regions.

Treatment:
• Radioactive iodine
• Surgery (thyroidectomy) if the goiter is large and cause
pressure symptoms.

Chapter 4
Toxic solitary nodule

Autonomous function nodule that produces excessive amount of

thyroid hormones.

Etiology:
Constitutive activation of TSH receptors due to mutation in TSH
receptor gene.

Clinical picture:
• Solitary thyroid nodule.
• Mainfestations of thyrotoxicosis.
• No opthalmopathy or dermopathy

Thyroid scintigraphy:
Hyperactive (hot) area, the rest of the gland is hypoactive
because TSH is suppressed by excessive thyroid hormones.

Treatment:
Radio-active iodine
Surgery: if the nodule is large and cause pressure symptoms.
Sub acute and silent thyroiditis

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 98 Thyroid Disorders

Clinical picture:
• Pain in the neck.
• Tender thyroid gland.
• Mild to severe thyrotoxicosis due to acute release of T4
and T3 into circulation from destructed thyroid follicles.
• Symptoms subside spontaneously over a period of weeks
or months.

Thyroid scintigraphy
• No RAIU
Treatment:
• Anti-thyroid drugs has no role because there is no ↑ in
thyroid hormone synthesis.
Chapter 4

• Symptomatic treatment.

Thyrotoxicosis factitia
Etiology:
Ingestion of large doses of T4 or thyroid hormone preparation
usually for the purpose of weight control.

Clinical picture:
• Manifestations of thyrotoxicosis.
• No goiter
• No opthalmopathy or dermopathy.

Thyroid scintigraphy:
• RAIU is markedly decreased.

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 Thyroid Disorders 99

Thyrotoxic Crisis

Definition: Thyrotoxic crisis also referred to as thyroid storm, is an

acute, rare life-threatening, hypermetabolic state induced
by excessive release of thyroid hormones in individuals with
thyrotoxicosis. It is an endocrinal emergency.

Cause:
• Thyroid storm is precipitated by the following factors in
individuals with thyrotoxicosis:
• Stress
• Sepsis in untreated patients
• Surgery with lack of preoperative preparation

Chapter 4
• Anesthesia induction
• Radioactive iodine (RAI) therapy
• Drugs : anticholinergic and adrenergic drugs such as
pseudoephedrine, salicylates; nonsteroidal anti-inflammatory
drugs [NSAIDs], chemotherapy and iodinated contrast agents
• Diabetic ketoacidosis
• Excessive thyroid hormone ingestion
• Withdrawal of or noncompliance with anti-thyroid
medications
• Direct trauma to the thyroid gland
• Vigorous palpation of an enlarged thyroid
• Toxemia of pregnancy and labor in older adolescents; molar
pregnancy

Clinical picture:
• History: patients may have a known history of thyrotoxicosis.
• General symptoms: hyperpyrexia, sweating, weight loss and
fatigue
• GIT :nausea, vomiting, diarrhea, Jaundice and acute
abdominal pain
• CNS :anxiety altered behavior, seizures, coma, in old age
apathy and bulbar symptoms from myopathy

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 100 Thyroid Disorders

• CVS: tachycardia, Cardiac arrhythmia as supraventricular

arrhythmias are more common, but ventricular tachycardia
may also occur, acute high-output heart failure, hypertension
with wide pulse pressure and later hypotension.
• Thyroid storm may be the initial presentation of
thyrotoxicosis in undiagnosed children, particularly in
neonates.

Management: emergency
Patients with thyroid storm should be treated in an ICU setting
for close monitoring of vital signs and invasive monitoring and
inotropic support.
Chapter 4

a- Anti-thyroid:
• Propylthiouracil: 200-400 mg/8h. (orally,rectally or
nasogstric).
• Propranolol in full dose is started immediately for
tachyrrhthmias (160 mg/d orally or 1 mg/4h IV)
• Na iodide or K iodide: 1 gm over 24h to ↓ release of thyroid
hormones.
• Hydrocortisone: 100 mg/8h IV or IM to ↓ release of T4 &
↓ conversion of T4 to T3 and to correct hypotension
➢ Thyrotoxic crises →↑↑ cortisol metabolism →relative
adrenal insufficiency →refractory hypotension.

B- Symptomatic:
• Antipyretics : ice bags and acetaminophen
• IV fluids for dehydration:
• Digoxin and diuretics for AF& HF
• Nasogastric tube for bulbar palsy, nausea and vomiting

c- Ttt of cause & ppt factors: e.g. antibiotics for infection

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 Thyroid Disorders 101

Struma ovarii (ovarian struma)

Etiology:
Teratoma of the ovary which contain hyperactive thyroid tissue.

Clinical picture:
• Mild thyrotoxicosis
• No goiter
• No opthalmopathy or dermopathy.

Thyroid scintigraphy:
• ↓ RAIU
• Total body scan reveals uptake of radioiodine in the pelvis.

Chapter 4
Thyroid carcinoma
• Follicular thyroid carcinoma rarely secretes thyroid
hormones.
• Metastatic thyroid cancer rarely present with
thyrotoxicosis.

TSH- Producing Pituitary Tumor

Etiology:
• TSH- producing macroadenoma of the pituitary.

Clinical picture:
• Rare.
• Mass effect of the pituitary tumor
• Mild thyrotoxicosis.

Investigation:
• Elevated T4, T3.
• Inappropriate elevation of TSH or within the normal range.

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 102 Thyroid Disorders

Amiodarone induced thyrotoxicosis

High iodine- containing drug , inducing thyroditis.

Hypothyroidism
Definition:
• It is a clinical and biochemical syndrome with manifestations of
thyroid hormone deficiency at target tissues.

Epidemiology:
• Prevalence is 4-8% of general population.
• Female to male ration is 3:1

Causes:
Chapter 4

• Post Thyroiditis
• Post surgical
• Post radioiodine
• Congenital

Presentation according to age:

• Cretinism: onset at infancy
• Juvenile myxedema: onset before puberty
• Adult hypothyroidism (myxedema): onset after puberty

Cretinism:
• Aplasia or hypoplasia of thyroid tissue
• Metabolic (dyshormonogenesis)
• Iodine deficiency
• Use of anti-thyroid drugs or radio iodine during pregnancy.
• Pendred`s syndrome (congenital hypothyroidism and nerve
deafness)

Clinical Picture:
• Subnormal body temperature, poor suckling
• Face: puffy eyes, depressed nasal bridge, macroglossia, thick
lips, delayed dentition

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 Thyroid Disorders 103

• Hands: square shaped

• Disproportionate dwarfism: shorter limbs, upper segment more
than lower segment, and height more than the span.
• Muscle weakness: waddling gait, protuberant abdomen, and
abdominal hernias
• Epiphyseal dysgenesis with thickening of the growing plates of
long bones.
• Skin: dry, rough, scaly, and cold. Deposition of myxomataous
tissue particularly in dorsum of hands, supraclavicular fossa and
face.
• Mental retardation: mental changes are irreversible if
hypothyroid state begins before one and half years, but if later
onset, they are reversible.

Chapter 4
• Cardiovascular: bradycardia, low voltage and ST-T changes in
ECG.

Investigations:
• High serum lipids.
• Epiphyseal dysgenesis on plain X Ray of bones.
• Low thyroid hormones with high TSH.

Screening:
• Screening of umbilical cord (or heel) blood is mandatory for all
newly borne whether delivery occurs at hospital or home,
because diagnosis of neonatal hypothyroidism may be delayed
and thyroid hormones are essential for brain development

Juvenile Myxoedema
• Onset of hypothyroidism in late childhood and before puberty.
• Normal mental functions
• Disproportionate dwarfism
• Epiphyseal dysgenesis
• Delayed puberty or paradoxically sexual precocity.
Adult hypothyroidism (myxoedema)

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 104 Thyroid Disorders

Causes:

A: Primary thyroid failure, thyroprevic:

• Idiopathic
• Thyroiditis:
• Post thyroidectomy
• Post radioiodine
• Goiterogens

B. Secondary thyroid failure (to pituitary failure), thyrotrophic:

C. Tertiary thyroid failure: hypothalamic leions

• Sometimes, causes of pituitary and hypothalamic origin are
Chapter 4

collectively termed " central hypothyroidism"

Clinical manifestations:
• Expressionless apathetic face, with puffy eyes and lost outer third
of eye brows hair.
• Malar flush
• Thickened lips and tongue
• Low body temperature with intolerance to cold weather.
• Skin is thick, dry, scaly, pale and coarse.
• Carotenoderma.
• Weakness, fatigue arthralgia and musculoskeletal pains.
• Slow movements and weight gain.

Cardiovascular manifestations:
• Sinus bradycardia and heart block.
• Pericardial effusion (cholesterol pericarditis), less prone to
produce hemodynamic compromise.
• Enhanced atherosclerosis, affecting coronaries and peripheral
arteries (hypertension, atherogenic lipid profile, and
hyperhomocystienemia)
• Myxoedematous heart disease of ischemic and metabolic
backgrounds.

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 Thyroid Disorders 105

• Hypertension especially diastolic due to invreased peripheral

resistance.
• Cardiomegaly and congestive heart failure.
• Rarely asymmetric septal hypertrophy (ASH).
• ECG changes: sinus bradycardia, prolonged P-R interval, low
volt QRS complexes, ST –T wave changes.

Neurologic manifestations:
• Poor cerebral performance, thinking, memory, and hypersomnia
• Hoarseness of voice, with slurred speech
• Suspended tendon jerks ( delayed muscle relaxation)
• Peripheral neuropathy
• Entrapement neuropathy eg. carpal tunnel syndrome.

Chapter 4
• Muscle hypertrophy involving gastrocnemius, back, and upper
limbs with EMG myopathic changes.
• Myxoedema madness with frank psychosis.
• Myxoedema coma.

Gastrointestinal manifestations:
• Atrophic gastritis with slow gastric motility.
• Atrophic intestinal villi with slow absorption, might lead to
steatorrhea.
• Constipation, megacolon and pseudo intestinal obstruction with
ileus.
• Ascites.

Reproductive manifestations:
• Menstrual disturbances as menorrhagia or oligomenorrhea.
• Subfertility and anovulation.
• Amenorrhea- galactorrhea syndrome
• Spontaneous abortion
• Pregnancy induced hypertension.
• Gynecomastia in males.

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 106 Thyroid Disorders

Urogenital:
• Reduced renal plasma flow and glomerular filtration rate.
• Increased total body water.
• Hyponatremia.
• Syndrome of inappropriate secretion of antidiuretic hormone
(SIADH).

Respiratory manifestations:
• Dyspnea: due to respiratory muscle weakness, cardiomyopathic,
pleural effusion, and pulmonary function abnormalities.
• Sleep apnea: obstructive due to macroglossia and enlarged
pharyngeal muscles, and central component due to reduced
ventilatory drive.
Chapter 4

• Sinusitis.

Metabolic manifestations:
• Slowing of metabolic processes which results in decreased
energy expenditure, oxygen consumption and use of substrate.
• Reduced thermogenesis, decreased appetite, with increased body
fat.
• Hypercholesterolemia, high LDL, high lipoprotein (a) and high
oxidized LDL. Serum cholesterol can be used as a marker for
tissue hypothyroidism i.e. the higher the cholesterol the lower the
thyroid hormones.
• Normal triglycerides or modestly elevated.
• Hyperhomocystienemia

Hematologic manifestations:
• Anemia: normocytic normochromic due to reduced
erythropoietin levels and low oxygen requirements may be iron
deficiency due to blood loss from menstrual troubles, or
macrocytic hyperchromic of associated pernicious anemia.
• Normal leucocytes and platelets.
• Bleeding tendency with prolonged bleeding time
(thromboathenia and low factor VIII).

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 Thyroid Disorders 107

Endocrinal manifestations:
• Decreased HGH secretion due to increased somatostatinergic
tone with resulting decrease of IGF-1.
• Moderate hyperprolactinemia due to high TRH (spill over).
• Wide pituitary fossa due to hyperplasia of pituitary thyrotrophs
which rarely cause distinct pituitary adenoma.
• Reduced bone turnover (decreased activity of osteoblasts and
osteoclasts).
• Decreased metabolic clearance and production of cortisol, with
normal serum cortisol.

Laboratory diagnosis:

Chapter 4
• High TSH and low FT4 in primary hypothyroidism.
• Central hypothyroidism has low TSH and low FT4.
• High TSH but normal FT4 diagnose subclinical
hypothyroidism.

Treatment:
• Replacement therapy with oral levothyroxine sodium in a daily
dose of 1.6 ugm/kg/day. With average 100-200 ug/day.
• Start with a low dose and gradual titration up depending on
severity and duration of hypothyroid state, age of the patient, and
presence of heart disease. In severely hypothyroid, elderly, or
having ischemic heart, start with low dose and titrate slowly.

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 108 Thyroid Disorders

Myxedema coma

• It is a rare, life- threatening clinical condition in patients with

long standing severe hypothyroidism.

Precipitating factors:
• Cold exposure.
• Infections.
• Drugs: diuretics, sedatives and tranquilizers.
• Trauma.
• Surgery.
• Stroke.
• Heart failure and acute MI.
Chapter 4

• GIT bleeding.

Clinical picture:
• The typical patient is elderly woman in winter season.
• Altered thermoregulation with hypothermia.
• Altered central nervous system with disorientation, lethargy,
psychosis and coma.
• Altered cardiovascular system: bradycardia and hypotension.

Laboratory diagnosis:
• Low FT4.
• TSH is usually high.
• CPK is sky high.

Treatment:
• Start with levothyroxine sodium 300-500 ugm IV, then 50-
100ugm/daily till oral therapy can be given. LT3 may be
combined with LT3.
• Hydrocortisone IV 100-200 mg daily in divided doses.
• Supportive measures:
• Hypothermia: blankets.

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 Thyroid Disorders 109

• Hypoventilation: mechanical ventilation.

• Hypotension: whole blood or saline cautiously.
• Hyponatremia: mild fluid restoration.
• Hypoglycemia: glucose IV.

Thyroiditis

Definition: inflammation of the thyroid gland:

Causes and characteristics:

1. Acute: suppurative or pyogenic thyroiditis, which is due to
bacterial infection

Chapter 4
2. Subacute: (de Quervain s) thyroiditis, which results from a viral
infection of the gland: multinuclear giant cells.
3. Chronic (the commonest): autoimmune thyroiditis; Hashimoto s
or atrophic: grossly lymphocytic or fibrotic
4. Others:
- Post- partum thyroiditis: lymphocytic.
- Drug- induced thyroiditis (amiodarone, interferon alpha)
- Radiation thyroiditis.
- Riedel s (chronic fibrosing) thyroiditis: extensive fibrosis.

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 110 Thyroid Disorders

Clinical presentation:

Forms of
Clinical presentation Thyroid function
thyroiditis
Acute: Painful, tender thyroid, Usually normal
suppurative fever
Subacute: (de Painful anterior neck, Early thyrotoxicosis,
Quervain s) preceding URTI, arthralgia,Occasionally late
generalized fatigue. hypothyroidism.
Autoimmune Hashimoto s: goiterUsually hypothyroid
(painless) Sometimes euthyroid
Atrophic: no goiter Rarely early
thyrotoxicosis
Chapter 4

High titres of
antithyroid antibodies
Post-partum Thyroid dysfunction within Transient
the first six month thyrotoxicosis or
hypothyroidism
Riedel s Hard, woody consistency of Usually normal
thyroid

Subacute Thyroiditis
(De Quervain, Acute viral Thyroiditis, Granulomatous
Thyroiditis, migrating Thyroiditis):

Def: acute inflammatory condition due to viral infection.

E.g. Mumps, coxcakie, adenovirus

Pathology: inflammatory reaction involving the capsule, destruction of

thyroid parenchyma, phagocytes.
C/P: fever, local pain in the neck radiating up .
Symptoms of thyrotoxicosis like sweats, palpitation.
On exam. The gland is exquisitely tender but no redness or hotness (
to exclude abscess).
Signs of thyrotoxicity.

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 Thyroid Disorders 111

Lab: initially toxic profile with low RAIU….then recovery …. Or reach

hypothyroid range.
Malignantly high ESR.
Negative thyroid autoantibodies.

ttt: NSAID
Short course of steroids 20 mg tds for a week.
Prognosis: complete resolution in weeks or months
Hypothyroidism in 10% of cases

Chronic Thyroiditis

Synonyms: Hashimoto Thyroiditis, chronic immune thyroiditis,

Chapter 4
lymphocytic thyroiditis:
Is considered the most common cause of hypothyroidism and goiter in
developed countries.
Auto immune thyroid spectrum at one end Graves and the other end
myxoedema.
Toxic Graves…euthyroid Graves….Hashimoto…idiopathic
myxoedema

Pathology: immunologic inflammation with heavy lymphocyte

infiltration.
Lymphoid follicles with germinal center may be found. Follicular
epithelium may be cytoplasm with basophilic cytoplasm (Hurthle cell).

Antibodies: anti TG
Anti peroxidase TPO (formerly called antimicrosomal)
TSH -receptor blocking Ab.
C/P:
painless condition
Goiter
Hypothyroidsm
Lab: normal or hypothyroid profile.
High titer of thyroid auto antibodies: anti TG, TPO.
FINAC: lymphocyte infiltration with Hurthle cells.

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 112 Thyroid Disorders

Complications:
Progressive hypothyroidism
Thyroid lymphoma (rare)… rapid growth inspite of T4 replacement…
diagnosed by surgical biopsy

Prognosis:
Goiter,
Hypothyroidism.
May develop Graves (Hashitoxicosis) with GRO and
dermopathy….Hashimoto blunt the toxic manifestations of Graves =
euthyroid Graves
Chapter 4

Differential diagnosis:
(1)- Other causes of hypothyroidism.
(2)- Other causes of hyperthyroidism.

Treatment
Acute: suppurative: Antibiotic therapy and incision and drainage if
fluctuant area within the thyroid should occur.

Subacute: (de Quervain`s): non- steroidal anti-inflammatory agents

and paracetamol in mild cases.
In severe cases, glucocorticoids can be effective. Propranolol can be
used to control associated thyrotoxicosis. T4 replacement is required if
the patient is hypothyroid.

Autoimmune thyroiditis: T4 replacement in hypothyroid patients.

Post- partum thyroiditis: most patients have a complete remission but

some may progress to permanent hypothyroidism and need for
replacement.

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 Thyroid Disorders 113

Thyroid carcinoma

Types:

type frequency Behavior prognosis

1- papillary 70% Slowly growing, Good
occurring in young
people.
2- follicular 20% Commoner in females Good if
resected
3-anaplastic <5% Aggressive Very poor
4-lymphoma <2% Variable May respond to
radiotherapy

Chapter 4
5- medullary 5% From parafollicular (C) poor
cells, secrete calcitonin,
often familial.

Etiology:
1. Neck irradiation papillary carcinoma.
2. MNG follicular carcinoma.
3. Hashimoto thyroiditis malignant lymphoma.
4. Genetic element Cowden syndrome (well differentiated thyroid
cancer & breast cancer & multiple hematomas).

Clinical picture:

Symptoms: the patient may be present by one of the following:

1. Long standing goiter then recent rapid increase in size, become
painful & the pain is referred to the ear (along the auricular
branch of vagus), invasive symptoms (progressive hoarseness,
dysphagia, dyspnea &hemoptysis).
2. Goiter of recent onset but rapidly growing with pressure &
infiltration symptoms.
3. Solitary thyroid nodule (hard, fixed, >1cm)

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 114 Thyroid Disorders

4. Occult presentation: the pt present by lymphatic or

haematogenous metastasis before the 1ry tumor is discovered
(e.g. lateral aberrant thyroid in papillary carcinoma).
5. Thyrotoxicosis with functioning follicular carcinoma or diarrhea
30% with medullary carcinoma (due to production of PGs or 5
hydroxytyrptamine).

Signs:
a) General examination: for manifestation of metastasis.
b) Local examination:
▪ Thyroid lump: hard, fixed (to the skin, trachea or
sternomastoid may
▪ infiltrate the carotid sheath loss of carotid pulsation (berr`s
Chapter 4

sign).
▪ CX LNS: enlarged >1cm, hard, fixed, not tender.

Investigation:
a- for the 1ry tumor:
- Laboratory:
1- Thyroid function tests.
2- Tumor markers:
▪ [Link]: increase in differentiated thyroid
carcinoma & decrease after resection, if increase
again recurrence.
▪ [Link]: increase in medullary carcinoma.
- Radiological:
• Thyroid scan: cold nodule
• Neck U/S: site, size &nature of the lesion (solid or cystic)
• CT &MRI
• Plain X-ray: punctate calcification, tracheal shift, retrosternal
extension.
- Endoscopic: indirect laryngoscopy for cord mobility
-biopsy
• FNAC
• true-cut needle biopsy.
• Open surgical biopsy.
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 Thyroid Disorders 115

b- for 2ry: metastatic work up e.g. bone survey, chest x-ray, abd. U/S
... etc

Treatment

1- When possible, thyroid carcinoma is treated surgically.

2- 131I therapy is of value if the carcinoma takes up the isotope (only
papillary and follicular types). If the pt had a subtotal thyroidectomy,
remaining thyroid tumor is ablated with high dose of 131I.
Replacement therapy is then given for 6 weeks. it is then stopped to
allow TSH level to rise followed by giving an ablative dose of 131I
to treat metastasis or persistent local disease. this may be repeated

Chapter 4
3-4 monthly as long as isotope scans show persistent metastatic or
local disease. the measurement of thyroglobulin in plasma may be
used as a tumor marker. Levels above 10ug/l indicate a high chance
of remaining disease.
3- Tumors which do not take up I are treated by radiotherapy to the
local tumor.
4- in medullary carcinoma, the patient`s family should be screened for
this tumor and other endocrine malignancies.

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CHAPTER

Adrenal Glands
 Adrenal Glands

Adrenal (Suprarenal) glands

5
Anatomy:

A normal adrenal gland in an adult weighs approximately 4 to 6

grams. The weight of each adrenal may increase by nearly 50 percent
during times of stress and pregnancy. Pathologic glands may reach 700
grams.
The adrenal glands are retroperitoneal and are located on the
superior medial aspect of the upper pole of each kidney. Each gland is
surrounded by a fibrous capsule and comprises an outer cortex and an
inner medulla; the cortex comprises 90% of the adrenal weight while
the medulla about 10%.
Arterial supply: The adrenal glands have a rich, multiple arterial supply
from three main groups of vessels: the superior, the middle and the
inferior suprarenal renal arteries (Right & Left).
Venous drainage:
• Venous drainage of left adrenal gland: The left adrenal
(suprarenal) vein drains into the left renal vein.
• Venous drainage of right adrenal gland: The right adrenal
(suprarenal) vein drains into posterior segment of the inferior
vena cava.

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 Adrenal-Glands 117

Anatomy of adrenal glands

Physiology:
The adrenal glands are composed of two functionally distinct
endocrine units, the adrenal cortex and medulla, contained within a
single capsule. Each has distinct embryologic, anatomic, histological,
and functional characteristics.

Chapter 5
Structure and functional zones of adrenal glands
1-Adrenal cortex function: The adrenal cortex is divided into three
functional zones:
• The zona glomerulosa secretes mineralocorticoids (aldosterone)
which regulate sodium and potassium homeostasis. It is primarily
under the control of the renin-angiotensin system.
• The zona fasciculata secretes glucocorticoids (most importantly,
cortisol). It is regulated by the corticotropin-releasing hormone
(CRH)-corticotropin (ACTH) system (Hypothalamic-pituitary
control).
• The zona reticularis secretes sex steroids
(dehydroepiandrosterone (DHEA), DHEA sulfate and small

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 118 Adrenal-Glands

amounts of testosterone) and it is under the control of ACTH and

perhaps other proopiomelanocortin (POMC)-derived peptides.

• Hypothalamic-pituitary-adrenal axis:
Corticotropin-releasing hormone (CRH) is secreted in the
hypothalamus in response to circadian rhythm, stress and other
stimuli. CRH travels down the portal system to stimulate ACTH
release from the anterior pituitary.
Circulating ACTH stimulates cortisol production in the adrenal.
The cortisol secreted (or any other synthetic corticosteroid
administered to the patient) causes negative feedback on the
hypothalamus and pituitary to inhibit further CRH/ACTH
release. The set-point of this system clearly varies through the
Chapter 5

day according to the circadian rhythm.

• Renin-angiotensin- aldosteron system (RAAS):
The enzyme, renin, is secreted by the kidney in response to
decreased renal perfusion pressure or flow; it cleaves the
angiotensin I from angiotensinogen (hepatic origin). Angiotensin
I is inactive but is further cleaved by angiotensin-converting
enzyme (ACE; present in lung and vascular endothelium) into the
active peptide, angiotensin II, which has two major actions
(mediated by two types of receptor, AT1 and AT2). The AT1
subtype which is found in the heart, blood vessels, kidney,
adrenal cortex, lung and brain mediates the vasoconstrictor
effect. AT2 is probably involved in vascular growth.
Angiotensin II causes rapid vasoconstriction and stimulates the
adrenal zona glomerulosa to increase aldosterone production. As
BP increases and sodium is retained, the stimuli to renin secretion
are reduced.
The renin-angiotensin system can be blocked at several points
with renin inhibitors, angiotensin-converting enzyme inhibitors
(ACEIs) and angiotensin II receptor antagonists (ARBs).

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 Adrenal-Glands 119

Chapter 5
2-Adrenal medulla function: The adrenal medulla synthesizes, stores
and secretes catecholamines, which modulate the body's sympathetic
response to stress. Although the adrenal medulla is not critically
necessary for survival, its secretion of epinephrine and other
compounds helps maintain the body's homeostasis during stress.

Assessment of Adrenal Function

A- Disorders of Glucocorticoids secretion:

1- Plasma cortisol:
The diagnostic utility of single plasma cortisol concentrations is
limited by the episodic nature of cortisol secretion and its appropriate
elevations during stress.
Normal levels:
• Levels at 8 a.m. range from 3 to 20 ug/ dL (80–550 nmol/ L).
• Values obtained later in the day are lower; at 10 p.m. to 2 a.m.,
the plasma cortisol concentrations are usually less than 3 ug/dL
(80 nmol/ L).

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 120 Adrenal-Glands

Levels during stress:

• Cortisol secretion increases in patients who are acutely ill, during
surgery, and following trauma. Plasma concentrations may reach
40–60 ug/dL (1100–1655 nmol/L).
• Midnight serum cortisol level: (blood sample obtained during
sleeping)
• It is highly accurate in differentiating patients with Cushing's
syndrome from normal subjects and from patients with pseudo-
Cushing conditions such as depression or alcoholism.
• Those with Cushing's syndrome have high midnight cortisol
levels > 7 ug/dL (> 100 nmol/L), though the 9 a.m. value may be
normal.
Chapter 5

2-Mid-night salivary cortisol:

Cortisol in the saliva is in equilibrium with the free and
biologically active cortisol in the blood. The normal salivary
cortisol level at midnight is less than 0.15 ug/dL (4 nmol/L).

3- 24h free urinary cortisol:

• Normally, less than 1% of the secreted cortisol is excreted
unchanged in the urine. However, in states of excess secretion,
plasma free cortisol therefore increases, as does its urinary
excretion.
• The normal range for urine free cortisol assayed is 5–50 ug/24 h
(14–135 nmol/24 h). (HPLC method)
• This method is particularly useful in differentiating simple
obesity from Cushing's syndrome, because urine free cortisol
levels are not elevated in obesity.

4- Plasma ACTH:
Normal range: 9–52 pg/mL (2–11 pmol/L).
In adrenal insufficiency:
• Primary adrenal disease: plasma ACTH levels are elevated.

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 Adrenal-Glands 121

• Pituitary ACTH deficiency and secondary hypoadrenalism:

plasma ACTH levels are "normal" or less than 10 pg/mL (2.2
pmol/L).
In Cushing's syndrome:
• Primary glucocorticoid-secreting adrenal tumors: plasma ACTH
is suppressed, and a level less than 5 pg/mL (1.1 pmol/L) is
diagnostic.
• Cushing's disease (pituitary ACTH hypersecretion): plasma
ACTH levels are normal or elevated.
• Ectopic ACTH syndrome: Plasma ACTH levels are usually
markedly elevated.
In Congenital adrenal hyperplasia:
• Plasma ACTH levels are also markedly elevated (common

Chapter 5
forms).

5- Dexamethasone suppression tests:

• Administration of a synthetic glucocorticoid to a normal subject
produces prompt feedback suppression of CRH and ACTH levels
and thus of endogenous cortisol secretion (dexamethasone is not
measured by most cortisol assays). Three forms of the test, used
in the diagnosis and differential diagnosis of Cushing's
syndrome.

6- ACTH stimulation tests:

• Synthetic ACTH is given to stimulate adrenal cortisol
production.

Adrenal suppression and stimulation tests.

Normal test
Test and Measure result or Use and
protocol positive explanation
suppression
Dexamethasone suppression tests (for Cushing's)

Overnight

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 122 Adrenal-Glands

1 mg on at 11 Plasma Plasma Outpatient

p.m. cortisol at 9 cortisol < 100 screening test.
a.m. next nmol/L Some 'false
morning positives'
'Low-dose'
0.5 mg 6-hourly Plasma Plasma For diagnosis of
Eight doses cortisol at 9 cortisol < 50 Cushing's
from 9 a.m. on a.m. on days nmol/L on syndrome
day 0 0 and +2 second sample
'High-dose' used in differential diagnosis
2 mg 6-hourly Plasma Plasma To differentiate
Eight doses cortisol at 9 cortisol on Cushing's disease
from a.m. on days day +2 less (pituitary ACTH
Chapter 5

9 a.m. on day 0 0 and +2 than 50% of hypersecretion)

that on day 0 from ectopic
suggests ACTH and
pituitary- adrenal tumors.
dependent
disease
ACTH (synacthen) (for Addison's)

Short
Tetracosactide Plasma Cortisol at To exclude
250 μg i.v. or cortisol at +30 min > primary adrenal
i.m. at time 0 times 0, +30 600 nmol/L (> failure
min 20ug/dl)
Long
Depot Plasma Maximum > To demonstrate or
tetracosactide 1 cortisol at 1000 nmol/L exclude adrenal
mg i.m. at time times 0, +1, Rise > 550 suppression
0 +2, +3, +4, nmol/L (rather than
+5, +8 and primary adrenal
+24 h failure)

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 Adrenal-Glands 123

7- CT and MRI: useful in localizing adrenal tumors.

8- Inferior petrosal sinus sampling:
Catheters are inserted via the femoral veins into inferior petrosal
sinus where ACTH can be measured directly.
• Difference between petrosal and peripheral vein ACTH levels
indicates pituitary Cushing disease.
• No difference between the two levels indicates ectopic cushing.

B- Disorders of Mineralocorticoids secretion:

Primary hyperaldosteronism can be diagnosed by:
1- Elevated plasma aldosterone level that is not suppressed with 0.9
% saline infusion (300 mmol = 2 liters over 4 hours) or
fludrocortisones administration.

Chapter 5
2- Suppressed plasma rennin activity. Plasma aldosterone: renin
ratio > 30.
3- CT and MRI are useful in localizing adrenal tumors.

C- Disorders of Androgens secretion:

• Androgen excess is usually evaluated by the measurement of
basal levels of these hormones. Assays are available for total
plasma levels of DHEA (Dehyrdroepiandrosterone), DHEA
sulfate, androstenedione, testosterone, and dihydrotestosterone.

D- Disorders of Adrenal medulla:

1- Measurement of urinary catecholamines and metabolites
(preferably metanephrines rather than vanillylmandelic acid
(VMA) - is a useful screening test for Pheochromocytoma. Many
drugs and dietary vanilla interfere with these tests.
2- Plasma chromogranin A (a storage vesicle protein) is also raised
in Pheochromocytoma.
3- MIBG (I131 metaiodobenzylguanidine): for detection of
medullary tumors.

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 124 Adrenal-Glands

Cushing Syndrome

Definition:
Cushing Syndrome refers to a diverse symptom complex
resulting from excess steroid hormone production by the adrenal
cortex (endogenous) or to sustained administration of glucocorticoids
(exogenous). The term “Cushing Disease” refers to over secretion of
ACTH from a pituitary adenoma while “Cushing Syndrome” is caused
by autonomous secretion from the Adrenals independent of ACTH
secretion.

Causes:
• Exogenous glucocorticoid intake ( Iatrogenic Cushing)
Chapter 5

▪ This is by far the commonest cause of Cushing

• ACTH independent Cushing
▪ Overproduction of glucocorticoids may be due to an
adrenal adenoma, adrenal carcinoma, or adrenal
hyperplasia. Glucocorticoid-secreting tumors may secrete
both glucocorticoids and androgens.
• In general, excess androgen secretion is suggestive of an adrenal
carcinoma rather than an adrenal adenoma. These glucocorticoid-
producing tumors do not usually secrete aldosterone,
• ACTH dependent Cushing by pituitary adenoma
▪ Pituitary adenomas that secrete ACTH are derived from
corticotroph cells in the anterior pituitary to produce
hyperplasia and stimulate the secretion of adrenal steroids.
• Ectopic Secretion:
▪ Ectopic ACTH secretion is caused by small-cell lung
tumors, carcinoid tumors, or other tumors with
neuroendocrine origin. These tumors themselves can
secrete ACTH,
▪ Ectopic CRH secretion leading to increased ACTH
secretion comprises a very rare group of cases of Cushing
syndrome.

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 Adrenal-Glands 125

Clinical Picture:
• Obesity:
▪ Generalized obesity in addition to centripetal
▪ Moon facies
▪ Buffalo hump
• Reproductive dysfunction:
▪ Gonadal dysfunction with menstrual irregularity in
females and loss of libido in both sexes
▪ Hirsutism
▪ Acne
• Psychiatric Abnormalities:
▪ Agitated depression
▪ Lethargy

Chapter 5
▪ Paranoia
▪ Overt Psychosis
• Bone:
▪ Osteoporosis
• Skin:
▪ Thinning
▪ Easy bruising
▪ Plethoric appearance
▪ Acne
▪ The typical, almost pathognomonic red-purple livid striae
greater than 1 cm in diameter are most frequently found on
the abdomen, upper thighs, breasts, and arms.
▪ Increased skin pigmentation due to overstimulation of
melanocyte receptors by ACTH
• Muscle:
▪ Myopathy
• Cardiovascular:
▪ Hypertension
▪ Together with other metabolic derangement, as diabetes,
may lead to increased mortality
• Infection:
▪ Fungal
▪ Reactivation of TB

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 126 Adrenal-Glands

▪ Wound infection and impaired healing

• Metabolic and Endocrine:
▪ Impaired glucose tolerance or Diabetes Mellitus
▪ Hypokalemic alkalosis
▪ Hypogonadotropic Hypogonadism ( reversible)
▪ Water retention
• Eye:
▪ Cataract
▪ Raised intra ocular pressure
▪ Exophthalmos because of increased retro orbital fat
Chapter 5

Laboratory Diagnosis :
A. Confirmation of hypercortisolism:
• High urinary free cortisol level and 17–
hydroxycorticosteroids
• Loss of diurnal variation
• Low-dose dexamethasone suppression test: 1mg
dexamethasone orally at 11pm and obtain plasma cortisol
level next morning at 8 am. Normally, the morning cortisol

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 Adrenal-Glands 127

level should be suppressed. In hypercortisolism, it remains

high.

B. Differention of Cushing Syndrome:

• Plasma ACTH level
• High dose dexamethasone suppression test: 8mg
dexamethasone/ day for 2 days are given. This high dose
potent steroid suppresses the cortisol level up to 50% of
the base line in pituitary cause but not in adrenal cause
(ACTH independent)

In addition to
• Hyperglycemia (80%)

Chapter 5
• Eosinophils,  Na+, K+

Radiological Diagnosis for Localisation

• Pituitary MRI with contrast
• Suprarenal CT
• Chest X-Ray or other radiology accordingly in case of ectopic
Cushing

Differential Diagnoses:
• Pseudo-Cushing Syndrome
• Depression
• Obesity
• Alcoholism
• Psychiatric Illness
• Anorexia Nervosa
• Bulimia Nervosa

Treatment
Surgical
• The treatment of choice for endogenous Cushing
syndrome is surgical resection of the causative tumor of
the pituitary by transsphenoidal approach. Successful

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 128 Adrenal-Glands

amelioration of hypercortisolism occurs in 60-80% of

cases.
• The primary therapy for adrenal tumors is bilateral
adrenalectomy.
• In ectopic Cushing surgical resection of the source of
ACTH .

Irradiation
• Irradiation of the pituitary could be reverted to when
transsphenoidal surgery is not successful or not possible.
It is less successful than surgery in adults, with a 40-50%
cure rate in adults and 85% cure rate in children. Late-
onset adverse effects include hypopituitarism.
Chapter 5

Medical
• When surgery is not successful or cannot be undertaken,
Medications used in the management of Cushing
syndrome include the following:
• Somatostatin analogs: Pasireotide
• Adrenal steroid inhibitors: Metyrapone, ketoconazole,
etomidate
• Glucocorticoid receptor antagonist: Mifepristone
• Adrenolytic agents: Mitotane

Postoperative management:
• Regardless of the adenoma's location, most patients will
require steroid replacement postoperatively at least in the
interim as long-term suppression of pituitary ACTH and
normal adrenal tissue does not recover immediately.
• Clearly, if both adrenals are removed, replacement with
prednisolone is a lifelong treatment.

Suprarenal failure
• Incidence : 3-4/ million/ year
• Prevalence : 40-60/ million
• More common in females
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 Adrenal-Glands 129

Primary Adrenal Insufficiency

In this condition there is complete destruction of the adrenal cortex

Causes:
• Autoimmune disease is the most common cause (90%) as
autoimmune adrenalitisor part of multiple polyglandular
autoimmune syndromes
• Tuberculosis (<10%)
• All other causes are rare such as:
Bilateral adrenalectomy
Infiltration: Sarcoidosis, amyloidosis, hemochromatosis,
Metastatic neoplasia
Hemorrhage (meningococcemia, anticoagulants, and trauma)

Chapter 5
Adrenal leukodystrophy
Acquired immunodeficiency syndrome

Secondary adrenal insufficiency

Causes:
• Following discontinuation of exogenous glucocorticoids or
ACTH for non-endocrinal disease leading to hypothalamic-
pituitary- adrenal axis suppression. the most common cause
• Following the cure of Cushing's syndrome
• Pituitary and hypothalamic lesions with inadequate ACTH
production such as
• Tumors
• Inflammation
• Infections
• Autoimmune lesions
• Granulomatous infiltration
• Trauma
• Pituitary-hypothalamic surgery or radiation
• Pituitary-hypothalamic hemorrhage (apoplexy)

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 130 Adrenal-Glands

Clinical picture
Symptoms
Vague and non-specific such as:
• Weight loss, Weakness
• Nausea, Vomiting, Anorexia, Malaise, Diarrhea
• Depression
• Impotence, Amenorrhea
• Salt craving
• Syncope from postural hypotension
• Abdominal pain
• Myalgia
Signs
• Postural hypotension: grey brown in over 90% of cases specially
Chapter 5

in New scars and Palmar crease and Buccal pigmentation

• Postural hypotension due to hypovolemia and sodium loss in 80-
90% of cases
• Loss of weight and General wasting
• Dehydration
• Loss of body hair
• Vitlligo if autoimmune
Investigation
• Low cortisol level: < 100nmol/l is Highly suggestive
• Short ACTH stimulation test: absent cortisol response Confirm
hypoadrenalism but Doesn’t differentiate Addison from ACTH
deficiency or iatrogenic suppression
• Plasma ACTH: High level (>80 ng/L) confirm 1ry adrenal
failure
• Long ACTH stimulation test Exclude adrenal suppression by
steroid or ACTH deficiency
• Serum aldosterone is reduced with high plasma renin activity
• Electrolytes shows Increased potassium, Low serum sodium
• Blood picture for decreased lymphocyte and eosinophil count
• May be hypoglycemia
• Chest X ray and Abdominal x-ray may show evidence of TB or
calcified adrenals
• Abdominal CT scan

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 Adrenal-Glands 131

Treatment of Hypo-adrenalism
• Replacement corticosteroids by Combination of glucocorticoids
(cortisone or hydrocortisone) and mineralocorticoids
(fludrocortisone).
• If Secondary hypoadrenalism is part of panhypopituitarism
Cortisol should be started before thyroxine therapy

Acute Hypoadrenalism(Addisonian crisis)

Life threatning condition which require urgent treatment with 100
mg IV hydrocortisone when suspected after a blood sample is
withdrawn to for later measurement of plasma cortisol
• several litres saline to treat dehydration and IV hydrocortisone
every 6 hours

Chapter 5
• Glucose infusion for hypoglycemia
Then shift to Oral replacement 20 mg hydrocortisone every 8
hours

Patient advice
• Never skip doses because it is life-threatening
• may increase dose because of: Infection, Injury, Stress and
Surgery
• Carry steroid card or wear Medic-Alert bracelet
• Keep ampule hydrocortisone at home

Primary Hyperaldosteronism

• Signs and Symptoms in Primary Hyperaldosteronism

• The condition of excess aldosterone secretion may result in
Hypertension with Hypokalemia

Causes
• Adrenal adenoma (Conn's syndrome)
• Bilateral adrenal hyperplasia

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 132 Adrenal-Glands

Clinical picture
• Hypokalemic alkalosis manifested by: episodic weakness,
Paresthesias, transient paralysis and tetany
• Diastolic hypertension with headache
• Hypokalemic nephropathy with polyuria & polydipsia

Investigation
• Plasma aldosterone: renin ratio (ARR): frequently used as a
screening test for the condition, but raised ARR alone does not
confirm the diagnosis. Drugs such as aldosterone antagonist and
angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs) may affect results.
• Elevated plasma aldosterone levels that are notsuppressed with
Chapter 5

0.9% saline infusion or fludrocortisone administration.

• Suppressed plasma renin activity
• Hypokalaemia is often present with high Urinary potassium
• Abdominal computed tomography (CT) scanning and MRI

Treatment
– surgical for adenoma
– medical for hyperplasia with spironolactone and aldosterone
receptor antagonist eplerenone

Pheochromocytoma

• is a rare, catecholamine-secreting tumor derived from chromaffin

cells
• Over 90% of pheochromocytomas are located within the adrenal
glands
• Extra-adrenal pheochromocytomas develop in the
paraganglionchromaffin tissue of the sympathetic nervous
system.
• 0.01-0.1% of hypertensive population

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 Adrenal-Glands 133

Clinical picture
▪ Due to catecholamine excess and frequently is intermittent
Symptoms
• Headache and flushing
• Diaphoresis
• Palpitations
• Tremor
• Nausea
• Weakness
• Anxiety and panic attacks
• Epigastric and flank pain
Signs
• Hypertension (paroxysmal in 50% of cases)

Chapter 5
• Postural hypotension (from volume contraction)
• Tachyarrhythmias
• Complications of hypertension as Hypertensive retinopathy,
Pulmonary edema
• Weight loss
• Pallor or flushing
• Neurofibromas
Pheochromocytoma Paroxysms: attacks of palpitation, sweating and
hypertension which could start Spontaneous or Precipitated by Drugs
or Strenuous exercise

Diagnosis
• Measurement of 24h urinary catecholamine and metabolites such
as metanephrines, vanillymandelic acid (VMA) is useful
screening test
• Raised plasma catecholamine
• Clonidine suppression: pheochromocytoma patients won’t
suppress their plasma norepinephrine with clonidine
• CT abdomen to localize tumour
• MRI more sensitive
• MIBG Scan (123I or 131I labelledmetaiodobenzylguanidine)
specially in extra-abdominal tumour

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 134 Adrenal-Glands

Management
• Tumors should be removed surgically if resectable
• Medical Pre operative treatment is mandatory with Combined 
and blockade
• Alpha blockade must precede beta blockade to avoid severe
hypertension
• If operation is not possible: long term Combined  and 
blockade can be used
Chapter 5

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CHAPTER

Reproduction
 Reproduction
6
Physiologic Actions of Gonadal and Placental Hormones
Male gonadal hormones:
• The primary hormone produced by the male testes is testosterone, a
steroid hormone important in:
a. The development of the male reproductive system,
b. The maturation of sperm cells,
c. The development of male secondary sex characteristics such
as a deepened voice, body hair, frontal balding and increased
muscle mass.
d. The maintenance of libido
and it has anabolic effect
• In addition, the testes produce the peptide hormone inhibin, which
inhibits the secretion of FSH from the anterior pituitary gland.
• FSH stimulates spermatogenesis.

Female gonadal hormones:

• The primary hormones produced by the ovaries are estrogens, which
include estradiol, estriol, and estrone.
• Estrogens play an important role in:
The development of the female reproductive system,
Regulation of the menstrual cycle,
The development of female secondary sex characteristics such as
increased adipose tissue and the development of breast tissue and
nipple, growth of pubic hair and the maintenance of pregnancy.
• Another significant ovarian hormone is progesterone, which
contributes to regulation of the menstrual cycle and is important in
preparing the body for pregnancy as well as maintaining pregnancy.
• In addition, the granulosa cells of the ovarian follicles produce
inhibin, which inhibits the secretion of FSH.

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 136 Reproduction

Puberty & its Disorders

Normal Puberty

Definition
Puberty is a physiological phase lasting 2 to 5 years, during
which the genital organs mature & secondary sex characters appear and
fertility is acquired.
Adolescence is the period of life during which the child becomes
an adult person i.e. the physical, sexual and psychological development
are complete.

Puberty represents the first part of adolescence

Chapter 6

The maturation of the hypothalamic pituitary gonadal (HPG) axis

is depend upon GnRH secretion, FSH and LH secretion from pituitary
& sex hormones gonadal secretion.

• Adrenarche: onset of adrenal androgen production and signals

the onset of puberty
• Thelarche: Onset of breast bud development - an estrogen
induced effect. Average - 10.8 yrs
• Pubarche: onset of pubic hair growth under influence of
androgen. Age-11.0 in female; 11.6 in males
• Menarche: onset of menstrual flow. Average age is 12.8 years
in the US
• Spermarche: first ejaculation - typically occurs by age 15

Female Secondary sex characteristics & genital growth

• Growth spurt
• Breast development
• Feminine Fat deposits
• Pubic hair then later axillary hair
• Body odor & acne
• Vagina & uterus enlarge
• Menarche

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 Reproduction 137

Male Secondary sex characteristics & genital growth

• About 2 years behind girls
• Growth of Genital Organs
• Nocturnal emission
• Pubertal Gynecomastia
• Acne and body odor
• Deepening voice
• Increased ms mass
• Pubic hair and later, facial hair
• Amount of body hair is hereditary
• Capable of ejaculation

Premature (precocious) puberty

Chapter 6
• Definition: Signs of puberty start in female <8; MALE <9 years
• Progression is variable or not as usual events
• Most serious effect: short stature (50%)
• Intellectual, psychosocial development follows chronologic age,
not stage of puberty
• Occurs 5 times greater in girls than boys
• Almost 75% of precocity in girls is idiopathic

Delayed puberty and Hypogonadism

• Definition: Absence of signs of puberty in female >13; MALE
>14 years.
It is either:
Delayed onset: in girls, breast bud does not appear till 13 years or
menarche does not occur till 16 years, and in boys, no secondary sex
characteristics till 14y. or
Delayed progression: in girls, menarche does not occur within 5 years
after breast bud, and boys should reach stage 5 pubertal development
4.5y after onset
Types
1- Constitutional delay in growth & development
2- Hypergonadotropic Hypogonadism
• Gonadal Dysgenesis e.g.

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In Males: Klinefelter’s Syndromes

In Femals: Turner‘s syndrome
• Other forms of primary gonadal failure e.g, Autoimmune,
trauma, Chemotherapy, radiation therapy

3- Hypogonadotropic Hypogonadism: may be

• Reversible as:
- Weight loss/anorexia
- Primary hypothyroidism
- Prolactinoma
• Irreversible as:
- Hypopituitarism, pituitary adenomas, malignant pituitary
tumors.
Chapter 6

- Craniopharyngioma.
- Congenital CNS defects (Kallmann’s syndrome)

4- Eugonadism
• Mullerian Agenesis
• Vaginal Septum
• Imperforate Hymen
• Androgen Insensitivity Syndrome

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 Reproduction 139

Approach to patient with delayed puberty and hypogonadism

1- Complete history & physical examination
2- X-rays for bone age
3- Skull imaging (if hypogonadotropic)
4- GnRH, LH, FSH prolactin, TSH levels
5- Appropriate adrenal and gonadal steroid levels
6- Patients with elevated gonadotropins need karyotype
7- IGF-1 (determines whether delayed puberty vs. growth hormone
deficiency)

Turner syndrome
• Affects females only, 1:2500; karyotype 45 XO.

Chapter 6
• Characteristics:
• Short stature, short neck with webbed appearance, low hairline
at the back of the neck, low set ears
• High palate, Cubitus valgus & Shortened fourth metacarpal
• Fail to develop breasts at puberty
• Incomplete ovary development: do not menstruate
• Internal genital organs do not develop normally
• Streak gonads
• Diagnosis by karyotype analysis, Normal intelligence

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Chapter 6

Klinefilter Syndrome
• Affects males only, 1:500 to 1:1000, often asymptomatic.
“karyotype 47 XXY”.
Characteristics:
• Small external genitalia, sterile.
• Small, firm testes and very low sperm count, increased leg
length, Gynecomastia.
• Feminized appearance: slightly curved hips and waist, lack of
body or facial hair, taller & overweight
• Diagnosis by karyotype of peripheral leukocytes

Kallman s Syndrome
• 1:10.000 in boys and 1:50.000 in girls
• Isolated LHRH deficiency (IHGH)
• Anosmia or hyposmia
• In infancy: micro phallus, cryptorchidism

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 Reproduction 141

• Tall, eunuchoid body proportions (long legs, long arms) since

minimal (adrenal only) testosterone production; minimal body
hair
• No karyotype needed for diagnosis, since 46XY
• Normal mental development
• Associated midline defects; Neurologic abnormalities (visual),
Renal anomalies or Midfacial defects
• MRI: aplasia or hypoplasia of olfactory bulbs

Amenorrhoea & Oligomenorrhoea

Definition:

Chapter 6
Amenorrhoea: is absence of periods, it may be either primary
(meaning a woman never developed menstrual periods) or secondary
(absence of menstrual periods in a woman who was previously
menstruating).
Oligomenorrhoea: Are markedly irregular long infrequent periods
often above 32 days

Causes:
Pregnancy:

Polycystic ovary syndrome

Polycystic ovary syndrome is the most common cause of
oligomenorrhoea and amenorrhoea in clinical practice.

Weight-related amenorrhoea
a- anorexia nervosa
A minimum body weight is necessary for regular menstruation.
Amenorrhea is common in anorexia nervosa which the extreme form of
weight loss. It is possible that alterations in leptin levels are responsible
for the hypothalamic dysfunction seen in this situation. Restoration of
body weight is usually effective in restoring menstruation.
b- Intensive physical training in athletes and dancers.

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Hypothalamic amenorrhoea
Amenorrhoea with low oestrogen and gonadotrophins in the absence of
organic pituitary disease, weight loss or excessive exercise is described
as hypothalamic amenorrhoea. This may be related to ‘stress’, to
previous weight loss or stopping the contraceptive pill, but some
patients appear to have defective cycling mechanisms without apparent
explanation.

Hypothyroidism
Oligomenorrhoea and amenorrhoea are frequent findings in severe
hypothyroidism in young women.

Genital tract abnormalities: such as an imperforate hymen, cause

Chapter 6

primary amenorrhoea.

Severe illness: even in the absence of weight loss, can lead to

amenorrhoea.

Turner’s syndrome

Investigations
• Basal levels of FSH, LH, oestrogen and prolactin allow initial
distinction between primary gonadal and hypothalamic–pituitary
causes.
• Ovarian biopsy may occasionally be necessary to confirm the
diagnosis of primary ovarian failure, although elevation of LH
and FSH to menopausal levels is usually adequate.

Treatment
• Treatment is that of the cause wherever possible (e.g.
hypothyroidism, low weight, stress, excessive exercise).
• Primary ovarian disease is rarely treatable except in the rare
condition of ‘resistant’ ovary, where high-dose gonadotrophin
therapy can occasionally lead to folliculogenesis.

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 Reproduction 143

• Hyperprolactinaemia should be corrected. In all other cases

oestrogen replacement is usually indicated to prevent the long-
term consequences of deficiency.

Hirsutism
Definition:
Excessive growth of terminal hair in a female in androgen
dependent areas.

Pathophysiology:
Vellus hairs are fine, lightly pigmented hairs that cover most of
the body before puberty.

Chapter 6
Pubertal androgens promote the conversion of these vellus hairs
to coarser, pigmented terminal hairs. However, some terminal hair
growth is androgen-independent (eg, scalp, eyebrows, lashes).

Dihydrotestosterone is the androgen that acts on the hair follicle

to produce terminal hair. This hormone is derived from both the
bloodstream and local conversion of a precursor, testosterone.
The local production of dihydrotestosterone is determined by 5-alpha-
reductase activity in the skin. Differences in the activity of this enzyme
may explain why women with the same plasma levels of testosterone
can have different degrees of hirsutism.
The level and duration of exposure to androgens, the local 5-alpha-
reductase activity, and the intrinsic sensitivity of the hair follicle to
androgen action determine the extent of conversion from vellus to
terminal hair.

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Causes:
1. Endocrine-related causes include:
a. adrenocortical disorders as Cushing syndrome, and CAH
b. ovarian disorders: Tumors (malignant or benign)
and PCOS
2. Medication-related as Anabolic steroids, Danazol,
Metoclopramide and Methyldopa.
3. Idiopathic hirsutism is is a diagnosis of exclusion and believed to
be due to cutaneousincrease activity of 5-œ-reductase or
enhanced skin sensitivity to androgen.
4. Familial hirsutism is a higher tendency to have a higher density
of hair follicles per unit area of skin.
• Patients with idiopathic or familial hirsutism usually have
Chapter 6

the onset of hirsutism shortly after puberty with a slow

subsequent progression.
• They have normal menses and fertility, as well as a normal
hormonal profile.

Polycystic ovary syndrome (PCOS)

PCOS is the most common ovarian disorder associated with hirsutism.
PCOS is characterized by multiple small cysts within the ovary (which
represent arrested follicular development) and by excess androgen
production from the ovaries.
However, the basic abnormalities in PCOS are functional, rather than
anatomic, in nature. In particular, levels of luteinizing hormone (LH)
are tonically elevated (with LH levels higher than those of follicle-
stimulating hormone (FSH).
PCOS present with amenorrhea/oligomenorrhea, hirsutism and acne
shortly after menarche and increase slowly and steadily in the teens and
twenties.

PCOS is frequently associated with:

• Elevated plasma insulin levels and insulin resistance.
• Hypertension, hyperlipidaemia and increased cardiovascular risk

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Clinical evaluation
Primary objective:
1. Confirm diagnosis
2. Determine degree
3. Exclude life threatening diseases

History
• Onset, progression & duration :
Rapidly progressive virilization: androgen secreting tumor
• Menstrual history :
PCOS, Pregnancy
• Family history :
Hair patterns are similar in families

Chapter 6
• Drug intake
• Symptoms of Cushing syndrome, prolactinoma or
hypothyroidism Laboratory Studies

Examination
General:
• Signs of virilization
• Obesity
• Cushing syndrome
• Thyroid disease
• Signs of insulin resistance e.g. acanthosis nigricans
• Breast:Galactorrhea {Hyperprolactinaemia can be accompanied
by increase in adrenal androgen}
• Pelvic:for masses

Degree of hirsutism
Scoring systems (Ferriman & Gallwey)

Laboratory studies
• Testosterone: The most important assay is the level of serum
testosterone. If the total serum testosterone level is normal,
measure the free serum level because hyperandrogenism (and

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 146 Reproduction

insulin resistance, if present) decreases sex steroid-binding

globulin.
• Dehydroepiandrosterone sulfate (DHEAS): elevated plasma
levels of DHEAS, an androgen synthesized almost exclusively
by the adrenal cortex, can indicate excess adrenal function.
Elevations in both testosterone and DHEAS suggest an adrenal
origin, whereas an isolated testosterone elevation indicates an
ovarian source.

Other laboratory tests include the following:

• Serum prolactin or FSH: Women with hirsutism and amenorrhea
of unknown cause should have a serum prolactin or FSH test to
evaluate for either a prolactinoma or ovarian failure.
Chapter 6

• Diabetes screening: Women with hirsutism, PCOS, obesity, or

acanthosis nigricans may have insulin resistance, and screening
for diabetes and hyperlipidemia is warranted.

Imaging Studies
• ovarian ultrasonography
• adrenal computed tomography scanning or magnetic resonance
imaging to evaluate for either ovarian or adrenal sources of
androgen production.

Treatment
Medical Care
I. General
• Reassurance:
Explain the condition, treatment regimen & the time
required
• Stop smoking
• Weight reduction:
II. Specific
I. Ovarian suppression:
OCPs: suppress ovarian androgen & ↑SHBG
II. Antiandrogens:

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 Reproduction 147

1. Spironolactone:in daily doses of 50-200 mg, blocks androgen

receptors. Spironolactone also decreases testosterone production
2. Cyproterone acetate:(teratogenic)
3. Flutamide

III. 5 alpha reductase inhibitors: Finasteride

IV. Insulin sensitizer: Metformin

III. Local
• Suppress hair growth: EflornithineHydochloride (Vaniqa)
• Remove hair pigment: Bleaching
• Temporary depilation: shaving, chemical depilators
• Temporary epilation: plucking, waxing

Chapter 6
• Permanent removal: Electrolysis, Laser hair removal system
•
Gynaecomastia

Definition:

Is the development of breast tissue in a male (usually bilateral but

sometimes unilateral).
• In approximately 25% of cases, the cause of gynecomastia is
unknown.
• About 10-25% of cases are estimated to result from the use of
certain medications.
• Pubertal gynecomastia occurs in perhaps 50% of normal boys,
often asymptomatic and usually resolve spontaneously within 6-
18 ms.
• In older male, gynecomastia requires a full assessment to exclude
potentially serious underlying ds such as bronchial carcinoma
and testicular tumors

Signs and symptoms:

Gynecomastia is defined clinically by the presence of a rubbery or firm
mass extending concentrically from the nipples.

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 148 Reproduction

• Gynecomastia should be differentiated from

pseudogynecomastia (lipomastia), which is characterized by fat
deposition without glandular proliferation.

Causes
• Physiological: Neonatal, pubertal, old age
• Hyperthyroidism
• Renal disease
• Liver disease
• Hypogonadism
• Oestrogen producing tumours (testis, adrenals)
• HCG- producing tumours (testis, lung)
• Starvation/refeeding
Chapter 6

• Carcinoma of the breast

• Drugs:
▪ Oestrogenic (oestrogen, digitalis)
▪ Antiandrogen (spironolactone, cimitidine)
▪ Others (cytotoxics, gonadotropins)

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CHAPTER

Calcium bone
 Calcium bone

Calcium Homeostasis
7
• Normal serum Ca is 8.5 -10.5 mg -It is subdivided into:
1-Ionized Ca: 50 %
- Biologically active form responsible for Ca action.
2-Non-ionized Ca: 50 % subdivided into:
A- Protein bound: (40 %) of no physiological significance
B- Ca complexes in bones & teeth: (10 %)
• Corrected serum Ca for serum albumin
= Serum Ca in mg% + 0.8 x (4 - albumin in gm %)
• Serum Ca Control:
Serum Ca – PO4 solubility product is kept constant (around 40)
by the interaction of hormones & pH of blood:
1-Parathormone (PTH): (N. 0. 1 -1 ng /ml) Ca&Po4
- Secreted from parathyroid gland in response to hypocalcemia to
act on:
A-Intestine: Ca absorption through conversion of 25-OH
cholecalciferol into 1.25 Dihydroxycholecalciferol
B-Kidney: Ca reabsorption & phosphate reabsorption.
C-Bone: osteoclast activity (resorption causing serum Ca)
2-Vitamin D:Ca& Po4 by acting on:
A-Intestine: Ca absorption
B-Kidney: -small dosePO4 retention
-large dose PO4 excretion
C-Bone: - in normal  bone resorption&Ca
- In rickets  Ca deposition
3-Calcitonin: Ca& P04 (bone resorption)
- Secreted from parafollicular (C-cells) of thyroid gland.
-Osteoclastic bone resoption
-  Renal excretion of Ca& Po4

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 150 Calcium Bone

4-Acid-base balance:
- Acidosis  ionized Ca
- Alkalosis  ionized Ca
5- Glucocorticoids:
- Ca& P04 absorption causing steroid induced osteoporosis.
6-T3&T4:
-  Bone mineral density osteoporosis in hyperthyroidism.
7-Growth hormone:
- Acting through insulin like growth factor-1 to maintain
normal bone mass.
- stimulate 1, 25 Dihydroxycholecalciferol production which
stimulates calcium absorption by gut.
8- Sex steroids:
Chapter 7

- Bone formation over resorption by direct effect on

osteoblast.
9- PTH related peptide:
- Produced by some malignant tumorshypercalcemia.

Hyperparathyroidism

Introduction:
Parathyroid hormone (PTH) is a polypeptide secreted from the
parathyroid glands in response to a decrease in the plasma
concentration of ionized Ca2+. PTH acts to increase the plasma
Ca2+ concentration in three ways:
1- It stimulates bone resorption.
2- It enhances intestinal Ca2+ and phosphate absorption.
3- It augments active renal Ca2+ reabsorption.

Definition:
Hyperparathyroidism means abnormal increase in PTH
secretion.

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 Calcium Bone 151

Causes:

(A) Primary hyperparathyroidism:

Sporadic solitary adenomas account for about 80 to 85 percent of cases
of primary hyperparathyroidism. Multiple gland hyperplasia accounts
for approximately 10 to 15 percent, double adenomas for an additional
2 to 5 percent, and parathyroid carcinoma for about 1 percent of cases
of primary hyperparathyroidism.

(B)Familial:
In this condition hyperparathyroidism occurs in the context of three
autosomal dominant inherited diseases:
1. Multiple endocrine neoplasia type 1(parathyroid, pancreas

Chapter 7
and pituitary.
2. Multiple endocrine neoplasia type 2a (parathyroid,
pheochromocytoma and thyroid medullary carcinoma)
3. Familial hypocalciuric hypercalcemia (FHH). Characterised
by hypocalciuria, mild PTH elevation and mild
hypercalcemia.

(C)Tertiary hyperparathyroidism:
This occurs following secondary hyperparathyroidism in case of CRF
due to prolonged PTH stimulation leading to development of
autonomous adenoma.

Clinical picture:
1. The most common clinical presentation of primary
hyperparathyroidism (PHPT) is asymptomatic hypercalcemia
detected by routine biochemical screening.
2. Symptoms and signs of hypercacemia:
Renal manifestations: polyuria, polydypsia, nephrolithiasis,
nephrocalcinosis, nephrogenic diabetes insipidus and renal
tubular acidosis.
Neuropsychatric manifestations: lack of concentration, confusion,
stupor and coma.

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 152 Calcium Bone

Gastrointestinal manifestations: anorexia, nausea, vomiting, peptic

ulcer, pancreatitis and conistipation.
Musculoskletal manifestations: muscle weakness, bone pain,
osteoporosis and osteitis fibrosa cystica.
Cardivascular manifestations: hypertension, bradycardia and
shortened QT interval.

Diagnosis:
1-Elevated PTH
2-Hypercalcemia
3-Hypophosphatemia
4-Detection of adenoma in isotopic scanning of parathyroid gland
5- Detection of osteitis fibrosa cystica, osteoporosis, kidney stones
Chapter 7

or
nephrocalcinosis in x-ray.
6- Other hormonal assay if MEN is suspected

Differential Diagnosis:
1. Clinical findings that favor the diagnosis of primary
hyperparathyroidism include an asymptomatic patient with
chronic mild hypercalcemia, a postmenopausal woman, a
normal physical examination, no other obvious cause of
hypercalcemia (such as sarcoidosis), no family history of
hyperparathyroidism, and no evidence of multiple endocrine
neoplasia.
2. Differentiate between primary, tertiary and familial
hyperparathyroidism.
3. Exclusion of other causes of hypercalcemia.
Secondary hyperparathyroidism: it is characterized by elevated
plasma PTH, hypocalcemia and hyperphosphatemia.

Treatment of hyperparathyroidism:
1- Lowering of serum calcium: (see treatment of hypercalcemia).
2- Treatment of the cause: (surgical removal of adenoma in primary
hyperparathyroidism, tertiary hyperparathyroidism and MEN).

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 Calcium Bone 153

Hypercalcemia
Definition:
Hypercalcemia is a relatively common clinical problem. It results when
the entry of calcium into the circulation exceeds the excretion of
calcium into the urine or deposition in bone.

Pathogenesis of hypercalcemia:
Hypercalcemia occurs when there is accelerated bone resorption,
excessive gastrointestinal absorption, or decreased renal excretion of
calcium.
(A)-Increase bone resorption:
1- Primary hyperparathyroidism (Parathyroid adenoma).

Chapter 7
2- Tertiary hyperparathyroidism (CRF).
3- Malignancy.
4- Thyrotoxicosis.
5- Other less common causes include: Immobilization, Paget
disease of bone,
antiestrogen (such as tamoxifen); and Hypervitaminosis A.

(B)- Increase calcium absorption:

1- Increase dietary calcium intake.
2- Excessive calcium supplementation.
3- Milk alkali syndrome (High intake of milk or calcium carbonate
in antiacids leading to hypercalcemia, metabolic alkalosis, and
renal insufficiency).
4- Hypervitaminosis D (vitamin D fortified milk or calcitriol in high
doses).

Causes of hypercalcemia:
Hypercalcemia can be produced by a variety of disorders, but primary
hyperparathyroidism and malignancy account for more than 90% of
cases.
(A) PTH-mediated hypercalcemia:
(1) Primary hyperparathyroidism (sporadic).
(2) Familial:-

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 154 Calcium Bone

MEN-I and –IIa.

FHH (Familial hypocalciurichypercalcemia).
(3) Tertiary hyperparathyroidism.

(B) PTH-independent hypercalcemia:-

(1) Hypercalcemia of malignancy: this usually occur due to
increased PTHrp, activation of extrarenal 1 alpha-
hydroxylase with increased calcitriol production or osteolytic
bone metastases.
(2) Vitamin D intoxication.
(3) Chronic granulomatous disorders as TB or Sarcoidosis
through activation of extrarenal 1 alpha-hydroxylase
(increased calcitriol).
Chapter 7

(c) Medications:-
• Thiazide diuretics.
• Lithium.
• Excessive Vitamin A.
• Theophylline toxicity.
(D)Miscellaneous:-
• Hyperthyroidism.
• Acromegaly.
• Pheochromocytoma.
• Adrenal insufficiency.
• Immobilization.
• Parenteral nutrition.
• Milk alkali syndrome.

Clinical manifestation:

The symptoms and signs associated with hypercalcaemia are typically

independent of the etiology.
• Mild hypercalcemia: Serum calcium <12 mg/dl may be
asymptomatic, or they may report nonspecific symptoms, such
as constipation, fatigue, and depression.

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 Calcium Bone 155

• Moderate hypercalcemia: Serum calcium of 12 to 14 mg/dL

may be well-tolerated chronically, while an acute rise to these
concentrations may cause marked symptoms, including polyuria,
polydipsia, dehydration, anorexia, nausea, muscle weakness, and
changes in sensorium.
• Severe hypercalcemia: calcium >14 mg/dL, there is often
progression of these symptoms. The symptoms and signs of
hypercacemia include:

1- Neuropsychiatric Disturbances:
Anxiety, depression, cognitive dysfunction, lethargy, confusion,
stupor, and Coma.

Chapter 7
2-Gastrointestinal Abnormalities:
Constipation, anorexia, nausea and Peptic ulcer disease.
Hypercalcemia due to primary hyperparathyroidism may
causePeptic ulcer disease as calcium-induced increases in gastrin
secretion. In patients with MEN1 coexisting Zollinger-Ellison
syndrome may be present.

3- Renal Dysfunction:
Hypercalcemia may cause polyuria, nephrogenic diabetes insipidus
and nephrolithiasis. Long-standing hypercalcemia and
hypercalciuria may lead to calcification, degeneration, and necrosis
of the tubular cells, and eventual tubular atrophy and interstitial
fibrosis and calcification (nephrocalcinosis).

4- Musculoskeletal Symptoms:
Profound muscle weakness, Bone pain due to reduction in
cortical bone mass may occur in individuals with
hyperparathyroidism.

5- Cardiovascular Disease:
Acute hypercalcemia: - shortened QT interval, arrhythmia and
ST-segment elevation.

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 156 Calcium Bone

Long-standing hypercalcemia: Deposition of calcium in blood

vessels, cardiac valves, coronary arteries, and myocardial fibers may
lead to hypertension; and cardiomyopathy.

Labotatory evaluation and Diagnosis:

• Serum calcium should be corrected for albumin, and an
elevated concentration should be confirmed by repeat
sampling.
• The initial goal of the laboratory evaluation is to assay serum
intact PTH level to differentiate between PTH-mediated
hypercalcemia and non-PTH mediated hypercalcemia.
• An elevated or high-normal value of PTH indicates primary
hyperparathyroidism.
Chapter 7

• vitamin D metabolites as 25-hydroxyvitamin D (25OHD) &

1,25-dihydroxyvitamin D (calcitriol), and PTHrP should be
measured.
• Additional laboratory data (including serum protein
electrophoresis for possible multiple myeloma, TSH, vitamin
A) will often lead to the correct diagnosis. Also, urinary
calcium excretion may be helpful in certain cases as FHH.
• Evidence of osteitisfibrosa on bone films is very specific for
primary hyperparathyroidism.

Treatment of hypercalcemia:
• Lowering the serum calcium concentration can be done by inhibiting
bone resorption, increasing urinary calcium excretion, or decreasing
intestinal calcium absorption. The optimal choice of different
modalities varies with the cause and severity of hypercalcemia.

(1) Mild hypercalcemia:

• Patients with asymptomatic or mildly symptomatic
hypercalcemia (calcium <12 mg/dL) do not require immediate
treatment.
• However, they should be advised to avoid factors that can
aggravate hypercalcemia, including thiazide diuretics and

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 Calcium Bone 157

lithium carbonate therapy, volume depletion, prolonged bed rest

or inactivity, and a high calcium diet (>1000 mg/day).
• Adequate hydration (at least 1.5- 2.0 liters of water per day) is
recommended to minimize the risk of nephrolithiasis.

(2) Moderate hypercalcemia:

• Tthey should follow the same precautions described above for
mild hypercalcemia.
• Acute rise of serum calcium may cause marked changes in
sensorium, which requires more aggressive therapy as described
for severe hypercalcemia.

(3) Severe hypercalcemia:

Chapter 7
• Patients with serum calcium >14 mg/dL, require more aggressive
therapy.
• Volume expansion with isotonic saline at an initial rate of 200
to 300 mL/h that then adjusted to maintain the urine output at
100 to 150 mL/h.
• Administration of salmon calcitonin (4 international units/kg)
and repeat measurement of serum calcium in several hours. If a
hypocalcemic response is noted, then the patient is calcitonin-
sensitive and the calcitonin can be repeated every six to 12 hours
(4 to 8 international units/kg).
• Bisphosphonate is indicated for longer-term control for
symptomatic hypercalcemia due to excessive bone resorption.
• Glucocorticoids are effective in treating hypercalcemia due to
some lymphomas, sarcoidosis, or other granulomatous diseases.
• Dialysis is generally reserved for those with severe life
threatening non responding hypercalcemia.

Hypoparathyroidism
Definition:
Hypoparathyroidism is defined as deficient PTH secretion and/or
action.

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 158 Calcium Bone

Causes:
1-Destruction of the parathyroid glands:
Surgical: hypoparathyroidism can occur after thyroid, parathyroid,
or radical neck surgery for head and neck cancer. It may be transient,
with recovery in days, weeks or months or permanent.
Autoimmune: Acquired hypoparathyroidism not related to
surgery is most often due to immune-mediated destruction of the
parathyroid glands. Autoimmune hypoparathyroidism is a common
feature of polyglandular autoimmune syndrome type I, which is a
familial disorder typically presents in childhood with candidiasis,
followed several years later by hypoparathyroidism, and then adrenal
insufficiency during adolescence.
Other causes of hypoparathyroidism due to parathyroid gland
Chapter 7

destruction include irradiation and storage or infiltrative diseases of

the parathyroid glands (hemochromatosis, Wilson's disease,
granulomas, metastatic cancer and HIV infection.

2- Abnormal parathyroid gland development: X-linked or in

autosomal recessive hypoparathyroidism due to abnormal parathyroid
gland development.

3- Altered regulation of PTH: Autosomal dominant or autosomal

recessive hypoparathyroidism may be due to mutations in the signal
peptide sequence of preproPTH, which impair the normal processing of
preproPTH to PTH.

4- Functional hypoparathyroidism: can be caused by both

hypomagnesemia and by acute severe hypermagnesemia.
Clinical manifestations:
(1) Symptoms and signs of hypocalcemia.
(2) In autoimmune form, there may be associated other diseases
as Addison s disease, alopecia, vitiligo and mucocutaneous
candidiasis.
(3) In Pseudohypoparathyroidism type 1b the appearance is
normal, but in type 1a disease the affected patient shows
different physical findings termed Albrights hereditary

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 Calcium Bone 159

osteodystrophy. These findings include obesity, short stature,

round face, short neck, shortening of the fourth and fifth
metacarpal and metatarsal bones, subcutaneous calcification,
sub average mentality, hypogonadism and hypothyroidism
without goiter.

Treatment: As treatment of hypocalcaemia

Hypocalcemia
Definition:
Hypocalcemia is an abnormal reduction in serum ionized calcium
concentration. Normal total serum calcium is 8.5-10.5 mg/dl and
normal ionized calcium is 4.65-5.28 mg/dl

Chapter 7
Major causes of hypocalcemia:
(A) Low PTH (hypoparathyroidism)hypocalcaemia:
1. Genetic disorders:
• Abnormal parathyroid gland development.
• Abnormal PTH synthesis.
• Activating mutations of calcium sensing receptor
(autosomal dominanthypocalcemia or sporadic isolated
hypoparathyroidism).
2. Post-surgical:
• Thyroidectomy, Parathyroidectomy or Radical neck
dissection.
3. Autoimmune:
• Isolated hypoparathyroidism due to activating antibodies
to calcium sensing receptor.
• Autoimmune polyglandular syndrome (associated with
chronic mucocutaneous candidiasis and primary adrenal
insufficiency).
4. Infiltration of the parathyroid gland by granulomatous diseases
as sarcoidosis, iron overload, Wilson`s disease or metastases.
5. Radiation induced destruction of parathyroid glands.
6. Hungry bone syndrome (post parathyroidectomy).
7. HIV infection.

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 160 Calcium Bone

(B) High PTH (secondary hyperparathyroidism) hypocalcaemia:-

1- Vitamin D deficiency or resistance
2- Parathyroid hormone resistance (Pseudohypoparathyroidismtype
1a and
1b): in this condition there may be either secretion of biologically
inactive PTH
or target organ (bone & Kidneys) resistance to PTH action. It is
characterized by hypocalcemia, hyperphosphatemia, and, in contrast to
hypoparathyroidism, elevated rather than reduced PTH concentrations.
3- Chronic renal failure.
4- Loss of calcium from the circulation as in hyperphosphatemia,
acute tumor lysis, acute pancreatitis, osteoblastic metastases, acute
respiratory alkalosis, sepsis or acute severe illness.
Chapter 7

(c) Drugs:-
1- Inhibitors of bone resorption (bisphosphonates, calcitonin),
especially in vitamin D deficiency.
2- Calcium chelators (EDTA, citrate, phosphate).
3- Phenytoin (due to conversion of vitamin D to inactive
metabolites).

(D) Disorders of magnesium metabolism:

Hypomagnesemia can reduce PTH secretion or cause PTH resistance
and is therefore associated with normal, low, or high PTH levels.

Clinical manifestations of hypocalcemia (tetany):

(A) Acute hypocalcemia:
1-Neuromuscular irritability:
Paresthesias (peri-oral, extremities), Muscle twitching, Carpo- pedal
spasm, and Laryngospasm.
2- Cardiac:
Prolonged QT interval, Hypotension, heart failure and Arrhythmia.
3- Papilledema.

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 Calcium Bone 161

(B) Chronic hypocalcemia:

1- Ectopic calcification (basal ganglia), Extrapyramidal signs,
Parkinsonism and Dementia.
2- Subcapsular cataracts.
3- Abnormal dentition in childern.
4- Dry skin.

(C) Latent tetany:

Chvostek`s sign: twitching of the upper lip after tapping on the facial
nerve below zygomatic arch.
Trousseau's sign: - carpal spasm after inflation of calf around the arm
above SBP for 2-3 minutes.

Chapter 7
Diagnosis of Hypocalcemia:
• Repeat measurement of serum calcium to confirm the diagnosis.
• measurement of serum intact PTH is the most valuable and should
be performed in all patients with hypocalcaemia (normal serum
intact PTH is 10-70 pg/ml.
• Other measurements that may be helpful include serum magnesium,
creatinine, phosphate, 25-hydroxyvitamin D, 1, 25-
dihydroxyvitamin D and alkaline phosphatase, amylase, and
urinary calcium excretion.

Treatment of Hypocalcemia:
• In patients with permanent hypoparathyroidism, the goals of
therapy are to relieve symptoms, to raise and maintain the
serum calcium concentration in the low-normal range, e.g., 8.0
to 8.5 mg/dL (2.0 to 2.1 mmol/L), and to avoid hypercalciuria
(maintain 24-hour urinary calcium below 300 mg).
1-Calcium:
• Patients with severely symptomatic hypocalcemia
(carpopedal spasm, tetany, seizures, decreased cardiac
function, or prolonged QT interval) require rapid
correction of calcium levels with IV calcium therapy.
• For those with milder symptoms of neuromuscular
irritability (paresthesias) and corrected serum calcium

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 162 Calcium Bone

concentrations greater than 7.5 mg/dL(1.9 mmol/L), initial

treatment with oral calcium supplementation (1.0 to 2.0
g elemental calcium daily) is sufficient.
2- Vitamin D:-
Calcitriol (1,25-dihydroxyvitamin D)in a dose (0.25- 2
µg/day)is the vitamin D. The metabolite of choice because
it does not require renal activation, it has a rapid onset of
action (hours), and a shorter half-life.
3- PTH: recently, synthetic PTH as a replacement ttt in
hypoparathyroidism

3- Magnesium: - To effectively treat hypocalcemia in patients with

concurrent magnesium deficiency, hypomagnesemia should be
Chapter 7

corrected first. Oral magnesium, typically 300 to 400 mg daily.

Osteoporosis (OP)

The most common metabolic bone disorder

Definition: Osteoporosis is a Systemic skeletal disease characterized

by: Low bone mass, with increased bone fragility and susceptibility to
fracture.

Defined by World Health Organization:

As a bone mineral density (BMD) of 2.5 or more (Standard
Deviation) below the mean value for young, healthy adult as measured
by dual-energy X-ray absorptiometry (DEXA).

Pathogenesis and Risk factors of Osteoporosis

Osteoporosis results from imbalance between bone formation
and resorption due to: Increased bone breakdown by osteoclasts, or
Decreased bone formation by osteoblasts.

There are two types of Osteoporosis: primary and secondary

Primary osteoporosis includes

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 Calcium Bone 163

1. Type I or postmenopausal osteoporosis: Occurs in females 10-15

years after menopause, due to decreased levels of estrogen
causing accelerated trabecular bone resorption.
2. Type II or senile osteoporosis: Affects elderly males and females
(above 65–70 years), related to nutrition and decreased physical
activity, affects mainly trabecular and cortical bones

Secondary osteoporosis:
Affects males and females at any age as a result of disease process or
medications.
General Risk factors of osteoporosis
Age: Affects 30% of over 50 years
Female sex: Women four times more affected than men.

Chapter 7
Caucasian and Asian race
Positive family history
Thin body habitus, Fair skin
Poor nutrition, Cigarette smoking

Medical diseases predisposing secondary Osteoporosis

• Prolonged immobilization.
• Endocrinal disorders: Cushing, Hyperparathyroidism,
Thyrotoxicosis, Hypogonadism, Diabetes mellitus
• Vitamin D insufficiency.
• Rheumatologic: RA arthritis, ankylosing spondylitis .
• Renal Osteodystrophy.
• Chronic liver disease, chronic obstructive pulmonary disease.
• Hematologic: myeloma, lymphoma and leukemia, hemophilia,
sickle-cell disease and thalassemia .
• Inherited: Osteogenesisimperfecta, Marfan syndrome .

Medications predisposing to secondary Osteoporosis:

Hormonal: Steroid-induced, L-Thyroxine, Aromatase inhibitors,
progesterone, Thiazolidinediones,Anti-androgens.
CNS: Barbiturates, phenytoin, antiepileptics, lithium.
Antimetabolite drugs: Methotrexate.
Anticoagulants, heparin and warfarin.
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 164 Calcium Bone

Proton pump inhibitors and chronic oral antacids.

Clinical Manifestation of Osteoporosis

1. Early osteoporosis is asymptomatic.
2. Pain due to mechanical derangement or Fractures (often low -
trauma fractures), especially Vertebral compression fractures,
Colles’ fractures, Fractures of the proximal femur, Up to 50% of
vertebral fractures are asymptomatic.
3. Deformities include dorsal kyphosis, lordosis, and loss of height.

Investigations of Osteoporosis
1. Conventional X-ray: shows vertebral compression fracture,
cortical thinning, decrease in the number of trabeculae. And
Chapter 7

increased radiolucency.
2. Dual energy X-ray absorptiometry (DEXA): Is the gold standard
in osteoporosis diagnosis usually of the lumbar spine
andproximal femur. It is precise, accurate, uses low dose of
radiation.
T-score: Compares the bone mineral density (BMD) to that of
young, healthy adult, BMD is classified by the WHO based on
𝑇score into categories such as: Normal (-1 or higher), Osteopenia
(between -1 and -2.5), Osteoporosis (-2.5 or less).
Z-score: Matches BMD to age matched control.
3. Serum ca, ph, Alk phosphatase: usually normal.
4. Increased urinary excretion of C-telopeptides.
5. Investigations to exclude other diseases predisposing to
secondary Osteoporosis.

Treatment of Osteoporosis
I- Non-drug Therapy
1- Treat any underlying conditions (e.g. hyperthyroidism)
andAvoid drugs that induce osteoporosis.
2- Weight bearing exercise and Fall prevention: Thirty minutes
of weight-bearing exercise three times a week may increase
BMD.
3- Life style modification: Stop smoking and increase Ca in diet.

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 Calcium Bone 165

4- Fractures require bed rest andconventional orthopaedic

means.

II- Drug therapy for OP

I- Antiresorptive therapy:
1-Bisphosphonates:
Action: Synthetic analogues of bone pyrophosphate adhere to
hydroxyapatite and are potent inhibitors of osteoclast activity.
Oral
Alendronate (daily, weekly)
Risedronate (daily, weekly, monthly)
Ibandronate (daily, monthly)
Intravenous

Chapter 7
Ibandronate (3 month)
Zoledronic acid (annual)

Adverse Effects:
1. Rare instances of erosive esophagitis and gastritis may occur , to
avoid this , Oral bisphosphonates should be taken in the fasting
state with a large drink of water, while the patient is standing or
sitting upright. The patient should subsequently remain upright
and avoid food and drink for at least 30 minutes.
2. Osteonecrosis of the jaw is seen following high dose I.V. (rarely
oral) nitrogen containing bisphosphonate in patients with
malignant disease.
3. Bisphosphonates are excreted primarily by the kidneys.,
Zoledronate has been associated with renal toxicity,
Bisphosphonates are not recommended for patients with
impaired renal function.

2-Selective estrogen receptor modulator (SERMs) (Raloxifene)

(type I osteoporosis):
Action
It is not a hormone, it activates oestrogen receptors in bone but has no
stimulatory effect on the endometrium. So it inhibits the effect of PTH
on osteoclastwithout trophic effect on breast or uterus

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 166 Calcium Bone

Adverse effects:
May cause or worsen hot flushes and also increase the risk of
thromboembolic disease.

3-Hormone replacement therapy (HRT) (type Iosteoporosis):

Mechanism of action: Estrogen suppresses bone resorption by
inhibiting osteoclasts.
Adverse effects:
1. Increase the incidence of breast and endometrial cancers
2. Increase in risks for deep venous thrombosis and gall bladder
disease.
Because of adverse effects, HRT is a second-line option for
osteoporosis except in early postmenopausal women at high fracture
Chapter 7

risk who also have perimenopausal symptoms.

4-Androgen: In men with osteoporosis who have clinical and

biochemical evidence of
hypogonadism, testosterone replacement is used.

5-Calcitonin: Nasal or subcutaneous: it Slows bone loss, Occasional

nausea, vomiting, flushing may occur.

6-Supplementation with calcium and vitamin D:

In those with low dietary calcium intake and at risk from vitamin D
insufficiency, calcium and vitamin D supplements should be advised,
the recommended dose is 800 IU of vitamin D and 1–1.2 g calcium
daily. Calcium alone is inadequate to completely inhibit the rapid bone
loss that occurs at menopause but it optimizes the response to other
antiresorptive agents.

II- Anabolic therapy:

Recombinant human parathyroid hormone peptide: (teriparatide)
are anabolic agents that stimulate bone formation. Parathyroid hormone
peptide therapy may cause hypercalcemia and is mainly indicated in
severe cases of vertebral osteoporosis or in women who fail to respond
to other therapies.

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 Calcium Bone 167

PAGET’S DISEASE OF BONE (Osteitis deformans)

Is a disorder of increased bone resorption with compensatory increased
bone formation, the new bone is structurally abnormal.
It affects men and women (2: 3) over the age of 40 years. The
prevalence of Paget disease increases with age, it occurs in up to 10%
of persons older than 80 years.

Etiology and pathogenesis

The cause of Paget's disease is unknown, both genetic and
environmental factors have been implicated. A number of genes
implicated in Paget’s disease encode proteins that are involved in
regulating the function of osteoclasts also; Paget’s disease may be
caused by a slow virus (paramyxovirus) infection.

Chapter 7
Initially, there is a marked increase in the rate of bone resorption in
localized areas, caused by large and numerous osteoclasts (lytic phase).
The osteolysis is followed by a compensatory increase in bone
formation (mixed lytic and blastic phase). The bone that is formed has
a disorganized pattern (woven bone), weaker than normal adult bone
but is thick (sclerotic phase), there is increased local bone blood flow
and fibrous tissue in adjacent bone marrow.

Clinical manifestations
• Paget's disease has a predilection for the axial skeleton. The
disease may involve one bone (monostotic, in 15%) or many
(polyostotic). The most common sites in order of frequency are
pelvis, lumbar spine, femur, thoracic spine, sacrum, skull and
tibia.
• The disease is asymptomatic in about 60–80% of radiologically
identified Paget’s disease.
• Symptoms include: Bone Pain, Deformity especially bowed tibia
and skull changes, there is pathological Fractures. Joint pain
occurs due to cartilage damage and osteoarthritis. Increased bone
blood flow causeshyperdynamic state and Cardiomegaly.
• Complications include: pathological Fractures, Deafness, Nerve
entrapment, Spinal stenosis, High output Cardiac failure,
Osteogenic sarcoma, and Hypercalcemia (only if immobilized).

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 168 Calcium Bone

Diagnosis
1. Bone survey: Pagetic bone has a characteristic appearance on
X-rays, there is Cortical thickening, osteolytic, and
osteosclerotic lesions in addition to deformities.
2. Isotope bone scan: useful in determining the extent and
activity of the disease.
3. An elevated level of alkaline phosphatase in the blood in
combination with normal calcium, phosphate, and
aminotransferase levels in an elderly patient are suggestive of
Paget's disease. Hypercalcemia occurs only after periods of
immobilization.
4. Elevated levels of serum and urinary hydroxyproline in active
disease.
Chapter 7

Treatment of Paget’s
Only indicated for: pain, deformity, high fracture risk, elevated Alk
Phosphatase 2-3 times above upper limit and Skull disease.
1- Bisphosphonates: Are usually the first medicine prescribed for
Paget's disease. They often make the disease inactive.
2- Calcitonin: if bisphosphonates therapy is contraindicated.
3- Diet and exercise: patients with Paget's disease should receive
1000–1500 mg of calcium, adequate sunshine, and at least 400
units of vitamin D daily.
4- Surgery for: Fractures, Bone deformity (osteotomy),
degenerative arthritis (joint replacement), and Neurosurgery for
spinal disease.

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CHAPTER

Obesity and
Metabolic
 Obesity and Metabolic
8
Introduction:
Macronutrients: Charbohydrates, proteins, fats. The average
daily caloric requirements is made up of 50% carb, 35% fat, 15% ptn
Micronutrients: Vitamins and minerals
Body weight depends on energy balance between intake &
expenditure
Intake depends on food availability, role of hunger, stimulus of good
food, metabolic changes
(e.g. hypoglycemia), the pleasure and habit of eating.
Energy expenditure = the sum of the basal metabolic rate (BMR), the
thermic effect of food eaten and the physical activity (occupational
and non occupational).
Energy requirements increase during the growing period, pregnancy
and lactation and sometimes in cases of inreased catabolism such as
infection and trauma.
Energy requirements ranges 25-30 kcal/kg under normal conditions
and increases to 35-50 kcal/kg under catabolic states.
A gain or loss of 1 kg of body weight denotes gain or loss of about
6000-7000 kcal

Definition:

Weight gain
By weight gain we usually mean obesity. Other causes of weight gain
include fluid retention as in oedematous states such as causes of
generalised oedema (heart failure, renal, hepatic oedema ), also by
intake of drugs .Rarely increased muscularity and body building could
lead to some gain of weight.

Obesity means: Excess body fat.

Rapid changes in weight are usually related to changes in body water
while changes in fat content develop more slowly.

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 170 Obesity and Metabolic

Causes:
1- Simple obesity: most common. Due to genetic, environmental and
behavioural factors
A state of positive energy balance. Weight change = energy intake -
energy expenditure
Energy intake (food/drink in kcal) = energy density(how rich) ×
portion size (how much) × frequency of intake ( how often).
Energy expenditure: Resting energu expenditure (BMR) + Physical
activity +Thermogenesis.
2- Secondary causes: e.g.
- Hypothyroidism.
- Cushing syndrome.
- Polycystic ovary syndrome.
Chapter 8

- Hypothalamic disorders: [Link], tumour or granuloma.

- Rare genetic syndromes: e.g. Laurence moon beidl, Prader
Willi syndrome.
- drugs e.g. corticosteroids, antidepressants, contraceptives.

Types of obesity:
Upper body obesity, apple shaped (previously termed android obesity)
and lower body obesity, pear shaped (previously gynecoid obesity).
Upper body obesity, diagnosed by the increased waist circumference,
associated with increased visceral fat accumulation

Effects of obesity = Complications and risks

1- Hypertension i.e. BP > 140/90. 10 kg increase of weight associated
with a 3.0 mm Hg higher diastolic pressure and a 2.3 mm Hg higher
systolic pressure.
2- Increased risk of coronary heart disease (CHD) and increased in
stroke.
3- Type 2 Diabetes especially with a more central distribution of body
fat. There is also insulin resistance.
4- Dyslipidemia: elevated total cholesterol levels, high triglyceride
levels, and decreased high density lipoprotein (HDL).
5- Coronary Heart Disease: Risks are lowest with BMIs of 22 or less
and increase with even modest elevations in BMI. There is increased

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 Obesity and Metabolic 171

atherosclerosis risk due to dyslipidemia, hypertension and metabolic

syndrome.
6- Obstructive sleep Apnea, particularly upper body obesity. May be
due to accumulation of fat in tracheo-pharyngeal area. arterial
hypoxemia, recurrent arousals from sleep, increased sympathetic
tone, pulmonary hypertension.
7- Osteoarthritis (degenerative joint disease). In women, it is
estimated that for every kilogram increase of weight, the risk of
developing osteoarthritis increases by 9 to 13%.
8- Hyperuricemia and Gout
9- Gallstones: Risk of either gallstones or cholecystectomy is high.
This is due to increased cholesterol synthesis and increased biliary
excretion of cholesterol.

Chapter 8
10- Cancer: Certain cancers are associated with overweight and
obesity, e.g. colon, endometrial, gallbladder and prostate cancer.
11- Menstrual Irregularity: Obesity in premenopausal women is
associated with menstrual irregularity and amenorrhea.
12- Polycystic ovarian syndrome, which is a combination of infertility,
menstrual disturbances, hirsutism, abdominal hyperandrogenism,
and anovulation.
13- Venous stasis.
14- NAFLD (= Fatty liver, steatosis and steatohepatitis).

Assessment of obesity: 1-Body mass index (BMI):

Normal BMI= 18.5 -24.9 kg/ m2.

Overweight > 25 -29.9 kg/ m2.
Obese > 30 kg/ m2 : Class I: 30 -34.9 kg/ m2. Class II: 35 -39.9 kg/m2.
Class III: > 40 kg/ m2. Extreme or severe obesity (previously morbid
obesity)

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 172 Obesity and Metabolic

2 - Waist circumference:
its measurement is especially important when BMI is less than 35
Kg/m2.
Waist: moderate risk 94 cms in men and 80 cms in women
high risk 102 cms in men and 88 cms in women
3- Waist hip ratio is less important: >0.9 in men and > 0.85 in women
4 - Estimation of % of body fat: Fat percentage >33% in women, >
25% in men identifies obesity. The standard techniques for measuring
visceral fat are magnetic resonance imaging (MRI) and computed
tomography (CT) scanning which are used for research purposes only.
Less expensive techniques for direct measurement of visceral fat
include abdominal ultrasonography and bioelectrical impedance
analysis.
Chapter 8

5- Identification of risks associated with obesity and other

cardiovascular risk factors e.g. HTN, smoking, high LDL, low HDL
cholesterol, impaired fasting glucose, family history of premature
atherosclerosis and increasing age.

N.B- Exclusion from weight loss therapy: Pregnant, lactating, major

psychiatric illness, serious illnesses for whom caloric restrictions might
exacerbate the condition.

Management of obesity:
1-Life style modification program: Aim to lose about 10 % of body
weight within 6 months
A- Nutrition
Low calorie diet i.e. reduces energy intake by 500- 1000 kcal / day
Very low calorie diets (less than 800 kcal) cause rapid weight loss,
which increases the risk of gallstone formation, dehydration, and
electrolyte abnormalities. There is greater regain of lost weight. Not
recommended.
B- Physical activity in adults:
Physical activity: Initially 30 minutes of moderate intensity 3-5 times
/week, eventually 60 min or more in most days. (Medical evaluation is
advised before starting activity program).
Activity generally should be increased slowly.

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 Obesity and Metabolic 173

Benefits:
1- it is associated with long-term weight loss maintenance.
2- has beneficial health effects, such as decreasing coronary heart
disease and diabetes, that are independent of weight loss itself.
3- Decrease loss of fat free mass associated with weight loss

C- Behavioural/ psychological interventions in adults

These include examining patient’s current eating and exercise habits to
find out what factors or situations may have contributed to excess
weight to start changing these behaviors.
Successful treatment is a life long effort

2-Pharmacological treatment in adults:

Chapter 8
1- Orlistat
Orlistat is considered as an adjunct to life style interventions in the
management of obesity.
A lipase inhibitor. It decreases absorption of fat
Dose: 120 mg once to tid.
Side effects: diarrhea, oily leakage in stool, -decreased absorption of
fat soluble vitamins
Vit supplementation of fat soluble vitamins (A, D, E, K) are needed.
2- Newly approved drugs include: Topiramate –phentermine
combination and lorcaserin.

3-Surgery:
Bariatric surgery, indicated in severely obese (BMI > 40 kg/m2) after
failure of other measures. Most effective obesity ttt but with more side
effects.
Includes restrictive surgery including sleeve gastrictomy and gastric
banding or restrictive and malabsorptive surgery such as gastric
bypass.

Management summary:
1- Diet: Caloric restriction (500-1000 less calories /day)
2- Balanced diet with complex carbohydrates, vegetables and
fruits, proteins and less fats.

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 174 Obesity and Metabolic

3- Exercise: especially for maintenance of weight loss.

4- Drugs.: Drugs decreasing digestion and absorption of fats e.g.
orlistat.
5- Other recently approved drugs available
6- Surgery: for morbidly obese with failure of other measures to
lose weight.

Metabolic syndrome

Metabolic syndrome is clustering of cardiovascular risk factors

including HTN, hyperlipidemia, glucose intolerance, obesity &
hyperinsulinemia. Other constituents include hyperuricemia, fatty liver
and microalbuminuria.
Chapter 8

These factors were labelled syndrome X by Reaven in 1988 who

suggested that Insulin resistance was its central characteristic, so it was
also termed insulin resistance syndrome.

Criteria for diagnosis of metabolic syndrome

At least 3 of the following 5 conditions:
1- Fasting glucose ≥100 mg/dL (or receiving drug therapy for
hyperglycemia)
2- Blood pressure ≥130/85 mm Hg (or receiving drug therapy for
hypertension)
3- Triglycerides ≥150 mg/dL (or receiving drug therapy for
hypertriglyceridemia)
4- HDL-C < 40 mg/dL in men or < 50 mg/dL in women (or
receiving drug therapy for reduced HDL-C)
5- Waist circumference: According to population or country
specific definitions.

Waist circumference:
- USA > 102 cms in men and >88 cms in women
- Europoid > 94 cms in men and >80 cms in women
- South east Asia > 90 cms in men and >80 cms in women

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 Obesity and Metabolic 175

Pathogenesis of the metabolic syndrome:

Potential etiologic categories:
1- Obesity and disorders of adipose tissue
2- Insulin resistance
3- genetic and acquired factors
4- 4-Other contributing factors:
Lack of physical activity, low cardio-respiratory fitness,
atherogenic diet, smoking , elevated LDL ,low household income,
family history of early coronary artery disease ,aging , post
menopausal status and more exposure to work stressors.

Treatment

Chapter 8
A-Lifestyle change and weight loss are considered the most
important initial steps in treating metabolic syndrome.
1- Dietary modification: inclusion of whole grains, fruits and
vegetables and lean sources of animal proteins including low fat
dairy products for insulin resistance.
1- Activity: exercise and weight loss improve hyperinsulinemia
and BP.
2- Behavioural modificaion: Relaxation and Meditation was
reported to improve glucose tolerance and lipid profile
3- Smoking sessation

B- Pharmacotherapy:
1- Metformin 500 mg bid reported to improve insulin resistance
and endothelial dysfunction
2- Antihyperlipidemic drugs: Bezafibrate is beneficial in subjects
with elevated TG
Statins in subjects with elevated LDL
Niacin in subjects with low HDL
3- Low dose aspirin: For prothrombotic state

N.B. Treatment of associated obstructive sleep apnea may also play a

significant role in the management of metabolic syndrome

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CHAPTER

Hyperlipidaemia
 Hyperlipidaemia
9
Definition:
Increased levels of lipids (fats) in the blood, including cholesterol
and triglycerides.

Types:
I- Primary hyperlipidaemia.
II- Secondary hyperlipidaemia.

I- Primary Hyperlipidaemia

Definition: Hyperlipidaemia due to genetic mutation of various

components of lipid metabolism.

Classification & clinical features:

Goldstein and Brown classification: (on the basis of genetic
mechanism)
a. Disorders of LDL - hypercholesterolaemia alone.
b. Disorders of VLDL and chylomicrons - hypertriglyceridaemia
alone.
c. Combined hyperlipidaemia.

Lipid phenotype Plasma lipid Elevated Clinical

level mg/dl presentation
A- Hypercholesterolaemia

1- Familial Heterozygotes
hypercholesterolaemia TC = 275-500 LDL -Tendon
(AD) Homozygotes xanthoma.
-mutation in LDL receptor TC > 500
gene resulting in aberrant -Tuberous
or complete absence of xanthoma
receptor protein.

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 Hyperlipidaemia 177

2- Familial defective apo TC = 250-350 LDL -Xanthelasma.

B100 (AD)
- mutation at a.a 3500 -Coronary heart
result in reducing the disease (CAD)
binding of LDL to its
receptors
3- Polygenic TC = 250-350 LDL - CAD
hypercholesterolaemia
-genetic & environmental
factors result in over
production and reduced
catabolism of LDL.
B- Hypertriglyceridaemia

1- Familial TG= 250-750 VLDL -No increase risk

Chapter 9
hypertriglyceridaemia of CAD
(AD)
-hepatic overproduction of
VLDL.
2- Familial lipoprotein TG > 750 Chylomicr -Pancreatitis
lipase deficiency (AR) ons -Eruptive
xanthoma
- absence of lipoprotein -Hepatomegally
lipase resulting in -Splenomegally
accumulation of -Retinal vein
chylomicrons in plasma thrombosis
- No accelerated
atherosclerosis
3- Familial apo CII TG > 750 Chylomicr -Pancreatitis
deficiency (AR) ons
- deficiency of apoprotein
CII which impairs
lipoprotein lipase function
result in accumulation of
both chylomicrons and
VLDL in blood
C- Combined hyperlipidaemia

1- Familial Combined TG=250-750 VLDL, -CAD

hyperlipidaemia (AD) TC=250-500 LDL -Insulin resistance
-No xanthelasma
-No xanthoma

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 178 Hyperlipidaemia

-mutation of lipoprotein
lipase gene
2-Dysbetalipoproteinemia TG=250-500 VLDL, -Tuberous
TC=250-500 Chylomicr xanthoma
- Defect in apoprotein E2 ons -Striae Palmaris
result in accumulation of -High risk for
both chylomicrons and atherosclerosis
VLDL in blood

- (AD): Autosomal dominant.

- (AR): Autosomal recessive.
- Tendon xanthoma: fat deposition on achilles tendons and extensor
tendons of knuckles.
- Tuberous xanthoma: on elbow, knee and buttocks.
Chapter 9

- Xanthelasma: on eye lids.

- Eruptive xanthoma: on trunk and extremities.
- Striae Palmaris: yellow- orange lines in palmar creases due to
cholesterol deposition.

Tendon xanthoma Tendon xanthoma

Tuberous xanthoma Xanthelasma

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 Hyperlipidaemia 179

Eruptive xanthoma Striae Palmaris

Cutaneous manifestations of hyerlipidaemia

II- Secondary Hyperlipidaemia

Chapter 9
Definition: Hyperlipidaemia secondary to systemic disorders or
drugs.

Causes:
1-Hypothyroidism
2-Diabetes mellitus (when poorly controlled)
3-Obesity
4-Renal impairment
5-Nephrotic syndrome
6-Hepatic dysfunction
7-Drugs: Oral contraceptives in susceptible individuals, thiazide
diuretics and corticosteroids.

Investigations for hyperlipidaemia:

• Most patients with hyperlipidaemia are asymptomatic and have

no clinical signs. Many are discovered during the screening of
high-risk individuals such as:
• Family history of coronary heart disease.
• Family history of lipid disorders.
• Presence of a xanthoma and xanthelasma.

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 180 Hyperlipidaemia

•Obesity, diabetes mellitus or hypertension.

• Acute pancreatitis.
• Undergoing renal replacement therapy.
• Measurement of plasma lipids should be done after 12-14h
fasting and should include:
Total cholesterol (normal value < 200 mg/dl)
Triglycerides (normal value < 150 mg/dl)
HDL (normal value 40-60 mg/dl)
LDL (normal value < 130 mg/dl) can be calculated from the
formula: LDL = Total cholesterol - (HDL + Triglycerides / 5)

Treatment for hyperlipidaemia:

Chapter 9

1- Diet:
• Reduce the total fat intake: Dairy products and meat are the
principal sources of saturated fat. Intake of these products should
therefore be reduced, and fish and poultry should be substituted.

• Substitution with monounsaturates and polyunsaturates:

Monounsaturated oils, particularly olive oil, and polyunsaturated
oils such as sunflower, safflower, corn and soya oil, should be
used in cooking instead of saturated fat-rich alternatives.

• Reduce the dietary cholesterol intake: Liver should be avoided.

Although eggs are rich in cholesterol their total contribution to
the body's cholesterol pool is small and they can still be part of a
balanced lipid-lowering diet.

• Increase the intake of fiber: reduce circulating lipid

concentrations.

• Reduce alcohol consumption: Excess alcohol is a cause of

secondary hyperlipidaemia, and may worsen primary lipid
disorders.
• Achieve an ideal bodyweight:

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 Hyperlipidaemia 181

2- Drugs:
Mechanism Contra- Adverse Therapeutic
Drug of action indications reactions effect
Statins Inhibit the - Active liver - Mild - 30-50%
e.g. rate-limiting disease transient reduction in
step in hepatic elevation of LDL
Simvastatin cholesterol - Pregnancy liver enzymes
Pravastatin synthesis - 10-20%
Fluvastatin (Hydroxymeth - Lactation -Diarrhoea reduction in
Atorvastatin yl glutaryl triglyceride
Lovastatin (HMG) CoA - Myositis
reductase) - Tiny effect on
HDL

Chapter 9
Inhibition of - Lactation - Diarrhoea - Reduce LDL
Cholesterol gut absorption by additional
absorption of cholesterol - Abdominal 10-15% if given
inhibitors e.g. from food and discomfort with a Statin
bile.
Ezetimibe - 10% reduction
in triglyceride

- 5% increase in
HDL
Cholesterol- - Bind bile Gastrointesti - 15-30%
binding resins acids in the nal side- reduction in
e.g. gut preventing effects: LDL
Colestyramine enterohepatic Constipation
circulation. Bloating - 5-15%
Colestipol - Liver makes rise in
more bile - Palatability triglyceride
acids from is a problem.
cholesterol, - Little or no
depleting the effect on HDL
cholesterol
pool
Fibric acid Limit - Severe - Mild - 10-15%
derivatives substrate hepatic or elevated liver reduction in
e.g. availability for renal enzymes LDL
hepatic impairment
Gemfibrozil

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 182 Hyperlipidaemia

triglyceride - Gallbladder - Reversible - 25-40 %

Bezafibrate synthesis disease myositis reduction in
Promote triglyceride
Fenofibrate action of - Pregnancy - Nausea
lipoprotein - Gallstones - 10- 40%
lipase formation increase in HDL

Mechanism Contra- Adverse Therapeutic

Drug of action indications reactions effect
Nicotinic acid inhibit lipid - Pregnancy, Value limited - 5-10%
and synthesis in breast- by frequent reduction in
derivatives the liver by feeding. side-effects: LDL
e.g. reducing free - headache
fatty acid - Flushing - 10-20%
Nicotinic acid concentrations - Nausea reduction in
Chapter 9

through an - Malaise triglyceride

inhibitory - Itching
effect on - elevated
lipolysis in fat liver enzymes - 10-20 %
tissue - Glucose increase in HDL
intolerance
Hyperuricae
mia
- Activation
of peptic
ulcers
- Reduce
Omega-3 Reduce - Occasional triglycerides in
marine hepatic VLDL nausea severe hyper-
triglycerides secretion triglyceridaemia

- No favorable
change in other
lipids.

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CHAPTER

Nutritional
Deficiency
 Nutritional Deficiency

Nutritional Disorders
10
Macro nutrients and micro nutrients
• Macro-nutrients: Protein, carbohydrates, and fats
• Micro-nutrients: water soluble vitamins, fat soluble vitamins,
and minerals

Macro-nutrients
• Energy: Necessary for all bodily function
• Protein:Necessary for structural development (muscle and bone)
• Fat
• Necessary for cell membrane and skin cell development

Dietary Reference Intakes

Macronutrient F M
Energy (Kcal) 1940 – 2200 2550 – 2900
Protein (g) 36 – 46 44 – 60
Fat 15 – 33% 15 – 33%

Water soluble vitamins:

Thiamin B: nervous system function, enzymatic energy release of

carbohydrates (beef, pork, liver, breads)

Riboflavin B2: Participants in enzymatic energy release of carbs, fat &

protein (milk, dairy, dark green vegetables, yogurt)

Niacin: Participates in enzymatic energy release of energy nutrients

(beef, pork, liver, breads, nuts)

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 184 Nutritional Deficiency

Folate:Red blood cell formation, new cell division (veg, seeds)

Vitamin B12 (Cobalamin): Red blood cell formation, nervous system
maintainance (animal prod).

• Pantothenic Acid
• Biotin (Vitamin H, CoEnzyme R)
• Vitamin B6 (Pyridoxine)
• Vitamin C

Fat soluble vitamins

1. Vitamin A
• Essential to vision, fetal development, immune response
• Found in dairy products, fish liver oils; as B-carotene found
Chapter 10

in many plants (e.g. carrots, mango)

2. Vitamin D
• Bone formation, calcium metabolism and absorption
• Found in sunlight, egg yolk, dairy products and fish liver oil
3. Vitamin E
• Cell membrane construction and maintenance
• In fats and oils, green leafy vegetables, poultry, fish
4. Vitamin K
• Blood clotting, protein synthesis
• In green leafy vegetables, liver, cabbage

Minerals:

Major “Bone”Minerals TraceMinerals

Calcium (bones) Iodine (thyroid function)
Phosphorus (DNA) Iron (hemoglobin)
Magnesium (bones) Zinc (enzyme, hormone)
Sodium (nerve impulse) Copper (abs. of iron)
Chloride (fluid balance) Flouride (bone & teeth)
Potassium ([Link]) Chromium (energy rel.)
Sulfur (some a.a.’s) Molybdenum (enzymes)
Manganese (enzymes)

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 Nutritional Deficiency 185

Selenium (antioxidant)
Cobalt (part of B12)

Malnutrition
A pathological state resulting from a relative or absolute
deficiency or excess of one or more essential nutrients; clinically
manifested or detected only by biochemical, anthropometric or
physiological tests.

Forms of Malnutrition
1. Undernutrition: Marasmus
2. Overnutrition: Obesity, Hypervitaminoses
3. Specific Deficiency: Kwashiorkor, Hypovitaminoses, Mineral

Chapter 10
Deficiencies
4. Imbalance: Electrolyte Imbalance

Vitamin A Deficiency
1. Vitamin A is important because it is essential to vision, fetal
development, immune response
2. 250 million children of pre-school age lack sufficient Vitamin A
in their diet.
3. 350,000 become blind each year, and half of them die within a
year of becoming blind.

Therapeutic uses of Vitamin A

1. Vitamin A deficiency
2. Boosting immunity of infants
3. Skin disorders
4. Acute promyelotic leukemia
5. Cancer prevention (lung & breast)

Toxicity of Vitamin A:
1. Dermatitis with xanthosis cutis
2. Hepatosplenomegaly
3. Bone pain & increased risk of fracture
4. Pseudotumor cerebri

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 186 Nutritional Deficiency

Vitamin D
1. Vitamin D comprises a group of sterols; the most important of
which are cholecalciferol (vitamin D3) &ergosterol (vitamin
D2).
2. Humans & animal utilize only vitamin D3 & they can produce it
inside their bodies from cholesterol.
3. Cholesterol is converted to 7-dehydro-cholesterol (7DC), which
is a precursor of vitamin D3.
4. Exposure to the ultraviolet rays in the sunlight convert 7DC to
cholecalciferol.
5. Vitamin D3 is metabolically inactive until it is hydroxylated in
the kidney & the liver to the active form
1,25Dihydroxycholecalciferol.
Chapter 10

6. 1, 25 DHC acts as a hormone rather than a vitamin endocrine &

paracrine properties.

Sources of Vitamin D
1. Sunlight is the most important source
2. Fish liver oil
3. Fish & sea food (herring & salmon)
4. Eggs
5. Plants do not contain vitamin D3

Vitamin D deficiency
1. Rickets in children.
2. Osteomalacia
3. Osteoporosis

Therapeutic Uses
1. Rickets & Osteomalacia
2. Osteoporosis
3. Psoriasis
4. Cancer prevention (prostate & colorectal)
5. Autoimmune diseases

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 Nutritional Deficiency 187

Toxicity
• Hypervitaminosis D: causes hypercalcemia,

Vitamin E
1. The term vitamin E describes a family of 8 antioxidants, 4
tocopherols (a,b, g, & d) and4 tocotrienols.
2. a-tocopherol is the active form of vitamin E in the human
body.

Functions
1. The main function of vitamin E is anti oxidant. It intercepts
free radicals & prevents destruction of cell membrane.
2. It protects the fat in LDL from oxidation.

Chapter 10
3. It inhibits platelets aggregation.
4. It enhances vasodilatation.
5. It inhibits the activity of protein kinase C.

Vitamin E Dietary Sources: vegetable oils, almonds & peanuts,

avocado, spinach and carrots (least).

Vitamin E deficiency
• Severe vitamin E deficiency causes:
1. Neurological symptoms (impaired coordination) & muscle
weakness.
2. Increased risk of cardiovascular diseases
3. Hemolytic anemia in children

Therapeutic Uses
1. Prevention of cardiovascular diseases
2. Diabetes Mellitus
3. Cancer prevention
4. Boost immunity
5. Dementia

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 188 Nutritional Deficiency

Toxicity
• Excess vitamin E may cause:
1. Impaired blood clotting leading to increased risk of
bleeding in some persons.
2. It is recommended that vitamin E supplements to be
stopped one month before elective surgery.

Vitamin K
1. The K is derived from the German word Koagulation.
2. There are 2 naturally occurring forms of vitamin K. Plants
synthesize phylloquinone (vitamin K1) & bacteria synthesize
menaquinone-3 (vit K2).
3. Menaquinone-4 is produced in animals from vit K1, but its
Chapter 10

function is yet to be discovered.

Functions
• Vitamin K is needed for production of vitamin K-dependent
coagulation factors in the liver.
• Other functions include:
1. Assist in bone mineralization. The mineral binding
capacity of osteocalcin requires vit K.
2. Gas6 is vit K-dependent protein identified in 1993. It is
important for neuronal function.

Sources of Vitamin K
• Bacteria in large intestine produce vit K2 and supply 40-50% of
human requirement.
• vegetable oils, almonds & peanuts, avocado & broccoli, spinach,
lettuce, parsley (raw)

Vitamin K deficiency
1. Is uncommon in adults. Only those with severe liver disease &
those on oral anticoagulants are at risk.
2. Exclusively breast fed & premature babies are at risk coz human
milk is low in vitamin K & their gut is not yet colonized with
bacteria.

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 Nutritional Deficiency 189

3. Hemorrhagic disease of the newborn is a serious threat to life &

routine vit k prophylaxis is recommended by the AAP.

Vitamin C deficiency
• Severe deficiency leads to Scurvy with the following
manifestations:
1. Bleeding & bruising easily
2. Hair & teeth loss
3. Joint pain & swelling
4. Fatigue & lack of concentration

Therapeutic Uses
1. Cardiovascular diseases

Chapter 10
2. Cataracts
3. Diabetes Mellitus
4. Cancer prevention
5. Common cold
6. Lead toxicity

Drug Interactions
1. Contraceptive pills & aspirin lower vitamin C level in plasma &
WBC.
2. Vitamin C in large dose blocks the action of warfarin &
interferes with interpretation of certain lab tests (bilirubin &
creatinine in serum and guaiac assay for occult blood).
3. Previous claims of serious toxic effects of vit C are not evidence-
based.

Vitamin B Complex
1. Group of 7 water soluble vitamins, thiamin, riboflavin, niacin,
pyridoxine, cobalamin, biotin & pantothenic acid.
2. Biotin & pantothenic acid deficiencies are extremely rare coz it
is found in numerous foods and also is synthesized by intestinal
bacteria.
3. Biotin deficiency may occur with prolonged antibiotic therapy &
ingestion of raw eggs.

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 190 Nutritional Deficiency

Thiamine, Riboflavin, Niacin, Pyridoxine

Are cofactors to enzymes in energy metabolism, hence, deficiencies
show up in quickly growing tissues such as epithelium.

Typical symptoms for the group include: Nerve cells use lots of
energy, so symptoms also show up.

In the nervous tissue:

Dermatitis Peripheral neuropathy

Glossitis Depression
Diarrhea Mental confusion
Lack of motor coordination
Chapter 10

Malaise

Thiamin (Vit B1)

1. Thiamin is rapidly converted to its active form, thiamin
pyrophosphate in the brain and liver by a specific enzymes,
thiamin diphosphotransferase.
2. TPP is necessary as a cofactor for the reactions of the pentose
phosphate pathway.
3. The dietary requirement for thiamin is proportional to the caloric
intake of the diet and ranges from 1.0 - 1.5 mg/day for normal
adults.

Risk of Thiamin Deficiency

1. Low intake & alcoholism
2. Increased consumption: Malaria & AIDS
3. Excessive loss: hemodialysis and diuretics
4. Anti-thiamin factors: tea & coffee.
5. Thiaminases found in raw fish, raw shellfish & in silkworms.

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 Nutritional Deficiency 191

Thiamine (Vitamin B1) Deficiency Beriberi:

Pathology:
• Biochemically, there is accumulation of pyruvic and lactic acid
in body fluids causing:
1. Cardiac dysfunction such as cardiac enlargement esp right side,
edema of interstitial tissue & fatty degeneration of myocardium
2. Degeneration of myelin & of axon cylinders resulting in
peripheral neuropathy and
3. In chronic deficiency states, vascular dilatation & brain
hemorrhages of Wernicke’s Disease, resulting in weakness of
eye movement, ataxia of gait and mental disturbance

Thiamine Deficiency (Beriberi)

Chapter 10
Three forms:
1. Wet beriberi: generalized edema, acute cardiac symptoms and
prompt response to thiamine administration
2. Dry beriberi: edema not present, condition similar to peripheral
neuritis w/ neurological disorders present
3. Infantile beriberi divided into:
4. Acute cardiac - ages 2-4 months; sudden onset of cardiac s/sx
such as cyanosis, dyspnea, systolic murmur & pulmonary edema
w/ rales
5. Aphonic - ages 5-7 months; insidious onset of hoarseness,
dysphonia or aphonia
6. Pseudomeningeal - ages 8-10 months; signs of meningeal
irritation w/ apathy, drowsiness & even unconsciousness; occurs
more often

Riboflavin (Vit B2)

1. Adequate amounts of B2 is present in eggs, milk, meat & cereals.
Deficiency is often seen in chronic alcoholics due to their poor
dietetic habits.
2. Symptoms associated with riboflavin deficiency include,
glossitis, seborrhea, angular stomatitis, cheilosis and
photophobia.

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 192 Nutritional Deficiency

3. Riboflavin decomposes when exposed to visible light. This

characteristic can lead to riboflavin deficiencies in newborns
treated by phototherapy.

Riboflavin (Vitamin B2)

Functions:
1. Acts as coenzyme of flavoprotein important in a. a., f. a. & CHO
metabolism & cellular respiration
2. Needed also by retinal eye pigments for light adaptation

Riboflavin (Vitamin B2) Deficiency

Clinical Manifestations:
Chapter 10

1. Characteristic lesions of the lips, the most common of which are

angular stomatitis and cheilosis
2. Localized seborrheic dermatitis of the face may result such as
nasolabial seborrhea or dyssebacia and angular palpebritis
3. Scrotal or vulvar dermatosis may also occur
4. Ocular s/s are photophobia, blurred vision, itching of the eyes,
lacrimation & corneal vascularization

Niacin (Vit B3)

1. Niacin is available in both animal & plant food and is made in
the body from tryptophane.
2. Severe deficiency causes pellagra with glossitis, dermatitis,
diarrhea, depression and dementia.
3. Hartnup disease, malignant carcinoid syndrome & Isoniazid can
lead to niacin deficiency .
4. In large doses niacin lowers plasma cholesterol but it elevates
blood glucose & uric acid levels, so it is not recommended with
diabetes & gout.

Pyridoxine (Vit B6)

1. Pyridoxine functions as a cofactor in enzymes reactions required
for the synthesis & catabolism of the amino acids as well as in
glycogenolysis.

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 Nutritional Deficiency 193

2. Widely available in diet & deficiency may follow INH

&pencillamine therapy.
3. Deficiency can cause neonatal seizures, cheilosis,
glossitis&neuroitis.

Pyridoxine Deficiency
Clinical Manifestations:
1. Three different types
• Neuropathic, due to insufficient neurotransmitter
synthesis, such as irritability, depression & somnolence
• Pellagrous, due to low endogenous niacin synthesis, such
as seborrheic dermatitis, intertrigo, angular stomatitis
&glossitis

Chapter 10
• Anemic, due to low porphyrin synthesis, such as
microcytic anemia &lymphopenia
2. In genetic diseases involving pyridoxal phosphate enzymes
also xanthurenicaciduria, cystathioninuria&homocystinuria
COBALOMIN (VIT B12)
1. B12 functions as a cofactor for enzymes required for the
catabolism of fatty acids & the conversion of
homocysteine to methionine.
2. B12 is not available in plant & deficiency may occur in
strict vegetarians & in pts with GIT problems & those on
prolonged antibiotic treatment.
3. Deficiency causes megaloblastic anemia, SACDC, & high
homocysteine in blood which is a risk of IHD & stroke.

Cobalamine (Vitamin B12) Deficiency

Absorption: Vitamin B12 + glycoprotein (intrinsic factor) from
parietal cells of gastric fundus  terminal ileum absorption + intrinsic
factor + Ca++  blood
Etiology:
• Congenital Pernicious Anemia: Lack of secretion of intrinsic
factor by stomach manifest at 9 months-10 years as uterine stores
become exhausted
• Inadequate intake or dietary deficiency rare

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 194 Nutritional Deficiency

▪ Strict vegetarian diet

▪ Not commonly seen in kwashiorkor or marasmus
▪ Breast-fed infants whose mothers had deficient diets or
pernicious anemia
• Consumption or inhibition of the B12-intrinsic factor complex
• Vitamin B12 malabsorption from disease of ileal receptor sites
or other intestinal causes

Cobalamine Deficiency

Clinical Manifestations:
1. Megaloblastic anemia that becomes severe
2. Neurological includes ataxia, paresthesias, hyporeflexia,
Chapter 10

Babinski responses, clonus & coma

3. Tongue smooth, red & painful

FOLIC ACID
1. Folic acid is obtained from yeasts and leafy vegetables as well as
animal liver. Animals can’t synthesize folate, thus, it must come
from diet.
2. Folate is needed for synthesis of nucleic acids
3. Deficiency causes megaloblastic anemia & neural tube defects in
utero.
4. Used for treatment of chronic hemolytic anemia.

Specific Nutritional Deficiencies

Iodine Deficiency
Iodine deficiency – thyroid
“Simple goiter is the easiest of all known diseases to prevent . . .
It may be excluded from the list of human diseases as soon as
society determines to make the effort” David Marine 1923

Iodine Deficiency: Severe

Goiter: most commonly recognized consequence (enlarged thyroid)

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 Nutritional Deficiency 195

Occurs when thyroid gland is unable to meet the metabolic

demands of the body through sufficient hormone production –
thyroid compensates by enlarging.

Cretenism: proximal pyramidal signs, intellectual impairment,

primitive reflexes
Only occurs with severe fetal iodine deficiency

Iron Deficiency
• Iron is critical for body:
1. Carries oxygen to tissues from lungs
2. Transports electrons within cells
3. Integral part of important enzyme reactions

Chapter 10
• Anemia is caused most commonly by iron deficiency (anemia is
found in 40-60% of women and children in developing countries)

Iron Deficiency Consequences

• Iron deficiency anemia
• Iron deficiency results in:
1. Decreased work capacity and work productivity
2. Permanently impaired development
3. Psychomotor development of anemic children will be reduced
by 5-10 IQ points
4. Increased morbidity and mortality from infections
5. Decreased growth

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