Endocrine

Thyroid
Hypothalmic hormone: TRH (Thyrotrpoin Releasing hormone)
stimulates Pituitary release of TSH
Pituitary hormone: TSH (Thyroid stimulating Hormone/Thyrotropin)
Feedback ● Stimulus for thyroid hormone production by the thyroid gland
(+)/ (-) ● Also exerts growth effects on thyroid follicular cells
Gland hormones: T4 (Thyroxine/Tetraiodothyronine) & T3 (Triiodothyronine)
T3, is the active form of thyroid hormone. Though it represents only 20% of the released hormone, the majority of T3
comes from the peripheral conversion of T4 to T3
T4 and T3 can then exert negative feedback on the anterior pituitary with high levels of T3/T4 suppressing TSH
secretion and low levels of T3/T4 stimulating TSH release (This feedback effect is a PHYSIOLOGICAL phenomenon
and gets “AGGRAVATED” in pathological state of the gland)

Thyroid hormone: “clinically relevant” Physiological functions ONLY mentioned here

Atmosphere of the body: induces Thermogenesis
Basal metabolic rate: Increases
 Sytemic
 Of almost EACH organ: so “activity” of many organs are influenced by thyroid hormones
CNS:
 During the prenatal period, it is needed for the maturation of the brain.
 Throughout the life: affect mood +concentration+ memory + alertness
“Dietary” effects:
 Induce lipolysis or lipid synthesis depending on the metabolic status
 Stimulate the metabolism of carbohydrates
 Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
Dermal: Influences breakdown of protein-mucopolysaccharides (Glycosaminoglycans and others) of dermal
connective tissue network. These protein-mucopolysaccharides are HYDROPHILIC (binds water)
Electrolyte: Sodium “conserving” hormone
Fertility:Thyroid hormone affects Fertility
Gynaecological: Affects menstruation, ovulation
Hypothyroidism
Types:
Primary: diseases intrinsic to the thyroid gland
Secondary: diseases Extrinsic to the gland: Underactive Pituitary leads to underproduction of TSH, so Thyroid
becomes underactive
Causes of Hypothyroidism:

Goitrous causes (i.e tendency to enlarge in size) Non-goitorus causes

I: Iodine deficiency P: Post I131 ablation
I: Inflammatory: Hashimoto’s Thyroiditis P: Post Thyroidectomy
I: Iatrogenic: Amiodarone/Lithium P: Postpartum Thyroiditis
I: Inborn error: Dyshormonogenesis P: Pituitary disease(Secondary hypothyroidism)
(due to enzyme deficiency)
All “I”s & all “P”s except Pituitary diseases: Primary Hypothyroidim ( so here TSH LEVEL will be HIGH)
“I”s: Glandular tissue is intact, so HIGH level of TSH can exert it’s “growth effect” on the gland leading to Goitre
“P”s: Glandular tissue is destroyed/ shrinks: so HIGH level of TSH CANNOT exert it’s “growth effect”, so NO goitre
Pituitary disease: Secondary hypothyroidism (so here TSH LEVEL will be LOW)
Clinical features: Develops very insidiously and can be widely variable
A: Asymptomatic
OR
≥ 1 of the followings
A: Asthenia: Weakness/lack of energy/lethargy
A: Appearance: facial puffiness with coarse features
dry lustureless hair with tendency of Hair fall
B: Body weight: gain
BP: DBP rises
C: Cold intolerance
C: Constipation
C: Congenital cases
 Children: growth failure, delayed dentition, pubertal delay or even rarely, precocious puberty.
 Neonates/infant: hoarse cry, prolonged jaundice, mottled skin, umbilical hernia, constipation, poor feeding
CNS:
 A:attention deficit
Biochemical “manifestation”
 B: behavioural disturbance
D: Dyslipidemia
 C: Concentration Lack
E: Electrolyte disturbance: Hyponatremia
 D: Dementia
 E: Extereme deficiency: Myxoedema coma/crisis: confusion/convulsion/coma
Dermal: dry, thick, coarse skin
E: Extremity:
 Bradycardia
 Carpal tunnel syndrome( Entrapment neuropathy of Median nerve)
 Skin: dry, thick, coarse with mildly edematous (deposition of hydrophilic protein-mucopolysaccharides)
 Delayed relaxation time of jerks: best elicited in ankle jerk
F: Fertility issues: subfertility/infertility
G: Goitre: MAY be visibile
G: Gyane: Erratic/irregular cycle
H: Husky voice

Investigations:
Blood: Subclinical hypothyroidism
[Link] function test (TFT): TSH, FT4, FT3 TSH is high, but the T4 is normal
1. Primary Hypothyroidism: low T4 and a high TSH level
2. Secondary Hypothyroidism: low T4 & low TSH
Parameter Subclinical Hypothyroidism Overt Primary Hypothyroidism Secondary Hypothyroidism
T4 Normal Low Low
TSH High High Low/Normal
2. Anti-TPO antibodies: Autoimmune thyroiditis: high levels of Anti-TPO antibodies

“Footnote” about TFT( Not a “must know” information)

T3 is not routinely measured in the diagnosis of hypothyroidism as in milder forms of hypothyroidism, the increased TSH stimulates the
selective production of T3 and this may result in a high/normal T3. However, in severe varieties of hypothyroidism, the T3 is also low.
Free hormone(FT4/FT3) estimations (which estimate the concentration of thyroid hormones that are not bound to circulating proteins)
are advantageous as they measure the metabolically active component, and also because they are not affected by conditions which
increase or decrease the levels of thyroid-hormone binding proteins.
Treatment: Hormone replacement therapy: Oral L-thyroxine
Decision to treat/ not to treat: OFTEN depends on the TSH level
Primary hypothyroidism Secondary hypothyroidism: Always start treatment
1. Overt Hypothyroidism: Always start treatment (there is still No “TSH tablet”!!..so treated with L-thyroxine)
2. Subclinical hypothyroidism
 TSH > 10 mIU/L: Always start treatment
 TSH levels of 5-10 mIU/L: Treat ONLY under certain clinico-biochemical situations

Pregnancy/planning for pregnancy Very high titre of Anti-thyroid antibodies

Infertility Dyslipidemia
Menstrual irregularities Unexplained hyponatremia
Goiter
(Normal Upper limit: although varies slightly with the ASSAY method 5 mIU/L is considered to be the “cut off”)
Principles of Thyroxine therapy
1. Dose: depends on the body weight. Dosing regime- ‘’Start low and go slow” particularly in elderly patients
2. Long term therapy, most of the time to be continued lifelong
3. Ideally to be taken in the morning in empty stomach

Patient monitoring/surveillance: This is for ALL patients who are on L-thyroxine replacement therapy
Target: to achieve & maintain Euthyroid state (means biochemically TFT should be brought back to NORMAL)
Periodic(4-6 monthly) TSH estimation- for surveillance FT4 and FT3 estimation is not essential
TSH high TSH Low
High/Low TSH…. means circulating thyroid
Undercorrection Overcorrection hormone is still giving Pituitary a “STRONG”
feedback in an attempt to achieve homeostasis
Compliance issue ??
…..Now think about the physiology of
Dose to be decreased
Pituitary- gland axis!!
Non Compliance Compliance okay

Rectify compliance Dose to be increased

SubClinical Thyroid Disease….just for your information (nothing more!!)

Though it is recognized that patients with SCTD may have subtle symptoms of thyroid dysfunction, the definition is
purely a biochemical definition: SCTD is defined as serum free T4 (FT4) and total or free T3 (FT3) levels within their
respective reference ranges in the presence of abnormal serum TSH levels. Serum TSH is undetectable or low in
subclinical hyperthyroidism (SHyper), and it is increased in subclinical hypothyroidism (SHypo)
 Myxedema coma (myxedema crisis)
Myxedema coma (myxedema crisis) is a rare but life-threatening condition that represents severe hypothyroidism
with physiological decompensation.
At risk patients: Occurs in patients with long-standing Undiagnosed or Undertreated hypothyroidism
Precipitating factor(s): “Physiological” stress:
1. Critical illness: eg. Infection, CVA, Heart failure 2. Severe Trauma 3. Post-operative stress
C/F
Hypothyroidism: PMH of hypothyroidism: may be +, but background hypothyroidism may be undiagnosed, so
Myxedema crisis can be the initial/first presentation of the patient
Hypothermia
Heart rate: Bradycardia
Hypotension (poor cardiac contractility due to profound deficiency of thyroxine)
Hypoactivity: Altered sensorium/Behavioural disturbance/Confusion/Convulsion/Coma/Delirium/Drowsiness
Hypoventilation: Drowsiness (CO2 retention due to central depression of ventilatory drive)
Hyponatremia: asymptomatic or symptomatic (Lack of thyroxine promotes Natreuresis)
Hypoglycemia: asymptomatic or symptomatic

Investigations:
Diagnostic purpose: Thyroid function test: Hypothyroid pattern:
Elevated TSH with low FT4 and FT3 indicates primary thyroid disorder
Low TSH level with low FT4 and FT3 indicates pituitary or hypothalamic dysfunction.
Assessment purpose: To look for any ppting factor+ biochemical disturbance associated with severe hypothyroidism
CBC Electrolytes: Na/K
CRP ABG
Ur+ Cr ECG
Infection/sepsis screen: CxR/Urine R.E/M.E/C.S+ Blood C/S+ Procalcitonin
Treatment:
Definitive:
1. Thyroxine replacement: High dose Levothyroxine (Ideally initially IV: IV thyroxine preparation is NOT available
in India, so we rely on PO/Ryles tube administration)
2. Corticosteroid: IV Hydrocortisone: until (an undiagnosed) adrenal insufficiency is excluded.
[Because if there is an underlying adrenal insufficiency there is a potential risk of precipitating acute adrenal insufficiency caused by
the accelerated metabolism (that follows T4 therapy) which increases demand of cortisol. Primary hypothyroidism may have
concomitant primary adrenal insufficiency as “autoimmune hypos” may affect multiple glands simultaneously. Secondary
hypothyroidism which is due to hypopituitarism, so also may have secondary adrenal insufficiency]

Supportive: ≥ 1 of the followings depending on clinical scenario

1. Hypothermia:
 Passive rewarming using ordinary blankets and a warm room
 Active rewarming using external devices: Bair Hugger blanket is the temperature management system
2. Hypotension: IV fluid resuscitation. Refractory hypotension may need vasopressors
3. Hypoventilation: Intubate and ventilate
4. Hyponatremia: IV Saline
5. Hypoglycemia: IV Dextrose
6. Treat any precipitating factor: Antibiotic: as sepsis is a common ppting factor
 Hashimoto thyroiditis
Characterised by destruction of thyroid cells by various cellular and antibody-mediated immune processes.
Pathophysiology
Initiating process - Ab to thyroid antigens- Anti-thyroid peroxidase (anti-TPO) + Antithyroglobulin (anti-Tg)

Inadequate hormone production and secretion Glandular size enlargement, but ultimately shrinks

Gradual destruction of the gland

Permanent Hypothyroidism
C/F
1. Many are asymptomatic till T4/T3 becomes significantly low
2. Frank features of Hypothyroidism……(if Hashimoto comes as Long Q…write c/f in details)
3. Goitre- initially and may be significant in size but ultimately gland shrinks
5. Associated autoimmunity diseases - Pernicious anemia, Adrenal insufficiency and Ty1 DM etc
Investigations
1. TFT- TSH + FT4, FT3 - normal/low (Low TSH with Normal T4 & T3 = Subclinical Hypothyroidism…see previous topic)
2. Antibody-Anti TPO/Anti TTG- confirms Hashimoto, however rarely antibody negative
2. USG of thyroid

Management
Pharmacotherapy: Thyroid hormone replacement- dose titrated Levothyroxine sodium administered usually for life.
Surgery: Indications for surgery include the following:
Large goitre with obstructive symptoms: dysphagia/ stridor (caused by external obstruction)

de Quervain thyroiditis/Subacute thyroiditis

A self-limited virus induced thyroid disease associated with a triphasic clinical course of thyrotoxicosis,
hypothyroidism, and finally complete recovery of thyroid function.
Pathophysiology
Initiating process –Viral Infection

Follicular destruction No Glandular enlargement, but tenderness+

Preformed T4 &T3 may "leak" into the circulation Transient Thyrotoxicosis (often symptomatic)

Gradual Exhaustion of follicles Hypothyroidism

Complete Recovery as viral infection settles

C/F
1. Systemic features- Fever/Sore throat 2. Frank features of Hypothyroidism
2. Transient Thyrotoxic features 4. Goitre- initially with significant tenderness
Investigations
1. ESR- often high 3. Antibodies- Negative
2. TFT- depends on the stage of the disease 4. USG of thyroid
 Thyrotoxic phase- TSH + FT4, FT3 – high
 Hypothyroid phase- TSH↑ + FT4, FT3 - normal/low
 Recovery phase and thereafter- Normal
Treatment
1. NSAID- for fever/sore throat 2. Thyrotoxic phase- symptomatic control with Beta blocker
3. Thyroid hormone replacement- usually not required as complete recover is the outcome in almost all cases
 Riedel thyroiditis
A chronic inflammatory disease of the thyroid gland, probably autoimmune in nature, characterised by dense fibrosis
that replaces normal thyroid parenchyma and often invades adjacent structures of the neck
C/F- any ≥ 1following
1. Thyroid manifestations- Many are euthyroid, but permanent hypothyroidism can develop
2. Compressive manifestations-
 Stridor - tracheal compression  Hypoparathyroidism
 Hoarseness - RL nerve involvement  Dysphagia- Oesophageal compression
3. Goitre- hard, fixed, painless goitre- the feel closely resembling anaplastic carcinoma. The character of the thyroid
gland is often described as stony or woody
4. Few ultimately develop extracervical manifestation of multifocal fibrosis-retroperitoneal/mediastinal fibrosis
Investigations
1. TFT- high TSH+ normal/low T4/T3
2. FNAB (B=biopsy)-fibrotic changes in the gland; however, cannot always reliably distinguish between RT and
anaplastic thyroid carcinoma and open surgical biopsy is required.
Treatment
1. Pharmacotherapy- Corticosteroids and Tamoxifen (both help- how??....wait till you become a DM endocrine!)
2. Thyroid hormone replacement
3. Surgery- serves dual purpose of establishing the diagnosis and relieving tracheal compression

Thyrotoxicosis
Thyrotoxicosis: the clinico-biochemical state resulting from excess thyroid hormone in the circulation/ system
(irrespective of the source where it is coming from)
Hyperthyroidism: an overactive Thyroid gland i.e sustained overproduction of hormone from the thyroid gland

Thyrotoxicosis with hyperthyroidism Thyrotoxicosis without hyperthyroidism

Primary hyperthyroidism Exogenous:
Immune: Graves’ disease ● Iatrogenic: Overcorrection of Hypothyroidism
Intrathyroid Hormonally active autonomous nodule(s) Ectopic Thyroid: Ovarian Teratoma(stuma ovarii)
 Solitary toxic nodule Excess release of stored hormone: Thyroiditis
 Multinodular disease ● Dequervians
Iodine excess (Jod-Basedow phenomenon) ● Post partum
Secondary hyperthyroidism
Pituitary disease: TSH-secreting pituitary adenoma
Pregnancy related: Gestational Trophoblastic disease (very high level of Beta HCG “MIMMICKS” TSH due to it’s
structural similarity with TSH)

Clinical manifestations of a thyrotoxic patient

Manifestations due to EXCESS circulating thyroid hormone Manifestations UNIQUE to the underlying disease
Hormone dependent & cause independent Disease dependent & hormone independent
CAUSED by hormone excess CAUSED by pathophysiology of that particular disease
Therefore these manifestations are present in May occur with each “thyrotoxicosis producing disease”
EACH thyrotoxic patient irrespective of the However that of Grave’s disease is most unique (& important)
cause or disease responsible for thyrotoxicosis
Most of the thyrotoxic manifestations are due to excess hormone leading to
 Increased sensitivity to the sympathetic nervous system
 Increased Basal metabolism
 Graves’ disease
Autoimmune disease characterized by a triad of Endocrinopathry, Opthalmopathy & dermopathy.
[Link]: Antibodies bind to the receptors “meant for TSH” of the thyroid cells & stimulates
thyroid hormone production & growth of the gland in an UNCONTROLLED manner
 Functional alteration: Hyperthyroidism with Thyrotoxicosis
 Sructural alteration: increase thyroid vascularity and growth Goiter
Activating 2. Infiltrative/Graves Ophthalmopathy
Antibody antibodies bind to the retro-orbital tissues T-cell inflammatory response + release of cytokines &
activation of fibroblasts accumulation of glycosaminoglycans + fibrofatty tissue/material
Retro-orbital accumulation of these may lead to
 Compression and/or Inflammation of Optic nerve
 Compression and/or Inflammation of EOM/EOM tendon
 Forward protrusion of the globe(eye ball)
[Link] dermopathy Activation of dermal fibroblasts leading to typical skin change: most
commonly seen in the anterior leg: hence called Pretibial myxedema
Endocrinopathy, Dermopathy & Opthalmopathy are independent of each other and therefore can occur in an
isolated manner or any varying combination
** “stimulating” antibodies are functionally SIMILAR to TSH but DON’T “listen” to the normal feedback inhibition

Thyroid Eye disease

Thyrotoxic eye manifestations Graves’ Opthalmopathy

Manifestations due to excess circulating thyroid hormone Manifestations due to Infiltrative Ophthalmoapthy
Sympathetic overactivity causes Spastic Muller’s muscle 1. Forward protrusion: Proptosis/Exophthalmos
Lead retraction Exposure keratitis: Red/gritty/painful eye
Stare look with infrequent blinking Extreme/Severe cases: Vison loss
Lid lag: lid doesn’t follow the globe during downward gaze Lid edema/redness
(Sensitisation of Mullers’s muscle to circulating Catecholamine) 2. Extraocular muscles(EOM) weakness:
Dipolpia
Weakness of EOMs ellictable
3. Optic nerve damage: Vision loss

For “Non MBBS- MS Opthlmos/ DM endocrinos” For “Final MBs”!!

NOSPECS classification of Grave’s Ophthalmopathy Dalrymple’s sign: Lid retraction
Score Kocher’s sign: Stare look
0 No signs or symptoms Stellwag sign: incomplete and infrequent blinking
1 Only signs Von graffe’s sign: Lid lag
2 Soft tissue involvement, with symptoms and signs Mobius sign: poor convergence (MR palsy)
3 Proptosis Goffory sign: absent creases in the forehead on
4 Extraocular muscle involvement superior gaze
5 Corneal involvement PS: Though it’s a favourite topic of MANY “……”
6 Sight loss (hmm..hmm!!) particularly in surgery ward…Thanks to
Corona, you don’t have to face them
 Proptosis vs Exopthalmus…another “favourite” of the same “….”
Basically NO DIFFERENCE!!!!... NO DIFFERENCE!!!!.... NO DIFFERENCE!!!!
Proptosis: defined as abnormal protrusion of the eyeball (“globe”) beyond the orbital margin
Although the word “Exophthalmos” is synonymous to it, it has become customary( NOT compulsory!!) to use the
term exophthalmos to describe a proptosis secondary to Thyroid eye disease( probably because “E”ndocrinologists
love the letter “E”!!)

Clinical diagnosis: by “looking” at the patient’s eyes

Confirmation: Hertel’s exophthalmometer: the distance between lateral orbital rim & corneal apex is used as a
measure for proptosis. Normally the distance varies between 10- 21 mm and is symmetrical in both eyes. Therefore a
distance of >21 mm or more than 2 mm asymmetry between the two eyes is abnormal.
Causes: depending on the cause it can be Unilateral or Bilateral
Vascular: Rero orbital “SOLs”: Aneurysm/Tumor/ Carotido-Cavernous fistula
Endocrinopahty: Graves’ disease(usually Bilateral)
Inflammatory So, Proptosis/Exophthalmus DOES NOT automatically mean
 Orbital cellulitis/Abscess/TB/Fungal granuloma it’s Graves/Thyroid patient!!
 Sarcoidosis/Histiocytosis/

For Next section…..Let’s recapitulate!!!!

Clinical features of a Thyrotoxic patient:

Includes
“EXCESS hormone dependent” manifestations ++ “DISEASE dependent/related UNIQUE” manifestations
NO relation with excess hormone
DOES NOT vary with the disease Causing Thyrotoxicosis VARIES with the disease Causing Thyrotoxicosis

Severity may vary depending on the degree of “excess hormone” Each disease may cause it’s unique manifestations
Present in ALL thyrotoxic patients but MOST COMMON in Graves disease
IRRESPECTIVE of the disease Causing Thyrotoxicosis
Clinical features of a Thyrotoxic patient:

The clinical manifestations of thyrotoxicosis are independent of its cause. However, certain features of a
THRYOTOXIC patient like size of the gland, presence or absence of extra thyroidal manifestations vary with the
underlying etiology and may provide clues to this.
Asymptomatic
OR ≥ 1 of the followings Thyrotoxic eye manifestations
 Lead retraction
Appearance:
 Stare look with infrequent blinking
 Face: Anxious/ restless
 Lid lag: lid doesn’t follow the globe during downward gaze
 Eye: Eye manifestations Manifestations due to Infiltrative Ophthalmoapthy: only in Graves’
BP: may be high  Forward protrusion: Exposure keratitis:
Body weight: rapid loss (but appetite preserved)  Red/gritty/painful eye
CNS: Neuropsychiatric  Vison loss
 Attention deficit; Anxiety  EOM weakness: 1. Diplopia 2. Weakness of EOMs ellictable
 Behavioural disturbance: Irritability  Optic nerve damage: Vision loss
 Concentration lack
 Disturbed mood
 Extreme cases: agitation/behavioural disturbance/confusion/convulsion/ delirium/emotional lability
Dermal: moist skin
Diarhhoea (Hyperdefecation)
Extremity
 Tachycardia
 Tremor: fine tremor
 moist palm
 Hyperreflexia
 Graves Dermopathy: ONLY in Graves’ disease: Bilateral, firm, shiny pink to purple-brown plaques or
nodules particularly over the shin: also called Pretibial Myxedema. Hair follicles are sometimes prominent,
giving a peau d'orange texture. Localised edema may develop.
Fertility: subfertility
Feels hot (Heat intolerance)
Gynae: Erratic mensturation
Goitre: ONLY in certain diseases
 Graves’ disease: May be diffuse goiter with Thyroid bruit
 Toxic adenoma: Nodule(s) may be palpable
Investigations:
Aim: [Link] diagnose thyrotoxic state [Link] diagnose the underlying disease

Biochemical confirmation of thyrotoxicosis: Thyroid function test: FT4, FT3, TSH estimation:
Typically shows Elevated FT4 and FT3; TSH level: varies according to the underlying disease

Supressed: Elevated:
Primary Hyperthyroidism Secondary (Pituitary disease) Hyperthyroidism
Thyrotoxicosis without hyeperthyrodism
Therefore TSH level acts an index of the pattern of underlying disease
Subclinical hyperthyroidism: suppressed TSH with Normal FT4 &FT3
 The ratio of T4 to T3 frequently has a characteristic pattern in different thyrotoxic states.
 Graves’ disease and toxic nodular goiter typically: increasedT3 production, with a T3 /T4 ratio > 20.
 Thyroiditis, I2 exposure, or exogenous levothyroxine intake: T4 is the predominant hormone and T3 /T4< 20.
 T3 toxicosis: A small number of patients may present with an increased FT3 and normal T4: called“T3 toxicosis”.
To diagnose the underlying disease: Nature of these tests depend on the pattern of Thyroid function test
Primary Hyperthyroidism pattern: “Investigate thyroid”
TSH-R antibodies: Grave’s disease
Imaging
1. Thyroid ultrasound: USG appearance is often suggestive of a particular underlying disease:
 Diffuse enlargement with increased blood flow: Graves’ disease
 Identification of thyroid nodule(s): Toxic Nodular disease

2. Nuclear medicine scanning: Radioactive iodine uptake scan: shows an increased uptake by an overactive gland
Distribution/ Pattern of increased uptake varies according to the disease:
 Diffusely increased uptake: Graves’ disease
 Foci/focus of increased uptake: Solitary toxic nodule/ Multiple toxic nodule (“hot nodule”)

Secondary Hyperthyroid pattern: (“Investigate Pituitary”): Pituitary function test +Imaging of Pituitary

Treatment of thyrotoxicosis

Supportive: Definitive: Curative treatment of the underlying disease

Manifestation directed Hormone directed Disease directed & depends on the underlying disease

Beta blockers Antithyroid drugs Surgery Radio I2 ablation

Manifestation directed: Sympatholytic drugs

1. Nonselective Betablocker: Propranolol [Link] Betablocker if Arrhythmia is the only problem

Propranolol blocks the response to catecholamines at the receptor site and ameliorate some of the manifestations of
thyrotoxicosis like tremor, palpitations, anxiety, excessive sweating, eyelid retraction, and tachycardia: effects
appear to be mediated largely through modulating the increased sensitivity to the sympathetic nervous system
induced by excess thyroid hormone. Propranolol (but not other β-adrenergic agents) may also weakly block the
conversion of T4 to T3 via a mechanism independent of its effect on catecholamine signaling.

Antithyroid drugs: used to make the patient Euthyroid by the the time a definitive treatment is being contemplated
therefore long term term use is reserved only when a definitive treatment is not feasible
1. Imazoles: Carbimazole/Methimazole [Link]

Radioablation: Radioactive Iodine ablation: 131I has become the most widely used therapy for hyperthyroidism.
RAI is considered effective, safe, and relatively inexpensive. The ionizing effect of β particles destroys the thyroid cells
by an early inflammatory response, necrosis of follicular cells, and vascular occlusion. Subsequently chronic
inflammation and fibrosis result in a decrease in thyroid size and an impaired ability to secrete thyroid hormone.
Ultimately, almost all patients develop hypothyroidism following 131I.
Surgery: Subtotal or total thyroidectomy
Indication of surgery:
Large goiter causing compressive symptoms or cosmetic disfigurement
Suspicion of malignancy
Graves’ ophthalmopathy (may paradoxically worsen after RAI ablation)
Pregnancy contraindication of RAI

Children contraindication of RAI

Patient preference
 Treatment of Graves’ disease

Rx of Endocrinopathy Rx of Ophthalmopathy Rx of Dermopathy

Treatment of thyrotoxicosis
Supportive: Definitive: Curative treatment
Manifestation directed: Beta blockers Surgery
Hormone directed: Antithyroid drugs Radio I2 ablation
Rx of Ophthalmopathy Ophthalmology referral
Supportive: Definitive:
Eye protection: Drugs: Methyprednisolone/Cyclosporine/Rituximab
Protective gears: Eye pad/Glass Orbital decompressive surgery
Lubricant: Artificial tear drop Orbital radiotherapy
Rx of Dermopathy: Topical corticosteroid
Thyrotoxic crisis
Thyroid storm (thyrotoxic crisis) is an acute, life-threatening, hypermetabolic state induced by excessive release of
Thyroxine in individuals with thyrotoxicosis.
Pathogenesis: Severely exaggerated effects of Thyroxine due to increased release (with or without increased synthesis)
Background: Underlying Thyrotoxicosis: undiagnosed or a known patient of thyrotoxicosis
Precipitating factors: Thyroid storm is precipitated by the following factors in individuals with thyrotoxicosis:
Sepsis RAI therapy
Surgery Noncompliance with antithyroid medications
Anesthesia induction Molar pregnancy
C/F: are due to ≥ 1 of the followings:
Hyperthyroidism: background of thyrotoxic manifestations
Hyperpyrexia
Hyperhydrosis: excessive sweating
Hyperactivity: anxiety/agitation/behavioural disturbance/confusion/convulsion/ delirium/emotional lability
Heart
● Hypertension with wide pulse pressure ● Heart rate:Tachycardia disproportionate to fever
● Hypotension in later stages with shock ● Heart Rhythm: Arrhythmia
Hyperperistalsis: Nausea, vomiting, diarrhoea, abdominal pain
Hyperreflexia
Investigations: Thyroid function test:
Low TSH level with high FT4 and FT3 indicates primary thyroid disorder
Elevated TSH with high FT4 and FT3 indicates excess TSH secretion: pituitary or nonpituitary source
Management:
Definitive:
1. Antiadrenergic drugs: Propranolol: orally or via nasogastric tube: dose based on heart rate and blood pressure
2. Antithyroid drugs: Carbimazole/Methimazole- to block further synthesis of thyroid hormones
3. Bile acid sequestrant: Cholestyramine prevents reabsorption of free Thyroxine in the gut
4. Conversion blocker: Glucocorticoids to decrease peripheral conversion of T4 to T3
5.’’Constipator”: Iodine compounds: Lugol iodine or KI: orally or via NG tube to block the release of Thyroxine
Supportive measures: ≥ 1 of the followings depending on clinical scenario
1. Supplemental oxygen 5. Heart: Antiarrhytmic
2. Ventilatory support 6. Hyperpyrexia: ice packs/cooling
3. Hypovolemia:IV fluid blankets/Paracetamol
4. Hypotension: IV fluid/vasopressors
 Solitary Thyroid nodule/Thyroid nodules
A single nodule or multiple nodules of the gland- palpable or radiologically visible
Causes/types/DD….(Short Notes)
1. Benign
a. Euthyroid b. Thyrotoxic/Hypothyroid
Benign cyst Toxic adenoma
Colloid nodule Thyroiditis
Hyperplastic nodule
2. Malignant: Medullary/Papillary/Follicular/Hurthle cell Ca (and many others!!)
C/F- depends on the cause
1. Thyrotoxic- usually pts of toxic adenoma
2. Euthyroid- Cyst/colloid/malignant
3. Nodule may/may not be palpable
4. Warning signs- suspicious of malignancy
1. Accelerated growth of nodule 5. Fixity to surrounding structures
2. Another lesion that suggests a distant
metastasis 6. Family history of thyroid cancer
3. Cervical Lymphadenopathy 7. Hoarseness of voice
4. Consistency: Hard
5. Painful nodule = benign, painless can be either
Investigations/Diagnostic approach(short notes)
1. TFT- Pattern depends on type of the nodule 2. Imaging-USG/Radionucleide Scan
Thyrotoxic patternToxic adenoma/de Quervain/ Rare pts of Hashimoto 3. Histopatholgical confirmation-
FNAB/FNAC
Hypothyroid pattern- Hashimoto
Normal TFT- Malignancy/Cyst/Colloid
Treatment: Thyroid nodule TFT
Imaging: USG Thyroid
The following USG patterns suggest malignancy: infiltration into regional structures
ill-defined borders, irregular shape
depending on USG patterns microcalcifications
absence of a halo
solidity
depending on USG patterns AP to transverse diameter ratio (A/T) > 1
suspicious regional lymph nodes
High risk/suspicion of malignancy Intemediate risk Low risk benign pattern Not meeting FNA size cut off
Surgery/ FNA if > 1 cm FNA if >1.5 cm FNA if >2 cm No FNA

Cytology

Malignant Suspicious Benign Indeterminate

Surgery Surgery Follow up Repeat FNA/ Excision biopsy

 Adrenal
Cortex Medulla

Hormone Neurotransmitters

Glucocroticoid Adrenal androgen Mineralocorticoid Adrenaline Noradrenaline

Cortisol Dehydroepiandrostenedione Aldosterone

Cortisol:
 Alters immunity
 BP ↑
 Bone: inhibits osteoblastic activity
 Collagen matrix: breakdown
 Diabetogenic
 Electrolyte: Na reabsorption & K excretion
 Fluid reabsorption
 Fat breakdown
Adrenal androgen: Reproductive function: musculinisation of females
Mineralocorticoid:
 Electrolyte balance: Na reabsorption & K excretion
 Fluid reabsorption

Hypothalamus: CRH/ Corticotropin releasing hormone

+ve stimulates
Pituitary ACTH/Corticotropin
Feed back stimulates
-ve Adrenal cortex

Glucocorticoid adrenal androgen

Aldosterone release
Mainly under Renin-Angiotensin- Aldosterone axis
 Cushing’s syndrome
Cushing’s syndrome represents the clinical syndrome resulting from prolonged and inappropriately high exposure of
the tissues to the glucocorticoids, irrespective of the source (Endogenous or Exogenous)
Cushing’s disease refers to the hypercortisolism that results from the excessive secretion of corticotropin (ACTH) by a
pituitary microadenoma.
Causes:
Cushing’s syndrome
With Hyperadrenalism Without Hyperadrenalism
Primary Hyperadrenalism (Non-ACTH dependent) Iatrogenic: Corticosteroid therapy
 Adrenal adenoma and carcinoma
Secondary Hyperadrenalism (ACTH dependent) By far the most common cause of Cushing
Think about these pts...They are “Glucocorticotoxic” but
Pituitary disease/Cushing’s disease
“excess” hormone is coming from an “exogenous” source
 ACTH secreting adenoma …So, “Endogenous” Pituitary-Adrenal axis is suppressed
Ectopic ACTH syndrome due to the negative feedback exerted by an excess hormone
state. So, practically the only source of steroid is the
Clinical features: “exogenous” one…That’s why if this supply is suddenly cut
(most are due to excess Glucocotricod +/- Androgen) off an acute adrenal insufficiency state develops as the
Asymptomatic endogenous axis will take some days to recover
That’s why ANYBODY on steroid for > 2 weeks if steroid
OR ≥1 of the followings needs to be stopped it is done in a step down manner
Appearance: (NOT ABRUPTY) to allow the axis time to recover: this
 Face: step down is commonly called TAPERING OFF STEROID
o Moon face
o Acne
o Hirsutism in females(excess facial hair)
 Trunk: centripetal obesity: Protruberant abdomen with thin limbs
 Central fat deposition: over areas like thoracocervical spine, supraclavicular region (Buffalo hump)
Body weight: Gain
Bone: Risk of osteoporosis: Asymptomatic Spontaneuos fracture: pain/ tenderness/ deformity
BP: Hypertension
CNS:
 Abnormal mood
 Attention deficit
 Behavioural disturbance: Irritibality
 Concentration lack
 Dementia
 Depression
 Euphoria
Dermal:
 Easy brusibility
 Thinning of the skin
 Poor wound healing
 Pigmentation particularly in Pituitary dependent cases( high level of ACTH
Extremity: Proximal myopathy
Fertility: Infertility
Gynaecological: Erratic mensturation
Glycemic: high
Gastric: Gastric ulcer/Gastritis
Investigations: [Link] confirm the diagnosis & type 2. To look for any complications
1. To look for any complications
a. Blood: Elcetrolytes
Glycemic profile
b. Bone densitometry scan: to look for any osteoporosis
[Link] confirm the diagnosis & type
Suspected Cushing’s

Rule out exogenous Cushing’s: H/o exogenous glucocorticoid intake

Confirm Cushing’s/Hypercortisolism
24-h urinary free Cortisol: high
Overnight Dexamethasone suppression test:
Overnight Dexamethasone suppression test:
8 am Serum Cortisol level is measured after a single dose of Oral Dexamethasone given in the night before of the test:
Nonsupressibility of cortisol below the physiological cut off range is diagnostic of Cushing’s

Type of Cushing’s: ACTH level estimation/ CRH stimulation test

Serum ACTH estimation
CRH stimulation test: measure ACTH after CRH adminn
ACTH : Low Serum ACTH : high

Non ACTH dependent cause ACTH dependent cause

Investigate adrenal Source: Pituitary/Ectopic
Adrenal imaging: CT/MRI Adrenal Pituitary imaging: CT/MRI
Ectopic source:CECT Chest/abdomen
Cortisol is secreted in a pulsatile manner with a circadian rhythmicity; therefore there is an “overlap” of similar values
between normal subjects and Cushing patients, so, basal serum cortisol is not used for the diagnosis of Cushing. Even
increased levels of morning basal serum cortisol have a low sensitivity for the diagnosis of Cushing. Although some studies
have tried to find a cut-off for basal serum cortisol in Cushing, different guidelines do not recommend its use in the
diagnosis of Cushing.
Because Pituitary- Adrenal axis inhibited by a high Glucocorticoid level so nonsupressibility of Glucocorticoid level below
the “cut off range” following an exogenous Glucocorticoid confirms “autonomous” release- but his cannot differentiate
between a Pitutary & an Adrenal disease.
Management:
Surgical management
ACTH dependent Cushing:
Pituitary tumor: Trans-sphenoidal pituitary surgery (TSS)- Excision of adenoma
Ectopic ACTH-secreting tumor: Resection if feasible

Non ACTH dependent Cushing: Adrenalectomy unilateral as in adenoma or malignancy

bilateral in case of bilateral hyperplasia
Bilateral adrenalectomy performed in bilateral adrenal nodular hyperplasia and for failed TSS need careful follow-
up with steroid replacement.
Medical management:
Indication: Drugs:
Preoperatively to control cortisol levels Adrenolytic: Mitotane
Modulate ACTH release: Cabergoline/Octreotide/Pasireotide
Surgery contraindicated/not feasible
Surgery has failed Inhibits glucocorticoid receptor: Mifepristone/Etomidate
Inhibit steroidogenesis: Metyrapone/Ketoconazole
 Adrenocrotical insufficiency/ Hypoadrenalism(Underactive adrenal cortex)
Primary ACI
Immune related: slowly progressive autoimmune destruction of the adrenal cortex: Addison disease
Intra-adrenal hemorrhage
Infections:
 TB
 HIV
 Waterhouse friderichsen syndrome: fluminat aderenal failure in a case of Meningococcemia
Infiltrative: adrenal metastasis/ Hemochromatosis
Iatrogenic
Secondary ACI: ACI due to pituitary disease: Hypopituitarism: Tumor/trauma/ Iscaemic necrosis/ Irradiation
Mechanism of clinical manifestations:
Glucocorticoid deficiency
Minerelocorticoid deficiency
Adrenal androgen deficiency

Mode of presentation: depending on the underlying disease manifestations may develop insidiously or rapidly
Clinical features
Asymptomatic
OR ≥1 of the followings
Asthenia(EXTREME weakness/lethargy)
Appearance: Tired looking
BP:
 Low symptomatic or asymptomatic
 Postural hypotension
 Severe hypotension and hemodynamic instability in cases of acute adrenal crisis
Body weight: loss
CNS: altered sensorium
Dermal: Hyperpigmentation: dark brown or black
Distribution: knuckles, elbows, knees, mucous membranes of the oral cavity (especially the dentogingival margins
and buccal areas).Sunexposed areas
Darkening/deepening of naturally pigmented ares: palmar crease, nipple, areola
Hyperpigmentation of the skin and mucous membranes often precedes all other symptoms by months to years.
It is caused by the stimulant effect of excess adrenocorticotrophic hormone (ACTH) on the melanocytes to produce
melanin. The hyperpigmentation is caused by high levels of circulating ACTH that bind to the melanocortin 1 receptor
on the surface of dermal melanocytes.
Extremity: Pigmentation
Electrolyte imbalance: Hyponatremia & Hyperkalemia
Fertility: subfertility/infertility
Physiology: Mineralocorticoide (to some extent Glucocorticoid)
Gynaecologyical
Na retention and K excretion
 Erratic mensturation
 Sparse axillary, pubic hair (due to lack of adrenal androgen)
Investigations:
Adrenocortical insufficiency(ACI) suspected
“Basic knowledge”about ACTH stimulation test
To confirm: ACTH stimulation test Measures the ability of the adrenal cortex to respond to
Cortisol level fails to show “expected/ Predictable” ACTH by producing cortisol appropriately.
rise above the physiological“cut off margin” after Pre ACTH administration: sample for Serum Cortisol level
After a single dose of IM ACTH injection
ACTH administration
Post ACTH serial blood samples are taken 30, 60, 90
minutes post ACTH administration…
ACI confirmed ”Pre & Post ACTH” serum Cortisol level is measured

To confirm type: Serum ACTH level

ACTH high ACTH low

Primary ACI (So, Investigate for “Adrenal disease”) Secondary ACI (So, Investigate for “Pituitary disease”)

CT/MRI of adrenal CT/MRI of Brain (Pituitary)

Pituitary Function test: Estimation of other Pit. Hormones

Treatment: Most of the patients need lifelong Hormone replacement

1. Glucocorticoid replacement: Synthetic Corticosteroid
Usually Hydrocortisone: dosing schedule 2/3 rd of the total dose in the morning and 1/3 rd in the evening
This is to mimic the normal/Physiological “circadian rhythm 24-hour fluctuation of cortisol levels”
2. Mineralocorticoid (Aldosterone) replacement: Often not needed as most of the synthetic glucocorticoids have
mineralocorticoid like activity. However, if required- synthetic Mineralocoritcoid- eg. Fludricortisone

Just for Information!!……Synthetic Corticosteroids( better known as “Steroid”)

Synthetic corticosteroids are exogenous analogues of naturally occurring glucocorticoids and mineralocorticoids
produced by the adrenal glands- they differ in their POTENCY
 Acute adrenal crisis (Addisonian crisis)
Potentially life threatening condition due to severe adrenocortical insufficiency.
Etiopathogenesis: Can develop in either of these 3 sets of patients:
Known Adrenocortical insufficiency patients where the condition is usually precipitated by any 1 of the followings:
Inadequate replacement of Glucocorticoid
Severe “pathological” stressful conditions like Critical illness/Post-operative stress, particularly if Hormone
replacement dose has not been proportionately increased in these situations beforehand
Unrecognized/Undiagnosed cases of adrenocortical insufficiency: this can be the initial presentation
Sudden/Rapid failure of a previously healthy gland: acute adrenal Hemorrhage
C/F
Hypoadrenalism: may be a known case of- in these patients a precipitating factor must be looked for
Hypotension: Unexplained shock, usually refractory to fluid and pressor resuscitation
Hypothermia: may occur
Hypoactivity: altered sensorium
Hypoglycemic episodes (due to lack of glucocorticoid)
Hyperpigmentation: may be present
Investigation:
Diagnostic purpose:
Random Serum cortisol: Very low level is indicative of adrenal insufficiency.
ACTH stimulation test: diagnostic test- treatment SHOULD be started on the basis of suspicion pending the result
Assessment purpose: To look for any ppting factor+ biochemical disturbance associated with severe hypothyroidism
CBC
CRP
Ur+ Cr
Electrolytes: Na/K
ABG
ECG
Infection/sepsis screen: CxR/Urine R.E/M.E/C.S+ Blood C/S+ Procalcitonin
Treatment:
Definitive: Glucocorticoids in supraphysiologic or stress doses.
Dexamethasone does not interfere with serum cortisol assay and, thus, may be the initial drug of choice. However,
because Dexamethasone has little mineralocorticoid activity, fluid and electrolyte replacement are essential.
Hydrocortisone 100 mg IV every 6 hours is the preferred treatment to provide mineralocorticoid support.
Delaying glucocorticoid replacement therapy while awaiting the results of the ACTH stimulation test is inappropriate
and dangerous.
Supportive:
Aggressive fluid replacement with 5% or 10% IV dextrose or Saline
Treatment of hyperkalemia
Look for a precipitating cause and administration of empiric antibiotics is indicated.
Vasopressors (Dopamine/Noradrenaline) may be necessary to combat hypotension.
 Pituitary
“bandmaster of the hormonal orchestra”, the pituitary gland synthesizes and releases various hormones that affect
several organs throughout the body
Hypothalamus
Median eminence:Trophic hormone releasing hormones Supraoptic & paraventricular nucleus: produce hormones
Via a portal venous system transport through the pituitary stalk
Stimulates Adenohypophysis Pituitary stored in Neurohypophyis

Adenohypophysis (anterior pituitary) Neurohypophysis (Posterior pituitary)

manufactures stores and releases
1. Adrenocorticotropic hormone (ACTH) (Not glandular and does not synthesize hormone)
2. Thyroid-stimulating hormone (TSH) [Link]: [Link] & delivery 2. Lactation & breast feeding
3. Luteinizing hormone (LH) [Link] (Vasopressin): maintenance of water balance
4. Follicle-stimulating hormone (FSH)
5. Growth hormone (GH)
6. Prolactin (PRL)
1. ACTH: controls production of the adrenal gland hormones cortisol & DHEA
2. Thyroid-stimulating hormone (TSH): controls thyroid hormone production from the thyroid gland.
3. LH and FSH: control fertility in both sexes and the secretion of sex hormones estrogen and progesterone testosterone
4. Growth hormone (GH): required for growth in childhood and has effects on the entire body throughout life.
5. Prolactin (PRL): required for breast milk production.
6. Oxytocin: required during labor and delivery and for lactation and breast feeding.
7. Antidiuretic hormone (vasopressin): helps maintain normal water balance.
Pituitary dysfunction
Hypopituitarism Hyperpituitarism
Tumor Trauma Tumor: a particular hormone secreting tumor
Iscaemic necrosis
Intrapituitary hemorrhage Infiltation Irradiation
Pattern of the diseases is such that often the all the Usually secrete a single hormone Rarely secrete ≥2
hormone producing cells of the anterior pituitary hormones manifestations are due to oversecretion of a
gets affected- simultaneously or one after another. particular hormone
So often leads to Panhypopituitarism
Pituitary tumor…MECHANISM OF CLINICAL EFFECTS

Hormonally non functioning Hormonally functioning

nonsecretory benign adenomas Secretory adenomas: typically monoclonal
i.e. secrete a single hormone Rarely secrete 2 hormones
Expanding tumour Endocrinopathy:
Depending on size due to oversecretion of a particular pituitary hormone
Compressive effects
TSH: Hyperthyrodism
 Adjacent Pituitary Hypofunctionning Hypopituitarism ACTH: Cushing syndrome
 Outside Pituiatry Optic chiasm Bitemporal Hemianopia LH& FSH: Hypergonadism
 raised ICT Headache GH: Acromegaly/Gigantism
 stalk effect Hyperprolactinemia Prolactin: Hyperprolactinemia
Hyperprolocatinemia in Pituitary disease
[Link] secreting tumor (Prolocatinoma) 2. “stalk effect “ of an expanding tumor: as the expanding tumor
compresses on the pituitary stalk hypothalamic Dopamine (which physiological inhibitor of Prolactin) cannot exert it’s
effect
 Gigantism/ Acromegaly
Gigantism refers to abnormally high linear growth due to excessive Growth Hormone while the epiphyseal growth
plates are open during childhood. Acromegaly is the same disorder of excessive Growth Hormone but occurs after the
growth plate cartilage fuses in adulthood.
Causes:
GH-secreting pituitary adenomas or hyperplasia Ectopic GH secretion by nonendocrine tumors
(Common cause) Hypothalamic tumors; GHRH tumors

C/F: Acromegaly can be an insidious disease. Manifestations which may precede diagnosis by several years, can be
divided into the following groups:

 Manifestations due to excess circulating GH ( most of these “excess GH” manifestations are mediated by IGF1
 Manifestations due to local mass effects of an intracranial (Pituitary) tumor (Compressive effect)
Asymptomatic
OR ≥1 of the followings
Appearance
 Enlargement of head size: Broad head
 Frontal bossing
 Prominent supraorbital ridge
 Enlargement of the lower lip and nose (the nose takes on a triangular configuration)
 Prognathism Wide spacing of the teeth and prognathism Prognathism
 Macroglossia
Body weight: Increase (Mild to moderate obesity)
BP: may increase (Secondary hypertension)
Cardiac: Cardiomegaly: Cardiomyopathy: Cardiac failure and/or Arrhythmias
CNS: Compressive manifestations:
 Raised ICT: headache/vomiting/papilloedema
 Optic chiasm: Bitemporal Hemianopia
DM
Dermal Of all the maifestations following 3 are indicator of the disease activity as
 Excessive sweating these 3 become stationary and regress once GH overproduction stops
 Hypertrichosis 1. BP
2. DM/Hyperglycemia
 Oily Doughy-feeling skin
3. Skin changes
 Acanthosis nigricans
 Noticeably large pores
Extremity
 Exaggerated growth of the hands and feet, with thick fingers and toes
 carpel tunnel syndrome
Fertility
Gynaecology
Gigantism:Tall stature
Galactorrhoea due to hyperprolactinemia: Either due to [Link] secreting tumors occasionally cosecrete Prolactin
Gynaecomastia 2. “Stalk effect” of the expanding tumor
Hoarse voice
Investigations:
1. Screening test: IGF-I: high; because of an excellent correlation between serum IGF-I levels and 24-hr GH secretion.

2. GH estimation following Oral glucose load: Because GH secretion is inhibited by Glucose, so nonsupressibility of
GH level below a cut off range following glucose confirms “autonomous” release.

(Random GH measurements, however, often are not diagnostic, because of the episodic secretion of GH, its short half-life, and the
overlap between GH concentration in individuals with acromegaly and individuals without the condition.)
3. Prolactin level: often high as pituitary adenomas co-secrete prolactin. However, a rise in prolactin may result from
stalk compression.
4. Pituitary adenomas may be associated with deficiencies of other pituitary hormones: so evaluation of the adrenal,
thyroid, and gonadal axis is important.

Imaging:
MRI of Pituitary: Because of the relatively high incidence of nonfunctioning, incidentally discovered pituitary
adenomas, imaging studies should be obtained only after a firm biochemical diagnosis of has been made.

CT scans: If MRI of the Pituitary does not show a tumor - CT chest/abdo to look for a nonpitutary tumor which can
be the source of ectopic secretion of GH

Treatment: No single treatment modality consistently achieves control of GH excess.

Pituitary adenoma:
Transsphenoidal surgery to completely remove the tumor is the treatment of choice, and it may be curative.
Medical management and/or Radiation: when Surgery not feasible/fails to remove the tumor completely
Pharmacologic Therapy:
 GH inhibitors: Somatostatin analogues: Octreotide Lanreotide, and Pasireotide
 GH receptor antagonists: Pegvisomant
 Dopamine-receptor agonists: Bromocriptine, Cabergoline
Radiation Therapy: Local Irradiation
Hypoptuitarism
Sheehan syndrome (“Pituitary crisis”)
Acute hypopiturasim following severe Postpartum hemorrhage.
Pathogenesis
Excessive blood loss during or after delivery may cause inappropriate vasospasm leading to severe ischaemia and in
such circumstances the pituitary cells may be damaged or die (necrosis).
(During pregnancy the pituitary gland will enlarge and may double in size. At this time hyperplastic gland is especially
vulnerable to "shock" and excessive maternal bleeding may induce the "shock" and the damage to the cells of the gland.
There appear to be two forms of the disorder; a chronic form and an acute form, depending on the amount of damage to the gland's
cells. The acute form reflects considerable damage so that symptoms become apparent soon after delivery. In chronic cases, the
volume of damage is much less and symptoms may not appear for months or years after delivery.)
Signs & Symptoms
1. H/O severe post partum haemorrhage
2. Refractory hypotension (adrenocortical failure) even after adequate volume resuscitation+ recurrent hypoglycemia
3. If the patient survives followings start to appear due to failure of Pituitary & “Pituitary dependent” glands:
 Failure of lactation after a woman has a baby(Prolactin deficiency)
 Menstruation does not begin again( gonadal hormone deficiency)
 Hypothyroidism: fatigue, dry skin, constipation, weight gain, sluggishness
 Adrenocortical insufficiency: fatigue, chronic hypotension, libido diminished, sparse axillary/pubic hair
 GH deficiency: Weakness, weight loss, loss of muscle strength
Investigations: Pituitary function test: Thyroid function/Adrenal function/Gonadal hormone level estimation
Treatment: Hormone replacement:
Ovarian hormone: Estrogen/Progesterone
Thyroid hormone: Thyroxine
Adrenocortical hormones: Hydrocortisone or prednisone are generally used to replace ACTH and cortisol
Growth hormone (GH) replacement therapy
Diabetes Insipidus
Diabetes insipidus (DI) is defined as the passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg)
Types & causes:
Central Diabetes Insipidus (Neurogenic): It is due to abnormality of ADH or AVP.
Any disturbance or injury of the hypothalamus and/or posterior pituitary is a potential cause
 Tumors  Infiltration: granulomatous diseases
 Trauma  Idiopathic
Nephrogenic Diabetes Insipidus due to nonresponse of kidneys to ADH.
 Congenital
 Acquired: hypercalcemia, Lithium therapy, AKI and advanced CKD.
(Primary Polydipsic Diabetes Insipidus: It occurs due to suppression of ADH by excessive fluid intake:
 Psychogenic
 Iatrogenic DI—excessive water drinking is prescribed as a treatment
Gestational Diabetes Insipidus: It occurs in pregnancy due to destruction of ADH by placental vasopressinase.
Gestational DI and primary polydipsia (dipsogenic DI); both are caused by deficiencies in AVP, but the deficiencies do not result
from a defect in the neurohypophysis or kidneys)
Clinical features: The predominant manifestations of DI are:
Polyuria: The daily urine volume is relatively constant for each patient but is highly variable between patients (3-20 L)
Polydipsia
Nocturia
Dehydration

Investigations:
Confirmatory test: Water deprivation test:
In healthy individuals, water deprivation leads to a urinary osmolality that is 2-4 times greater than plasma
osmolality. The time required to achieve maximal urinary concentration ranges from 4-18 hours.
In central and nephrogenic DI, urinary osmolality will be less than 300 mOsm/kg after water deprivation.
After the administration of ADH, the osmolality will rise to more than 750 mOsm/kg in central DI but will not rise at
all in nephrogenic DI.
Treatment
Supportive: When oral intake is inadequate and hypernatremia is present, provide fluid replacement
Definitive: Desmopressin: 1-desamino-8-D-arginine Vasopressin (DDAVP): A synthetic analogue of ADH with
potent antidiuretic activity but no vasopressor activity
 Intranasal solution/ Intranasal spray: commonly used
 Parenteral for IV/IM injections/ Oral tablets: rarely used.
 Parathyroid
In the nonpathologic state, PTH secretion enhances Ca 2+ absorption from gut and kidney and stimulates osteoclastic
bone resorption (transfer of calcium from bone fluid to the blood).

Hyperparathyroidism
Overproduction of parathyroid hormone (PTH) by one or more abnormal parathyroid glands.
Types:
[Link] hyperparathyroidism: Hyperfunctioning of the parathyroid glands themselves due to an intrinsic disease.
Oversecretion of PTH due to a [Link] adenoma 2. Parathyroid hyperplasia 3. Parathyroid carcinoma (RARE)

[Link] hyperparathyroidism is due to physiological (i.e. appropriate) secretion of parathyroid hormone (PTH) by
the parathyroid glands in response to hypocalcemia. The most common causes are vitamin D deficiency and CKD
(Lack of vitamin D – reduced Ca absorption by the intestine – hypocalcemia - increased parathyroid hormone secretion. In CKD -
failure to convert vitamin D to active form in the kidney. The bone disease in secondary hyperparathyroidism caused by renal
failure is termed renal osteodystrophy).
[Link] hyperparathyroidism is seen in patients with long-term secondary hyperparathyroidism which eventually
leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels i.e the gland becomes an
autonomous one.

Clinical features:
1.“hypercalcaemic” symptoms can include:
A- Appetite loss D- dehydration
Abdominal cramp/ pain E- Excessive thirst
B- Bodyache- joint/muscleache Emesis
C- Constipation F- Fatigue
Confusion Frequent urination
Convulsion
2. Potential Dangers of “missed” or untreated Primary Hyperparathyroidism:
• Bone fractures: Osteoporosis and osteopenia
• Kidney stones
• Peptic ulcers
• Pancreatitis
• Nervous system complications: Psychosis/depression/dementia

Investigations:
Blood:
Serum Ca 2+ - elevated serum calcium
serum PTH concentration- “inappropriately” elevated
Serum urea and creatinine (to assess kidney function)
Serum PO4 3- - Normal/Low/high
Urine test – 24 Hour urine calcium (to exclude a rare condition familial hypocalciuric hypercalcaemia)
Imaging:
[Link] abdomen: imaging of the kidneys (to exclude stone formation)
Imaging of the pancreas (to exclude pancreatitis)
[Link] X-Rays and Bone densitometry scan (DEXA scan)- To determine the detrimental effect of prolonged PTH on
the skeleton.
[Link] imaging with Technetium 99m SESTAMIBI scan – This is a radiolabelled nuclear medicine scan of the
thyroid that preferentially localises a single abnormal parathyroid adenoma that may be amenable to minimally
invasive parathyroid surgery.
Treatment
Primary Hyperparathyrodism
1. Definitive treatment: Surgical excision of the abnormal parathyroid glands
2. Supportive treatment: Management of severe hypercalcemia in the acute setting
 [Link] term/ Emergency treatment: in case of dangerous hypercalcemia/symptomatic hypercalcemia
[Link] fluid: intravascular volume expansion with sodium chloride
[Link] diuretics: Furosemide once the intravascular volume is restored.
[Link]: Calcitonin and IV bisphosphonate as a temporary measure prior to surgery
 b. Long term treatment:
[Link]: Alendronate/Risedronate/Zolendronate, has been shown to improve the Bone Mineral
Density(BMD) in patients with primary hyperparathyroidism. Treatment with a bisphosphonate can be considered in
patients with hyperparathyroidism and low BMD who cannot, or will not, undergo surgery.
[Link] drug: Cinacalcet activates the calcium-sensing receptor and inhibit parathyroid cell function.
Cinacalcet results in reduction of PTH levels, reduction and even normalization of serum calcium.

Secondary hyperparathyroidism: treat the cause/ effects

[Link]: [Link] binders [Link] D supplementation [Link]
[Link] D deficiency: Vitamin D supplementation

Hypoparathyroidism
Underactivity of the Parathyroid glands with underproduction of Parathyroid hormone.
Hypoparathyroidism can have the following causes: “ 5 I”
1. Iatrogenic: Inadvertent injury to the glands or their blood supply during thyroidectomy/parathyroidectomy or
other surgical interventions in the central part of the neck- inadvertent injury to the glands or their blood supply is still
common. When this happens, the parathyroids may cease functioning. This is usually temporary but occasionally long
term (permanent).
2. Immunological: Autoimmune invasion and destruction- occur as part of Autoimmune Polyendocrine syndromes.
3. Infiltrative: Hemochromatosis
4. Inherited: Atrophied or absent parathyroid glands
5. Insufficient Mg: Magnesium depletion causes relative PTH deficiency and end-organ resistance to PTH action

Clinical features: mainly Hypocalcemic manifestations:

1. Muscle cramps involving the back and legs.
2. Insidious hypocalcemia may cause mild encephalopathy and should be suspected in patients with unexplained
dementia, depression, or psychosis.
3. Tetany characteristically results from severe hypocalcemia but can result from reduction in the ionized fraction of
serum calcium without marked hypocalcemia, as occurs in severe alkalosis. Tetany is characterized by the following:
Sensory symptoms consisting of paresthesias of the lips, tongue, fingers, and feet
Carpopedal spasm, which may be prolonged and painful
Generalized muscle aching
Spasm of facial musculature
Tetany may be overt with spontaneous symptoms or latent and requiring provocative tests to elicit-
Chvostek sign is an involuntary twitching of the facial muscles elicited by a light tapping of the facial nerve just
anterior to the exterior auditory meatus.
Trousseau sign is the precipitation of carpal spasm by reduction of the blood supply to the hand with a tourniquet or
BP cuff inflated to 20 mm Hg above systolic BP applied to the forearm for 3 min.
Investigations: [Link] Ca: typically Low 2. Serum PTH: Low
Treatment: 1. IV Calcium- Ca-Gluconate or Oral Ca-Carbonate 2. Recombinant Parathyroid hormone:Teriparatide
 Diabetes Mellitus
Syndrome characterized by inappropriate hyperglycemia with an absolute or relative deficiency of insulin secretion

World Health Organization (WHO) criteria:

 Fasting plasma glucose (FPG) ≥ 126mg/dl
and/or
 Oral glucose tolerance test (OGTT) with 75 gms of anhydrous glucose: 2 hours post plasma glucose ≥ 200 mg/dl
and/or
 Glycated haemoglobin (HbA1c) ≥ 6.5%
and/or
 Random plasma glucose ≥ 200mg/dl in the presence of classical diabetes symptoms
NB:
Asymptomatic individuals with a single abnormal test should have the test repeated to confirm the diagnosis unless
the result is unequivocally abnormal.
FPG is defined as glucose estimated after no caloric intake for at least 8-12 hours
Types/Classification
1. Type 1 diabetes: due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency
2. Type 2 diabetes: due to a progressive loss of β-cell insulin secretion frequently on the background of insulin
resistance
3. Gestational diabetes mellitus (GDM): diabetes diagnosed in the second or third trimester of pregnancy that was not
clearly overt diabetes prior to gestation
4. Specific types of diabetes due to other causes:
Neonatal diabetes
Maturity-Onset Diabetes of the Young [MODY]
Secondary diabetes:
Secondary Diabetes: DM that results as a consequence of another medical condition.
Chronic Pancreatic disease: Diseases of the exocrine pancreas – Chronic Pancreatitis/ Cystic fibrosis
Drug induced: Corticosteroid
Endocrinopathies: Cushing syndrome/ Acromegaly/Pheochromocytoma
Ferrous: Hemochromatosis
Type 1 Diabetes: Insulin dependent Diabetes/Juvenile onset Diabetes
a. Immune Mediated Diabetes (Type 1a): results from a cell mediated autoimmune destruction of the beta cells of the
pancreas. Autoantibodies associated with the T1DM are islet cell autoantibodies (ICA), antibodies to insulin (IAA),
antibodies to glutamic acid decarboxylase (GAA or GAD) and protein tyrosine phosphatase (IA2 or ICA512)
b. Idiopathic Diabetes (Type 1b): Some forms of type 1 diabetes have no known etiologies. Some of these patients have
permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity. Only a minority of
patients with type 1 diabetes fall into this category.
Type 2 diabetes:
Results from predominantly insulin resistance with relative insulin deficiency. This form of diabetes frequently goes
undiagnosed for many years because hyperglycemia develops gradually and in earlier stages is often not severe
enough for the patient to develop any of the hyperosmolar symptoms of diabetes. Nevertheless such patients are at an
increased risk of developing macrovascular and microvascular complications and these may be present even at the
time of diagnosis. However, in the course of time they also become Insulinopenic & are likely to require insulin for
better glycemic control.
Clinical fetaures/clinical Assessment of diabetes Patient:
Aims:
1. To look for Hyperglycemic manifestations
2. To look for metabolic symptoms
3. To look for any complication: these may be present on first presentation or may develop later
4. To look for any other Atherosclerotic(Vasculopathic) Risk factors
5. Dietary & drug compliance
6. To look for any secondary causes of DM

1. Hyperglycemic symptoms:
 h/o Polyuria  Visual disturbances
 h/o Polydipsia  Balanitis/balanoposthitis/vulvovaginitis/vaginiti
 h/o Polyphagia s: Genital itching/irritation
 Delayed healing of ulcers
2. Metabolic symptoms
 h/o Weight loss: often RAPID and SIGNIFICANT
 h/o generalized weakness
3. Symptoms suggesting development and severity of complications:
a. Macrovasculopathy:
1. Cerebrovascular disease:
 h/o TIA/CVA
2. Coronary artery disease:
 h/o Angina/ MI
3. Peripheral vascular disease
 h/o Claudication
 h/o gangrene
 h/o amputation
b. Microvasculopathy:
1. Nephropathy (Kidney disease):
 h/o swelling: Any Facial puffiness/Any Pedal edema
 h/o decreased urine output
 h/o breathlessness
2. Neuropathy:
1. Sensory Neuropathy:
 h/o Sensory impairment: altered sensation or painful feet or arm
 Foot ulcers
2. Autonomic neuropathy
 Bladder: h/o incontinence
 Gastrointestinal function: h/o Constipation/ flatulence
 Symptoms of Orthostatic hypotension: Portural dizziness/ black out
 Erectile dysfunction
3. Retinopathy:
 h/o retinopathy
 Any visual disturbance
4. Risk factors for atherosclerosis:
 Activity status: exercise lack  Cigeratte smoking
 BP: Hypertension  Dyslipidemia
 BMI: obesity  Family history: atherosclerotic disease
5. Dietary & drug compliance
 Current nutritional status  Current treatment and glycemic status:
 Eating pattern medications, compliance
6. Evaluation for possible causes of secondary diabetes mellitus.
Examination: Important findings with their clinical relevance:
 Arterial pulse: poor peripheral pulses: Peripheral vascular disease
 BMI: atherosclerotic risk factor
 BP: risk factor
 BP: Lying and standing: Postural drop: Autonomic neuropathy
 Cardiac: Gallop/Basal crackles: heart failure
 CNS: focal neurodeficit: CVA/TIA Sensory impairment: Neuropathy
 Edema: CKD/CCF
 Eye: Fundoscopy: To look for retinopathy: ophthalmoscopic evaluation by ophthalmologist
 Foot: Ulcer/gangrene/cellulitis: Neuropathy/ Peripheral vascular disease
Investigations:
1. To confirm DM
2. Glycemic control monitoring: frequency of monitoring depend on glycemic status
3. To look for complications: Exact nature and frequency of these tests depend on presence/absence of complications,
however some of the tests are monitored even if clinically no evidence of complications are there.
4. To look for any other Atherosclerotic (Vasculopathic) Risk factors
1. To confirm DM & Glycemic monitoring: Blood: FBG, PPBG, HbA1c
Diagnostic criteria for diabetes: Any 1 of these
Plasma Glucose Normal Imapaired Diabetes
Fasting < 110 mg/dl > 110 mg/dl but ≤ 125 mg/dl ≥ 126 mg/dl
OGTT (Post prandial) < 140 mg/dl > 140 mg/dl but ≤ 199 mg/dl ≥ 200 mg/dl.
HbAIc < 5.7 % 5.7%- 6.4% ≥6.5%
Random BG ≥200 mg/dL with classic symptoms of hyperglycemia or hyperglycemic crisis
In fasting state, venous and capillary glucose are the same, but it differs in the PP state.

Glycemic monitoring: Target/ Criteria Glycemic Control

Target values for glucose control for HbA1c and capillary plasma glucose are as follows:
HbA1c < 7.0 %
FPG < 115 mg/dl
PPG < 160 mg/dl
To look for complications: Exact nature and frequency of these tests depend on presence/absence of complications,
however some of the tests are monitored even if clinically no evidence of complications are there.
1. CBC: Hb, TC,DC, ESR
 Hb: Low: may be due to CKD
 TC,DC, ESR: high: infection
2. Serum urea creatinine: raised: CKD
3. Urine analysis: To assess Albumiuria
 Urine dipstick analysis: Proteinuria
 Urinary Microalbumin- Creatinine ratio( MACR): To assess Albumiuria
4. ECG
5. Echocardiography
To look for any other Atherosclerotic (Vasculopathic) Risk factors: Blood: Lipid profile
Special tests: ONLY indicated if a particular complication is suspected
Suspected complication Relevant investigations
Coronary artery disease Exercise tolerance test/Tread mill test(TMT)/Myocardial perfusion
scan/Angiography
Cerebrovascualr disease CT Brain/ Carotid Doppler
Peripheral vascular disease Doppler study of peripheral arteries/Peripheral angiography
Neuropathy Nerve conduction study(NCS)/NCV
Treatment:
Treatment of DM

Glycemic control Treatment of complications Treatment of atherosclerotic risk factors (if present)
depends on complication(s) Activity status: exercise lack
Lifestyle Pharmacotherapy BP: Hypertension
modification [Link] hyoglycemics BMI: obesity 1. Lifestyle
modifin
1. Diet 2. Insulin Cigeratte smoking 2. Drugs
2. Exercise Dyslipidemia
Glycemic control
Lifestyle modification:
A. Diet:
1. Energy (calories): 25-30 cal/kg IBW - reduce in obese and increase in underweight
2. Protein 0.8 g/kg body weight.
3. Fats: 20-25% of total calories
4. Carbohydrates: 55-60% of total calories. Encourage complex carbohydrates i.e. mainly grains, cereals, pulses.
B. Exercise: Regular physical exercise
Pharmacotherapy/Medications:
1. Oral Hypoglycemic agents (OHAs)/Oral Antidiabetic drug (OAD)
1. Increasing insulin secretion:
 Sulfonylureas(SU): Glimepiride/Gliclazide/Glyburide
 Meglitinide analogs: Repaglinide/Mitiglinide
 D-Phenylalanine derivative: Nateglinide
2. Reduction of insulin resistance (Insulin sensitisers): Thiazolidinediones (TZD): Pioglitazone/ Rosiglitazone
3. Reduction of hepatic glucose output: Biguanides: Metformin
4. Reduced carbohydrate absorption: Alpha glucosidase inhibitors(AGI): Voglibose/Acarbose
5. Incretins:
GLP1 receptor agonist: Exenatide/Liraglutide/Lixisenatide
DPP-4 Inhibitors (Gliptins): Vidagliptin/Linagliptin/Saxagliptin
6. SGLT 2 inhibitors: Canaglifozin/Dapaglifozin/ Empagliflozin
2. Insulin
Basal insulin is the background insulin that is normally supplied by the pancreas and is present 24 hours a day,
whether or not the person eats.
Bolus insulin refers to the extra amounts of insulin the pancreas would naturally make in response to glucose taken in
through food.
Types:
Short acting: [Link]
Rapid acting: 1. Aspart 2. Lispro 3. Glulicine
Intermediate acting: Neutral protamine hagedorn (NPH)
Premixed: Intermediate acting Insulin + Short/Rapid acting Insulin: 70:30/ 75:25/ 50:50
 NPH+ Regular
 Insulin aspart protamine suspension + Insulin aspart
 Insulin Lispro protamine suspension + Insulin Lispro
Long acting [Link] 2. Detemir 3. Degludec
Intemediate/Long-acting “basal” insulins begin working in 1-2 hours but are released slowly so they can last up to 24
hours, providing that background insulin that is needed around the clock.
Fast-acting “bolus” insulins generally begin working within 15-30 minutes. Each of these bolus insulins is designed to
be taken just before a meal and have a duration of up to 5- 6 hours, so they counteract postprandial glycemic surge
Hyperglycemia: drug strategy
Start Glucose lowering medications when lifestyle interventions alone are unable to maintain/achieve target glucose
Lifestyle measures to continue throughout the use of these medications
Consider a new agent or dose increase of a medication with “ SUGAR”monitoring every 2-3 months
Choice of drug (s) depend on following factors:
Age Duration of Diabete
BMI Duration of DM
Complications Education status about Diabetes
Contraindication Financial condition
Glycemic status Hypoglycemia risk
Type of DM

Type 1 DM Type 2 DM: depending on GLYCEMIC control

Insulin: 1. OHA only 2. OHA + Insulin 3. Insulin only
Basal Regime: Long acting Insulin
+ OHA(s): usually a Single OHA is started
Bolus regime: Short/Rapid acting Insulin Dose increase or add a new agent depending on response every 2-3 m
Glucose lowering effect:
 High: Metformin, SU, TZDs, GLP-1 agonists
 Comparatively lower: Meglitinides, DPP-4(-)ors, SGLT2(-)ors,AGI
Insulin:
 Basal insulin once daily: NPH or Glargine or Detemir
 Once or twice daily Premix insulin (biphasic insulin)
Indications of Insulin therapy in DM
1. Type 1 DM- ALL patients
2. Type 2 DM
Long term Insulin treatment
In newly diagnosed patient: at the time of diagnosis are symptomatic and have one of the following: –
 HbA1C more than 9%
 Fasting hyperglycemia in excess of 250 mg/dl
 Post prandial hyperglycemia in excess of 300 mg/dl
 In catabolic stage
In patients with already established diagnosis:
 If a trial of adequate doses of three non-insulin agents for 6-9 months fails to achieve HbA1c to target levels
 Presence of contraindications preclude use 1 or >1 OHAs
Short term insulin therapy
1. All diabetics with Acute metabolic complications- DKA/HHS (HONC)
2. All diabetics admitted during a critical illness- eg. Sepsis/stroke/MI
3. All diabetics- To achieve glycemic control during pre/intra and post oprve period (depending on the type of surgery)
 Complications of DM
1. Acute- those develop over hours- days 2. Chronic- those develop over years
a. Metabolic complications-
a. DKA a. Macrovasculopathy
b. HHS a. Cerebrovascular disease
c. Hypoglycaemia b. Coronary artery disease
b. Acute presentation of a chronic complication c. Peripheral vascular disease

a. CVC/TIA b. Microvasculopathy
b. Myocardial Ischaemic event a. Retinopathy
c. Acute ischaemic limb b. Neuropathy
c. Nephropathy

Diabetic Retinopathy
It is an ocular manifestation of diabetes which affects most of the DM patients who have had diabetes for ≥20 years
C/F
Initial stages- generally asymptomatic
Advanced stages- floaters, blurred vision & progressive loss of visual acuity
Signs of diabetic retinopathy:
Stages
1. Nonproliferative diabetic retinopathy
Presence of microaneurysm(s)-due to capillary wall outpouching
Dot and blot hemorrhages- due to microaneurysms rupture
Hard exudates- due to leakage of serum lipids and proteins from the vessels
Cotton-wool spots: due to infarctions from occlusion of arterioles
2. Proliferative diabetic retinopathy- can be vision threatening
Neovascularisation: hallmark of PDR
Pre retinal hemorrhages: pockets of blood within the space between the retina and the posterior hyaloid face
Vitreous hemorrhage
Retinal detachment
3. Maculopathy- Can occur at any stage
Macular Oedema
Investigations
1. Glycemic assessment- FBS/PPBS/HbA1c
2. Fundus Fluorescein angiography (FFA)
3. Optical coherence tomography (OCT)

Treatment:
a. Strict/ Tight Glycaemic control
b. Ophthalmological Rx- Urgent referral IF PDR or Maculopathy OR impaired vision
1. Pharmacotherapy
Triamcinolone: Administered intravitreally
Bevacizumab/ Ranibizumab: Administered intravitreally- reduces macular edema and neovascularization
2. Laser photocoagulation- Panretinal photocoagulation is used in the treatment of PDR.
3. Regular Ophthalmological screening- FOR ALL DIABETICS starting 6-8 years after the onset of DM
 Diabetic Neuropathy

Diabetic neuropathy is the most common complication of diabetes mellitus (DM), affecting as many as 50% of patients
with type 1 and type 2 DM

Types
Sensory Neuropathy- commonest type
Numbness or deadness- typically in distal part of the extremities
Loss of balance- especially with the eyes closed
Painless injuries due to loss of sensation
Painful Neuropathy- burning/prickling/tingling/electric shock like feelings
Peripheral neuropathy can lead to foot ulcers and leg amputation
Foot ulcer shows signs of infection- thick yellow exudate + erythema + fever + necrotic tissue
O/E impaired superficial + deep sensation in the distal part of the extremity to start with (Glove and stocking)
Motor Neuropathy
Distal or proximal or more focal weakness
LMN signs in the distribution of the affected nerve(s)
In the most common presentation of diabetic neuropathy with symmetrical sensorimotor involvement Sensory loss+
minor weakness of the toes and feet may be seen; severe weakness is uncommon
Autonomic neuropathy- may involve
Cardiovascular- Sinus tachycardia/Orthostatic hypotension/Sinus arrhythmia/Syncope or Presyncope
Gastrointestinal- Abdominal pain/Bloating/ Constipation/ Diarrhoea/Emesis/ Fecal incontinence
Genitourinary- Poor urinary stream/Feeling of incomplete bladder emptying/Straining to void/Erectile Dysfunction
Investigations
Glycaemic assessment- FBG + PPBG+ HbA1c
For Neuropathy- Electrophysiological tests - NCV & EMG
Imaging studies- MRI of the Cervical and/or Thoracic and/or Lumbar regions may help to exclude another cause for
symptoms mimicking diabetic neuropathy.
Management
1. Awareness- patient to be made aware of potential foot complication
2. Foot care- regular foot examinations
3. If necessary, refer the patient to a podiatrist.
4. Infected diabetic foot ulcer or gangrene
 Antibiotic
 Antiseptic dressing
 Surgical Debridement
 Amputation
5. Painful Neuropathy- Gabapentin/ Pregabalin/Amitryptiline
6. Erectile dysfunction- Phosphodiesterase type 5 (PDE5) inhibitors- Sildenafil/Tadanafil
7. Orthostatic hypotension
 Increase dietary fluid and salt intake
 Compression stockings may help
 Diabetic Foot

Complication arising due to compromise of the blood supply from macrovascular disease often in association with
lack of sensation because of neuropathy.
C/F- Predisposes persons with DM to foot infections.
Signs and symptoms
1. Peripheral Vascular disease related manifestations
 Claudication/Poor distal pulses/ severe cases ischaemic ulcer
2. Peripheral Neuropathy related manifestations
 Numbness or deadness- typically in distal part of the extremities
 Loss of balance- especially with the eyes closed
 Painless injuries due to loss of sensation
 Painful Neuropathy- burning/prickling/tingling/electric shock like feelings
3. Diabetic foot infections typically take one of the following forms
 Neuropathic ulcers +/- secondary infection
 Cellulitis- Tender, erythematous skin
 Deep skin and soft-tissue infections- painful induration of the soft tissues in the extremity Wound discharge is
usually not present
 Osteomyelitis- pain at the site of the involved bone. Deep, penetrating ulcers and deep sinus tracts are usually
located between the toes or on the plantar surface of the foot.
Investigation
1. TC, ESR/CRP- elevated if infection 3. Blood culture results may be positive
2. Aspirated exudate- gram stain/CS 4. Osteomyelitis- X-ray
5. US Doppler +/- Peripheral Angiography- for Ischaemic limb
Management- Treatment of diabetic foot infections varies by type
1. Cellulitis – antibiotics
2. Deep skin and soft-tissue infections – Antibiotic but additional debridement is usually indicated
3. Osteomyelitis – Antibiotic
Surgical debridement is essential
Amputation- if necessary
4. Ischaemic limb- Amputation, if necessary
Diabetic Nephropathy
Syndrome characterized by persistent albuminuria +/- Progressive decline GFR +/- Elevated BP
C/F
1. Edema secondary to hypoalbuminemia
2. Features of CKD
4. Patients may have physical findings associated with long-standing diabetes mellitus like
 Hypertension  Evidence of diabetic neuropathy
 Peripheral vascular occlusive disease  Evidence of DM Retinopathy
Investigations
1. 24-hour urinalysis/Urinary ACR: Microalbuminuria or Macroalbuminuria
2. Blood- Urea, Cr, FBG, PPBG, HbA1c
3. USG KUB- For kidney size- normal to increased in the initial stages & later shrunken with CKD.
4. Renal biopsy is not routinely [Link] is indicated if the diagnosis is in doubt or if other kidney disease is
suggested.
Treatment
Tight Glycaemic control Tight control of Dyslipidemia
ACE-i/ARB Supportive treatment for CKD- if established CKD
Tight BP control
 HbA1c
Haemoglobin A1c (Glycated Hb) reflects the average blood glucose concentration over the course of the RBC lifespan,
roughly 120 days in normal individuals. It provides different but complementary information to a single glucose
concentration.

Values for DM diagnosis Values for DM/Glycaemic control

Normal- 4% and 5.6%. Ideal control < 7%
Increased risk of DM/Impaired GTT- 5.7% and 6.4% Average control 7- 7.9%
Diabetic ≥ 6.5% Bad control ≥ 8%
Pitfalls
HbA1c is usually a reliable indicator of DM diagnosis & Glycaemic control except:
Patients with symptoms of diabetes for less than two months
Patients at high diabetes risk who are acutely ill
Patients taking medication that may cause rapid glucose rise- eg. steroids, antipsychotics.
Patients with acute pancreatic damage, including pancreatic surgery
Pregnancy
Presence of other factors that influence HbA1c and its measurement:
 Situations where the RBC lifespan is significantly less than 120 days will give rise to low HbA1c
Increased red cell turnover: blood loss, hemolysis, haemoglobinopathies
OHA/OAD
There are 5 categories of OHAs/OADs
1. Increase sensitivity to insulin (ISAs- Insulin-sensitizing agents) + Decreased Hepatic Glucose output
 Metformin
 Thiazolidinediones: Rosiglitazone; Pioglitazone
2. Provoke Pancreas to produce more Insulin (Secretagogue)
 Sulfonylurea: Glimepiride; Glipizide; Gliclazide; Glibenclamide; Glyburide
 Meglitinides: Repaglinide; Nateglinide
3. Incretin like effects: Dipeptidyl peptidase IV inhibitors (DPP4 –tors):
 Vidagliptin/Sitagliptin/Linagliptin/Saxagliptin
 GLP-1 analogues- Exenatide; Liraglutide
4. Inhibits Intestinal Glucose absorption: α-glucosidase inhibitors: Voglibose; Acarbose
5. Inhibits Renal Glucose absorption: Inhibitor of Sodium-Glucose Linked Transporter (SGLT)
 Canagliflozin; Dapagliflozin; Empagliflozin
Indications of OHA- Type 2 DM- either a single agent or combination of drugs
The choice of the OHA(s) depend on following factors
Age
BMI
Complications
Contraindication
Duration of Diabetes
Education status about Diabetes
Financial condition
Glycemic status
Hypoglycemia risk
 DKA…..V. Important
Diabetic ketoacidosis (DKA) is an acute, potentially life-threatening metabolic complication of diabetes characterized
by hyperglycemia, ketoacidosis, and ketonuria that mainly occurs in patients with Type1DM and rarely in Type 2DM.
Background of the patient- Pts are usually a Ty 1 DM pts- hitherto (until now) undiagnosed or a known case.
Precipitating Factor- May be present and if present usually is one of these
1. Missing dose(s) of Insulin 3. Critical Illness
2. Infection
Pathophysiology Severe Insulin deficiency + ↑counter-regulatory hormones (Glucagon/GH/cortisol)
↑↑hepatic gluconeogenesis + glycogenolysis + ↑↑lipolysis

severe hyperglycemia increased serum free fatty acids

polydipsia and polyuria Glucosuria ketogenesis (acidic intermediate)

osmotic diuresis ketogenesis (acidic intermediate)

dehydration Ketonemia + Ketonuria

accumulation of organic acids

metabolic acidosis (ketoacidosis)

Therefore main problems in DKA are-

2. Dehydration 5. Abnormally high Glucose level
3. Ketoacidosis/Ketonemia 6. Associated ppting factor (if any)–Infn/illness
4. K- imbalance
Hyperkalemia: Often present initially & is caused by a shift of potassium from the intracellular to the extracellular
space in an exchange with hydrogen ions that accumulate extracellularly in acidosis + due to insulin deficiency.
Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis.
Hypokalemia: As these patients get started on IV Insulin, K gets rapidly shifted into cells ([Link] to [Link])
Symptoms
1. May be a known case of Ty-1 DM or undiagnosed DM- therefore may give recent h/o Wt. loss+/-Polyphagia +/-
Polyuria- these are due to underlying DM
2. Dehydration related manifestations
 Altered sensorium  Dry mucous membranes
 BP: Hypotension  Decreased skin turgor
 CRT: prolonged  Extremity:Tachycardia
 Disorientation  Excess thirst
 Dry skin
3. Ketonemia/ Ketoacdisis related manifestations
 Nausea and vomiting  Kussmaul Breathing- Rapid, shallow breathing
 Abdominal pain  Severe Acidosis arrhythmias suddenly
 Acetone (ketotic) breath odour- Fruity smell
4. Abnormal high Glucose related manifestations-
 Polyuria/Polydipsia/Polyphagia
5. Associated ppting factor (if any) related manifestations
 H/o missing Insulin doses recently
 Active infection- Fever/Chill+ rigor+ Symptoms of focal infection- URTI/LRTI/UTI etc.
 Any other critical illness
Investigations
Tests To look for/Aim of the test/Potential abnormality
1. CBG- ↑↑ Immediately and thereafter at regular interval
2. Hb,TC,DC,CRP- ↑TC/CRP- Infection
3. Ur,Cr- ↑- Dehydration
4. Electrolytes-Na, K, Cl Dyselectrolytemia
5. ABG Metabolic Acidosis- pH, HCO3, CO2
6. Ketone levels Ketoniemia
7. Urine Ketone Ketonuria
8. Amylase and lipase May be non-specifically high in DKA- does not suggest Pancreatitis!!
9. Sepsis screen- If febrile or infection is suspected
10. CxR/Urine- R.E/M.E/C.S/Blood C.S
Many of these tests particularly blood biochemistry are to be repeated at regular interval till pt. become stable

Management
Goals/Aims
1. Rx of Dehydration- Fluid resuscitation 3. Correction of K-imbalance- KCl
2. Reversal of the Ketoacidosis- 4. Reduction of Abnormal glucose- Insulin
 Alkalinising agent- NaHCO3 5. Rx Associated precipitating cause/factor, if any

1. Dehydration Rx- Fluid resuscitation- Rate/amount depends on volume status + cardiac and renal status

a. Initial correction either by Isotonic NaCl solution or Ringer Lactate

b. Recommended schedule for restoring fluids is as follows:
1. Administer 1-2 L during the first hour. 4. Administer 1 L every 4-6 hours, depending on the
2. Administer 1 L during the second hour. degree of dehydration
3. Administer 1 L during the following 2 hours
c. When euvolemic, switch to half Normal NaCl, particularly if hypernatremic
d. When blood sugar is ≤ 200-180 mg/dl, Isotonic NaCl is replaced with 5-10% D to prevent any hypoglycaemia
induced by Insulin infusion
2. K- imbalance- KCL infusion should be started from the beginning as Insulin will start to shift K rapidly
into cells causing Extracellular Hypokalemia- KCl is added to the infusion fluid
If K is greater than 6 mEq/L- no K supplement If K is 3-4.5 mEq/L- KCl 20 mEq/h
If K is 4.5-6 mEq/L- KCl 10 mEq/h
Monitor Potassium level regularly

3. Ketoacidosis-
NaHCO3 infusion only if decompensated acidosis starts to threaten the patient's life.
Rapid administration of NaHCO3 can cause cerebral oedema particularly in children.

4. Abnormal Glucose- Insulin Infusion- Monitor blood glucose at bedside every hour till it’s stabilized
Initially Continuous IV Short acting Insulin infusion using an infusion pump
5. Antibiotic- Empiric antibiotics on suspicion of infection
6. Anticoagulation- Prophylactic Heparin- Severe dehydration can cause hyperviscocity precipitating DVT
7. After the patient is stable further/a long term management plan of DM should be drawn up.
 Hyperosmolar hyperglycemic state (HHS)…..V. Important

Hyperosmolar hyperglycemic state (HHS) is an acute, potentially life-threatening metabolic complication of diabetes
characterized by hyperglycemia, hyperosmolarity, dehydration without significant ketoacidosis & ketonuria that
mainly occurs in patients with Type 2 DM and rarely in Type 1 DM.
HHS was previously termed hyperosmolar nonketotic coma (HONC); however, the terminology was changed because
coma is found in very few pts of HHS.

Background of the patient- Pts are usually Type 2-DM pts- hitherto (until now) undiagnosed or a known case.

Precipitating Factor- May be present and if present is usually one of these

1. Missing dose(s) of Insulin/OHA 3. Critical Illness- Stroke/MI/PE/underlying
2. Infection CKD/ CHF are at increased risk

Pathophysiology Severe Insulin deficiency + ↑counter-regulatory hormones (Glucagon/GH/cortisol)

↑↑hepatic gluconeogenesis + glycogenolysis + No significant lipolysis

severe hyperglycemia No Ketonemia + Ketonuria

polydipsia and polyuria Glucosuria No metabolic acidosis (ketoacidosis)

osmotic diuresis

dehydration
(Unlike DKA, in HHS significant ketoacidosis DOES NOT occur, but the reason for this is NOT CLEAR. Contributing
factors likely include the availability of insulin particularly in Portal circulation in amounts sufficient to inhibit
ketogenesis but insufficient to prevent hyperglycemia. In addition, levels of counter-regulatory hormones like GH are
found to be lower in patients with HHS than in those with DKA.)

Therefore main problems in HHS are-

1. Dehydration 4. Abnormally high Glucose level
2. Ketoacidosis/Ketonemia- NO 5. Associated ppting factor (if any)–Infn/illness
3. K- imbalance
Hyperkalemia: Often present initially & is caused by a shift of potassium from the intracellular to the extracellular
space in an exchange with hydrogen ions that accumulate extracellularly in acidosis + due to insulin deficiency.
Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis.
Hypokalemia: As these patients get started on IV Insulin, K gets rapidly shifted into cells([Link] to [Link])
Symptoms-HHS usually develops over a course of days to weeks, unlike diabetic ketoacidosis (DKA), which develops
more rapidly, over the course of a few days. Often, a preceding illness results in several days of increasing
dehydration.
1. May be a known case of Ty-2 DM or undiagnosed DM- therefore may give recent h/o Wt. loss+/-Polyphagia +/-
Polyuria- these are due to underlying DM
2. Dehydration related manifestations
 Altered sensorium  Decreased skin turgor
 BP: Hypotension  Extremity:Tachycardia
 CRT: prolonged  Excess thirst
 Disorientation
 Dry skin 3. K-----ABSENT
 Dry mucous membranes
4. Abnormal ↑↑ Glucose related manifestations- Polyuria/Polydipsia/Polyphagia
5. Associated ppting factor (if any) related manifestations
  H/o missing OHA dose/ Insulin doses recently
 Active infection- Fever/Chill+ rigor+ Symptoms of focal infection- URTI/LRTI/UTI etc.
 Any other critical illness
Investigations
Tests To look for/Aim of the test/Potential abnormality
1. CBG - High- Immediately and thereafter at regular interval
2. Hb,TC,DC,CRP- ↑TC/CRP- Infection
3. Ur,Cr- ↑- Dehydration
4. Electrolytes-Na, K, Cl Dyselectrolytemia
5. ABG No metabolic Acidosis- BUT may occur due to associated illness eg. sepsis
6. Ketone levels No Ketoniemia
7. Urine Ketone No Ketonuria
8. Sepsis screen- If febrile or infection is suspected
CxR/Urine- R.E/M.E/C.S/Blood C.S
9. ECG/Cardiac enzymes- if MI is suspected
10. CT Brain ( IF pt is drowsy)- to rule out CVA
Many of these tests particularly blood biochemistry are to be repeated at regular interval till pt. become stable
Management
Goals/Aims
1. Rx of Dehydration- Fluid resuscitation 3. Reduction of Abnormal glucose - Insulin
2. Correction of K-imbalance- KCl 4. Rx Associated precipitating cause/factor, if any

1. Dehydration Rx- Fluid resuscitation- Rate/amount depends on volume status + cardiac and renal status

a. Initial correction either by Isotonic NaCl solution or Ringer Lactate

b. Recommended schedule for restoring fluids is as follows:
1. Administer ≥ 2 L during the first hour. 4. Administer 1 L over next 4 hours, depending on the
2. Administer 1 L during the second hour. degree of dehydration
3. Administer 1 L during the following 2 hours 5. Thereafter depending on clinical situation
c. When euvolemic, switch to half Normal NaCl, particularly if hypernatremic
d. When blood sugar is ≤ 200-180 mg/dl, Isotonic NaCl is replaced with 5-10% D to prevent any hypoglycaemia
induced by Insulin infusion
2. K- imbalance- KCL infusion should be started from the beginning as Insulin will start to shift K rapidly
into cells causing Extracellular Hypokalemia- KCl is added to the infusion fluid
If K is greater than 6 mEq/L- no K supplement If K is 3-4.5 mEq/L- KCl 20 mEq/h
If K is 4.5-6 mEq/L- KCl 10 mEq/h
Monitor Potassium level regularly
3. Abnormal Glucose- Insulin Infusion- Monitor blood glucose hourly at bedside till it’s stabilized
Initially Continuous IV Short acting Insulin infusion using an infusion pump
4. Antibiotic- Empiric antibiotics on suspicion of infection
5. Anticoagulation- Prophylactic Heparin- Severe dehydration can cause hyperviscocity precipitating DVT
6. After the patient is stable, further/a long term management plan of DM should be drawn up- adjust Insulin and/ or
OHAs on the basis of glucose level.
 SGLT 2 inhibitor
Sodium-dependent glucose cotransporters/ sodium-glucose linked transporter (SGLT) are a family of glucose
transporter found in the Small intestinal mucosa (SGLT1) and the Proximal tubule of the nephron. They contribute
to renal glucose reabsorption.
Mechanism of glycaemic control
These drugs by inhibiting subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of
the renal glucose reabsorption lowers blood glucose level. Additionally water is eliminated by osmotic diuresis,
resulting in a lowering of blood pressure.
Indication
As an adjunct to diet and exercise to improve glycaemic control in adults with T2 DM, not recommended in patients
with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Drugs Canagliflozin; Dapagliflozin;Empagliflozin
S/E
Hypotension
Ketoacidosis
Impairment in Renal Function
Hyperkalemia
Hypoglycemia (with concomitant use with Insulin and Insulin secretagogues
Incretin
Incretins are a group of GI hormones that decrease blood glucose levels.
Functions:
1. Stimulates increase amount of insulin released during postprandial state
2. Slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying
3. Inhibit Glucagon release from the alpha cells of the islets of Langerhans
Physiology
The two main incretin like molecules are
1. Glucagon-like peptide-1 (GLP-1)
2. Gastric inhibitory peptide: also called Glucose-dependent insulinotropic polypeptide or GIP
Both GLP-1 and GIP are inactivated by Dipeptidyl peptidase-4 (DPP-4)

GLP 1 agonist

2 groups OHAs exert hypoglycaemic effects by affecting Incretins

1. DPPP4 inhibitors- Gliptins-Vilda/Saxa/Lina/Sita
2. Incretin mimics- GLP-1 analogues- Exenatide; Liraglutide
 Next few topics are for the “Short notes” lovers!!.......
Primary Hyperaldosteronism/ Conn's syndrome…(“Ordinary lovers!!”)
Overproduction of Aldosterone
Types:
Primary/ Conn's syndrome: Excess production of Aldosterone from the adrenal glands due to “Intrinsic” disease of
the adrenal: hyperplasia or tumors: Aldostreone secreting adrenal adenoma
Secondary: CCF/CLD/Nephrotic syndrome/ CKD (these lead to overactivation of RAAS…“high renin” state leading to

Overproduction of Aldosterone
Clinical features: Resistant hypertension with recurrent Hypokalemia
Suspect if:
Those who have sustained blood pressure above 150/100 in three separate measurements taken on different days;
People who have hypertension resistant to three conventional antihypertensive drugs;
People whose hypertension is controlled with four or more medications;
People with hypertension and low levels of Potassium in the blood;
Those who have hypertension and a mass on the adrenal gland called an adrenal incidentaloma;
Young people with hypertension and a family history of early-onset hypertension (before age 30)
All hypertensive first-degree relatives of patients with primary Aldosteronism
Investigations:
Blood:
1. Electrolyte: Na, K: typically Recurrent Hypokalemia
2. Aldosterone Renin ration (ARR) (Low plasma renin plus High plasma aldosterone concentration)
ARR value in an individual that is higher than the cutoff indicates primary hyperaldosteronism
3. Imaging: CT Adrenals
4. Adrenal venous sampling (AVS) to make the distinction between unilateral and bilateral adrenal disease
Treatment
Surgical: Laparoscopic adrenalectomy for patients with unilateral PA (ie, aldosterone-producing adenoma [APA] or
unilateral adrenal hyperplasia
Medical: If a patient is unable or unwilling to undergo surgery or bilateral disease: medical treatment with
Mineralocorticoid receptor antagonist: Spironolactone/ Eplerenone

Dwarfism…( “ Extra-Ordinary lovers!!”)

Dwarfism generally defined as an adult height of 4 feet 10 inches or less.
2 broad categories:
Disproportionate dwarfism- If body size is disproportionate- very short trunk and shortened (but disproportionately
large) limbs with head disproportionately large compared with the body. Examples are
Achondroplasia
Spondyloepiphyseal dysplasias
Diastrophic dysplasia
Almost all people with disproportionate dwarfism have normal intellectual capacities
Proportionate dwarfism A body is proportionately small if all parts of the body are small to the same degree and
appear to be proportioned like a body of average stature. So the head, trunk and limbs are all small, but they're
proportionate to each other. Examples are
Growth hormone deficiency
Turner syndrome
Investigation- Hormone study/skeletal xrays/Genetic tests
Treatment- GH in appropriate cases Social/Occupational rehabilitation
 Metabolic syndrome......(“obsessive lovers!!)
Metabolic syndrome is a multiplex risk factor that arises from insulin resistance accompanying abnormal adipose
deposition and function.
It is a risk factor for Coronary artery disease, Diabetes, NASH.
C/F- ≥ 1 of the following
Hypertension
Hyperglycemia-DM and its complications
Hypertriglyceridemia- Xanthomas or Xanthelasmas
Abdominal obesity
Chest pains or shortness of breath: Suggesting the rise of cardiovascular and other complications
Acanthosis nigricans- In patients with insulin resistance
Metabolic syndrome is diagnosed when a patient has at least 3 of the following 5 conditions:
FBG ≥100 mg/dL (or receiving drug therapy for hyperglycemia)
BP ≥130/85 mm Hg (or receiving drug therapy for hypertension)
TG ≥150 mg/dL (or receiving drug therapy for hypertriglyceridemia)
HDL< 40 mg/dL in men or < 50 mg/dL in women (or receiving drug therapy for reduced HDL-C)
Waist circumference ≥ 40” men or 35” in women
Treatment
1. Lifestyle modification- lose weight/Healthy diet +/- dietary modification
2. Medications
Antihypertensive Antidiabetic- Preferred agent is an Insulin-sensitizing
Antilipidemic- Statin/Fibrate agent - Metformin

Achondroplasia… (“Orgasmic” lovers!!!)

Achondroplasia is one of the most common cause of disproportionately short stature. This disorder usually results in
the following:
 An average-size trunk
 Short arms and legs, with particularly short upper part of the arms and that of legs
 Limbs are short but disproportionately large compared with the body
 Short fingers, often with a wide separation between the middle and ring fingers
 Limited mobility at the elbows
 A disproportionately large head, with a prominent forehead and a flattened bridge of the nose
 Progressive development of bowed legs
 Progressive development of swayed lower back
 An adult height around 4 feet