Slide set 1 BMS Confidential – For Internal Use Only

Hepatology:
The basics
 BMS Confidential – For Internal Use Only

Introduction

• Hepatology is the study of the liver from an

anatomical, physiological and pathological point of
view
• The liver:
– Is an organ which is essential to life
– Metabolises nutrients
– Purifies the blood
– Synthesises, stores and releases various substrates
– Performs at least 500 different functions

2
 BMS Confidential – For Internal Use Only

Hepatology: The basics

I. Anatomy of the liver

II. The physiological role of the liver
III. Major hepatic syndromes
IV. The main diseases of the liver

3
 BMS Confidential – For Internal Use Only

Anatomy of the liver

• The liver
– An organ consisting of cells (hepatocytes) grouped
into characteristic functional units
– A complex and fragile organ involved in many vital
functions
– Large functional reserve
• >70% must be damaged before function is impaired

4
Minuk GY. Can J Gastroenterol 2003;17:418–424
 BMS Confidential – For Internal Use Only

Anatomy of the liver

A. Descriptive anatomy
B. Functional anatomy

5
 BMS Confidential – For Internal Use Only

Descriptive anatomy

• Location
– The largest accessory gland
of the digestive tract
• Adult weight: 1.0 to 2.3 kg

– Located beneath the

diaphragm, on the right-
hand side

Waugh A, Grant A. Ross and Wilson anatomy and physiology in health and illness, 9th Ed. Edinburgh: 6
Churchill Livingstone; 2001.
 BMS Confidential – For Internal Use Only

Descriptive anatomy

• External configuration
– Upper surface: 2 lobes (left and right)
– Lower surface: 4 lobes (right, left, quadrate and
caudate)
Inferior vena
Caudatecava
Left lobe lobe Portal vein
Hepatic
artery

Common hepatic
duct

Right lobe

Falciform ligament
Gallbladde
Quadrate r
lobe of the liver and biliary system, 11th Ed. Oxford: Blackwell Science; 2002. 7
Sherlock S, Dooley J. Diseases
 BMS Confidential – For Internal Use Only

Descriptive anatomy

• Vasculature
– The liver receives about 1.5 litres of blood per minute:
• 1.2 L via the portal vein
• 0.3 L via the hepatic artery
Double vasculature

6
5.0L
Blood flow (L/min)

5
4

2 1.5L
1.2L
1 0.3L
0
Hepatic Portal vein Liver Body
artery

8
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Descriptive anatomy

• Vasculature
– The portal vein and its branches
• Supply the liver with blood rich in metabolites, which the
hepatic cells store and convert
Functional circulation of the liver

– The hepatic artery and its branches

• Supply the liver with blood rich in oxygen, which is essential
for life and hepatic cell activity
Nutritional circulation of the liver

9
Damjanov I. Pathology for the health-related professions, 2nd Ed. Philadelphia, PA: W.B. Saunders Co; 2000.
 BMS Confidential – For Internal Use Only

Descriptive anatomy

• Did you know?

– Venous blood in the portal system may contain toxic
substances or infectious agents
– Venous blood is purified (detoxification) before being
released into the general circulation

10
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Descriptive anatomy

• Vasculature
– The hepatic venous system
• The hepatic veins collect all the blood flowing from the liver
and channel it into the inferior vena cava, which returns
venous blood to the heart

11
Lindsay DT. Functional human anatomy. St. Louis, MO: Mosby; 1996.
 BMS Confidential – For Internal Use Only

Descriptive anatomy
Inferior vena cava
Hepatic veins
Left lobe
Right lobe

Hepatic artery
Portal vein

Mesenteric veins
Intestine

12
Lindsay DT. Functional human anatomy. St. Louis, MO: Mosby; 1996.
 BMS Confidential – For Internal Use Only

Descriptive anatomy

• The bile ducts

– Bile plays an important role in digestion
– Bile is secreted by the hepatic cells into small vessels
known as the canaliculi
– After bile is produced, it is excreted through the bile
ducts into the intestine or stored in the gallbladder
• Intrahepatic bile ducts collect bile from the canaliculi then
unite to form right and left extrahepatic bile ducts that flow
into the common bile duct

1. Waugh A, Grant A. Ross and Wilson anatomy and physiology in health and illness, 9th Ed. Edinburgh:
Churchill Livingstone; 2001. 2. Tortora GJ, Grabowski SR. Principles of anatomy and physiology, 10th Ed. 13
New York, NY: John Wiley & Sons, Inc.; 2003.
 BMS Confidential – For Internal Use Only

Descriptive anatomy
Right hepatic duct
Neck
Left hepatic duct
Schematic diagram
of the bile ducts
Common hepatic duct
Cystic duct Common bile duct
Gallbladder
Pancreas
Main bile duct

Duodenum

1. Waugh A, Grant A. Ross and Wilson anatomy and physiology in health and illness, 9th Ed. Edinburgh:
Churchill Livingstone; 2001. [Link] GJ, Grabowski SR. Principles of anatomy and physiology, 10th Ed. New 14
York, NY: John Wiley & Sons, Inc.; 2003.
 BMS Confidential – For Internal Use Only

Anatomy of the liver

A. Descriptive anatomy
B. Functional anatomy
– Hepatic lobules
– Sinusoids
– Bile ductules
– Hepatic acinus

15
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Functional anatomy

• Each vascular segment of the liver is made up of

many smaller units called lobules
• However, the hepatic lobule has no clear
functional significance
• The functional unit of the liver is the hepatic
acinus

16
Rubin E, Farber JL. Pathology, 1st Ed. Philadelphia, PA: JB Lippincott Company; 1988.
 BMS Confidential – For Internal Use Only

Functional anatomy

• The hepatic lobules

– Hexagonal anatomical units consisting of plates of
hepatocytes centred on a centrolobular vein
– The liver contains
50,000 to 100,000 Centrolobular
lobules vein

Sinusoids Portal space

17
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Functional anatomy

• The hepatic lobules

– The lobules are separated by a portal triad or portal
tract which contains 3 elements:
• A branch of the hepatic artery
• A branch of the portal vein
• A bile canaliculus

18
Rubin E, Farber JL. Pathology, 1st Ed. Philadelphia, PA: JB Lippincott Company; 1988.
 BMS Confidential – For Internal Use Only

Functional anatomy

• The sinusoids
– Exchange zones
• Blood from the portal vein and hepatic artery:
– Flows into the sinusoids from the interlobular spaces
– Flows into the central collector, the centrolobular vein (which joins to
the suprahepatic veins, connected to the inferior vena cava)
– Purification zones
• Contain macrophages or Kupffer cells, which ingest and destroy
foreign bodies and dead cells
• Further removal of toxins and other metabolites that diffuse from
the sinusoids is carried out by the hepatocytes

1. Waugh A, Grant A. Ross and Wilson anatomy and physiology in health and illness, 9th Ed. Edinburgh:
Churchill Livingstone; 2001. 2. Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, 19
PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Functional anatomy

• Bile ductules
– Provide routes between hepatocyte plates
– Consist of epithelial cells
– Collect the bile secreted by the hepatocytes and carry
it out of the liver via the right and left hepatic ducts

20
Rubin E, Farber JL. Pathology, 1st Ed. Philadelphia, PA: JB Lippincott Company; 1988.
 BMS Confidential – For Internal Use Only

Functional anatomy

• Key point…
– In the liver, the hepatitis B virus only infects and
replicates within hepatocytes

21
Ganem D & Prince AM. N Engl J Med 2004;350:1118–1129
 BMS Confidential – For Internal Use Only

Functional anatomy
Kupffer cell Bile in bile
Hepatocyte plate in sinusoid ductules Interlobular
Centrolobular vein bile duct

Schematic diagram Portal vein

of a hepatic lobule
showing hepatocyte
plates and sinusoids rtal space)
obular space

Hepatocytes

Hepatic
artery
Blood circulating in sinusoids
formed by endothelial cells

Waugh A, Grant A. Ross and Wilson anatomy and physiology in health and illness, 9th Ed. Edinburgh: Churchill 22
Livingstone; 2001.
 BMS Confidential – For Internal Use Only

Functional anatomy

• The hepatic acinus

– The liver's actual functional unit
• Lozenge-shaped structure, limited by 2 portal areas and 2
centrolobular veins
Schematic diagram of the hepatic
acinus
Hepatic lobule
Portal space
Centrolobular vein

Hepatic acinus

23
Rubin E, Farber JL. Pathology, 1st Ed. Philadelphia, PA: JB Lippincott Company; 1988.
 BMS Confidential – For Internal Use Only

Functional anatomy

• The hepatic acinus Portal space:

Limit of the lobule - Venule
- Arteriole
- Bile duct

Zone 3 (furthest from

Limit of acinus the portal space) is
less oxygenated:
greater vulnerability
1 to viruses and toxins
Portal space 2
3 Centrolobular vein

24
Rubin E, Farber JL. Pathology, 1st Ed. Philadelphia, PA: JB Lippincott Company; 1988.
 BMS Confidential – For Internal Use Only

Functional anatomy

• Regeneration of hepatic tissue

– Rapid division of healthy hepatocytes to compensate for cell
deaths
– Occurs after:
• Partial hepatic resection
• Toxic damage to hepatocytes
• A viral infection (for example: hepatitis B)
– If hepatocytic regeneration is inadequate or
non-functional  hepatic insufficiency
– If regeneration is uncontrolled: structural disorganisation 
cirrhosis  hepatocellular carcinoma

25
Minuk GY. Can J Gastroenterol 2003;17:418–424
 BMS Confidential – For Internal Use Only

Hepatology: The basics

I. Anatomy of the liver

II. The physiological role of the liver
III. Major hepatic syndromes
IV. The main diseases of the liver

26
 BMS Confidential – For Internal Use Only

The physiological role of the liver

• The liver
– Is a mixed gland
• Exocrine function: Bile production
• Endocrine function: Involved in carbohydrate, protein and
lipid metabolism
– Also plays a part in storing and supplying iron and
vitamins
– Synthesises many enzymes
– Purifies the blood

27
 BMS Confidential – For Internal Use Only

The physiological role of the liver

A. Exocrine function of the liver

B. Endocrine function of the liver
C. Other liver functions

28
 BMS Confidential – For Internal Use Only

Exocrine function of the liver

• Bile secretion
– Important role during digestion
• Helps to neutralise gastric acid
• Emulsification of lipids for easy digestion
– Hepatocytes continuously produce 700–1200 mL
of bile per day
• Bile is stored in the gallbladder
• During digestion, bile is routed to the duodenum via the intra-
and extra-hepatic bile ducts

29
Davies A, et al. Human Physiology. 1st Ed. London: Churchill Livingstone; 2001
 BMS Confidential – For Internal Use Only

Exocrine function of the liver

Bile salts excreted
in the bile
• Bile secretion
– Bile contains:
Bile is stored in the
• Water gallbladder until
• Bile salts the next meal

• Bile pigments
– Including bilirubin Bile salts return
• Bile acids to the liver via the
portal circulation
• Cholesterol
• Ions Bile salts are
• absorbed by the
Phospholipids terminal ileum

Tortora GJ, Grabowski SR. Principles of anatomy and physiology, 10th Ed. New York, NY: 30
John Wiley & Sons, Inc.; 2003.
 BMS Confidential – For Internal Use Only

Exocrine function of the liver

Macrophage
1
1 Haemoglobin is phagocytosed
Haemoglobin and split into a haem molecule
Bilirubin Globin and a globin molecule
Metabolism Hgb
2 The non-conjugated bilirubin
binds to plasma albumin
2 Non-conjugated bilirubin + albumin
3
Non-conjugated bilirubin + 3 In the hepatocyte, the bilirubin
is conjugated with different
glucuronic acid or other substances substances (glucuronic acid)
Conjugated forming conjugated bilirubin
bilirubin
4 4 Gut bacteria transform nearly
50% of conjugated bilirubin
Conjugated into soluble urobilinogen
bilirubin Urobilinogen

5a 5% of urobilinogen is excreted
by the kidneys into the urine
5b Urobilinogen
5b Some urobilinogen is reabsorbed
5a 5c Stercobilin and re-excreted by the liver
Kidney 5c Most urobilinogen is excreted in
the faeces in form of stercobilin

31
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

The physiological role of the liver

A. Exocrine function of the liver

B. Endocrine function of the liver
C. Other liver functions

32
 BMS Confidential – For Internal Use Only

Endocrine function of the liver

• The liver is involved in the metabolism of many

substances:
– Carbohydrates
– Lipids
– Proteins
– Hormones
– Drugs

33
 BMS Confidential – For Internal Use Only

Endocrine function of the liver

• Carbohydrate metabolism
– Glycogen is stored by the liver
– Hypoglycaemia (low blood glucose)  glycogen
converted into glucose via glucagon
– Hyperglycaemia (high blood glucose)  glucose
converted into glycogen via insulin

– The liver also synthesises glucose from amino acids

or fatty acids = gluconeogenesis

34
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Endocrine function of the liver

• Carbohydrate metabolism

Glucogenesis Glycogenolysis

Glucose

Glycogen Glucose

Glucose

35
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Endocrine function of the liver

• Lipid metabolism
– The liver
• Converts and distributes lipid molecules
• Synthesises:
– Fatty acids
– Triglycerides
– Lipoproteins: HDL, LDL and VLDL (which carry triglycerides
and cholesterol)
– Cholesterol
– Phospholipids

36
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Endocrine function of the liver

• Protein metabolism

– The liver's protein synthesis activity is vital

• Proteins are used in the construction of membranes and cell
organelles
• Around 90% of plasma proteins are formed in the liver

– The main plasma proteins are:

• Albumin: transports many different molecules
• Coagulation factors: 13 factors needed for the coagulation

37
Guyton A, Hall J. Textbook of Medical Physiology. 9th Ed. Philadelphia, PA: WB Saunders Co; 1996
 BMS Confidential – For Internal Use Only

Endocrine function of the liver

• Drug metabolism
– Drugs are:
• Usually lipid soluble and hydrophobic
• Converted in the hepatocytes, usually via P450 cytochromes
 formation of polar metabolites which are hydrophilic and
can be eliminated in bile or urine

– Drugs can be:

• Enzyme inhibitors
• Enzyme activators

38
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The physiological role of the liver

A. Exocrine function of the liver

B. Endocrine function of the liver
C. Other liver functions

39
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Other liver functions

• Storage
– Iron
• Essential for haemoglobin synthesis in red blood cells
• Stored in the form of ferritin
• Ferritin is released from the liver into the circulatory system
when blood levels are low
– Many vitamins, especially:
• Vitamin A
• Vitamin D
• Vitamin B12

40
 BMS Confidential – For Internal Use Only

Other liver functions

• Key point…
– Severe hepatic disease can disturb hepatic functions
(e.g. drug metabolism, vitamin supply)

41
 BMS Confidential – For Internal Use Only

Hepatology: The basics

I. Anatomy of the liver

II. The physiological role of the liver
III. Major hepatic syndromes
IV. The main diseases of the liver

42
 BMS Confidential – For Internal Use Only

Major hepatic syndromes

• Cholestasis
• Cytolysis/necrosis
• Hepatic failure
• Portal hypertension

43
 BMS Confidential – For Internal Use Only

Cholestasis

• Definition
– Reduction or absence of bile excretion in the digestive
tract
• Causes
– Bile duct obstruction (extrahepatic cholestasis)
• May be due to lithiasis or pancreatic/bile duct cancer
– Reduction or absence of bile production
(intrahepatic cholestasis)
• May be due to hepatitis, cirrhosis or autoimmune disease of
the bile ducts

44
Sherlock S, Dooley J. Diseases of the liver and biliary system, 11th Ed. Oxford: Blackwell Science; 2002.
 BMS Confidential – For Internal Use Only

Major hepatic syndromes

• Cholestasis
• Cytolysis/necrosis
• Hepatic failure
• Portal hypertension

45
 BMS Confidential – For Internal Use Only

Cytolysis/necrosis

• Definition
– Destruction of liver cells
• Causes
– Viral infection (e.g. hepatitis B)
– Toxic substances: e.g. certain drugs, alcohol,
Death Cap mushroom (Amanita phalloides)
– Muscular trauma and disease
– Obesity, diabetes
– Biliary lithiasis

46
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Cytolysis/necrosis

• Clinical consequences
– Persistent necrosis can lead to fibrosis
– Death (fulminant hepatitis)

• Biological consequences
– Release of transaminase enzymes (ALT/AST) and
iron into serum

47
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Major hepatic syndromes

• Cholestasis
• Cytolysis/necrosis
• Hepatic failure
• Portal hypertension

48
 BMS Confidential – For Internal Use Only

Hepatic failure

• Definition
– Reduction or halting of hepatic functions
• Can be acute or chronic
• Causes
– Poor perfusion of hepatic tissues due to fibrosis or
cirrhosis (hepatocytes less functional)
– Direct hepatocyte destruction (e.g. severe acute
hepatitis, fulminant hepatitis B)
– Combination of both phenomena

49
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Hepatic failure

• Clinical features
– Jaundice
– Hypoalbuminemia, which predisposes to peripheral
oedema
– Hyperammonemia, which may result in hepatic
encephalopathy
– Metabolic disorders: hypoglycaemic episodes
via  glucose synthesis

50
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Major hepatic syndromes

• Cholestasis
• Cytolysis/necrosis
• Hepatic failure
• Portal hypertension

51
 BMS Confidential – For Internal Use Only

Portal hypertension

• Definition
  blood pressure in the portal vein
• Causes
– Circulatory obstruction, which may be:
• Prehepatic: obstructive thrombosis and narrowing of the portal
vein; massive splenomegaly causing shunting of blood into the
splenic vein
• Intrahepatic: cirrhosis, which is the most common cause of portal
hypertension
• Posthepatic: severe right-sided heart failure; constructive
pericarditis; hepatic vein outflow obstruction

52
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Portal hypertension

• Clinical consequences
– Development of digestive varicose veins, particularly
oesophageal
• Major risk: rupture of these varicose veins can cause a
potentially fatal haematemesis
– Ascites (effusion of plasma into the peritoneal cavity)
– Congestive splenomegaly
– Hepatic encephalopathy

53
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Hepatology: The basics

I. Anatomy of the liver

II. The physiological role of the liver
III. Major hepatic syndromes
IV. The main diseases of the liver

54
 BMS Confidential – For Internal Use Only

The main diseases of the liver

• Hepatitis
• Fibrosis
• Cirrhosis
• Liver cancer

55
 BMS Confidential – For Internal Use Only

Hepatitis

• Hepatitis is any ‘inflammation of the liver’, no matter

what the cause
• Hepatitis can be:
– Acute or chronic (persisting for more than 6 months)
– Caused by:
• Viruses
• Toxic substances (e.g. alcohol)
• Drugs (e.g. anti-inflammatories, antibiotics)
• Metabolic disease (e.g. Wilson's disease, which leads to the
accumulation of copper in the liver)
• Autoimmune disease

56
Andreoli T. Cecil Essentials of Medicine, 5th Ed. Philadelphia, PA: WB Saunders Co; 2001.
 BMS Confidential – For Internal Use Only

Acute viral hepatitis: General

• Clinical signs
– Asymptomatic, unnoticed
– Symptomatic, with or without jaundice (icterus)
– Suddenly severe, or fulminant

57
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Acute viral hepatitis: General

• Symptoms
– Conjunctival and skin jaundice, linked to cholestasis:
icteral phase
– Faeces light in colour, urine dark, possible associated
pruritis
– Jaundice may be preceded by a pseudo-influenza
syndrome or pre-icteral phase with high temperature,
headache, asthenia, anorexia, arthralgia and myalgia

58
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Acute viral hepatitis: General

Headache

• Symptoms High
temperature
Jaundice
Asthenia

Anorexia

Arthralgia

Dark urine
Normal or
colourless faeces
Myalgia
Pre-icteral phase
Icteral phase

59
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Acute viral hepatitis: General

• Fulminant hepatitis
– Massive hepatic cell necrosis (cytolysis)
– Characterised by encephalopathy linked to hepatic
failure
– Fatal progression in 80% of cases (if the patient does
not receive an urgent transplant)
– Rare: about 1% of cases of acute hepatitis B

60
Andreoli T. Cecil Essentials of Medicine, 5th Ed. Philadelphia, PA: WB Saunders Co; 2001.
 BMS Confidential – For Internal Use Only

Acute viral hepatitis: General

• Laboratory markers
– Elevated transaminases (often to levels >20 x ULN)
– Elevated GT and alkaline phosphatases
– Hyperbilirubinaemia
– Inflammatory syndrome characterised by increases in
SS, C-reactive protein and globulins
– Decreases in prothrombin and albumin levels may be
evident (signs of hepatocellular insufficiency)

61
Andreoli T. Cecil Essentials of Medicine, 5th Ed. Philadelphia, PA: WB Saunders Co; 2001.
 BMS Confidential – For Internal Use Only

Acute viral hepatitis: General

• Disease progression dependent on virus

– Spontaneous clearance (cure)
• Usually observed for hepatitis A
– Development of chronic infection
• Hepatitis B: Rare (<10% in adults) but more common in
cases of neonatal infection (90% in children infected early in
life, ~30% infected from 1 to 5-years-old)
• Hepatitis C: Frequent (75–85% of infections)

1. Everson G & Weinberg H. Living with hepatitis B: a survivor’s guide, 1st Ed. Long Island, NY: Hatherleigh 62
Press; 2002. [Link] EASL Jury. J Hepatol 2003; 39:S3–S25.
 BMS Confidential – For Internal Use Only

Chronic viral hepatitis: General

• Definition
– The existence of hepatic lesions linked to the
persistent presence of the virus (usually B or C) and
illness progressing for more than 6 months
• Clinical course may involve:
– Spontaneous remission (rarely)
– Indolent disease without progression for many years
– Rapidly progressive disease and development of
cirrhosis after a few years

63
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Chronic viral hepatitis: General

• Clinical signs
– Variable and not predictive of outcome
– Only sign of chronic disease may be persistently elevated
serum transaminases
– Most common symptom is fatigue
– Other symptoms may include:
• Malaise
• Loss of appetite
• Mild jaundice
– Few physical findings

64
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Chronic viral hepatitis: General

• Complementary examinations
– Hepatic examination
• May detect an  in transaminases, often fluctuating
– Liver biopsy
• Considered to be the 'gold standard'
– Aetiological examination
• Virological methods (ELISA and PCR) are used to diagnose
the viral nature of chronic hepatitis
• Viral load measurements used to quantify the level of virus in
the blood / liver

65
The EASL Jury. J Hepatol 2003; 39:S3–S25.
 BMS Confidential – For Internal Use Only

Chronic viral hepatitis: General

• Liver biopsy
– Confirms diagnosis of hepatitis, using microscopic
techniques to detect histological lesions
– Used to assess the degree of necroinflammation
(grade) and fibrosis (stage)
– Results expressed by scoring system:
• Knodell
• Ishak
• METAVIR

66
Lai CL & Locarnini S (Editors). Hepatitis B Virus. London: International Medical Press; 2002.
 BMS Confidential – For Internal Use Only

Chronic viral hepatitis: General

The clinical outcomes of chronic hepatitis B

Healthy Liver Liver Cancer

5–10% of
CHB-infected
individuals1
Recovery

Acute Infection Chronic Infection Cirrhosis

Liver Death
Transplantation (25-40%)
Up to 90%
dependent on 30% of HBV-infected
<1% age of individuals may
infection2 progress to cirrhosis1
Liver Failure
Fulminant
Hepatitis

5–50 years

67
1. Locarnini S, et al. Antivir Ther. 2004; 9:679–693. 2. The EASL Jury. J Hepatol 2003; 38:S3–S25.
 BMS Confidential – For Internal Use Only

The main diseases of the liver

A. Hepatitis
B. Fibrosis
C. Cirrhosis
D. Liver cancer

68
 BMS Confidential – For Internal Use Only

Fibrosis

• Definition
– The formation of fibrous scar tissue in the place of
normal hepatic tissue
• Clinical consequences
– The deposition of collagen has lasting consequences on
patterns of hepatic blood flow and the perfusion of
hepatocytes
• Increased portal hypertension
– Continued fibrosis results in the development of cirrhosis

69
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Fibrosis

• Common causes
– Inflammation (chronic hepatitis)
– Direct toxic insult
– Liver fibrosis is the hallmark of virtually any chronic liver
disease
• Staging and grading systems are used to assess
the severity of fibrosis / cirrhosis
– Knodell, Ishak and METAVIR
– Collagen staining (Sirius red)

70
Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
 BMS Confidential – For Internal Use Only

Fibrosis
Ishak stage:
Ishak stage: Fibrosis
Appearance Categorical
Categorical description measurement*
assignment

No fibrosis (normal) 0 1.9%

Fibrous expansion
of some portal areas ± short fibrous 1 3.0%
septa

Fibrous expansion of most portal

2 3.6%
areas ± short fibrous septa

Fibrous expansion of most portal

areas with occasional portal to portal 3 6.5%
(P–P) bridging
Fibrous expansion of portal areas
with marked P–P bridging as well as 4 13.7%
P–C
Marked bridging (P–P and/or P–C),
with occasional nodules 5 24.3%
(incomplete cirrhosis)

Cirrhosis, probable or definite 6 27.8%

* Proportion (%) of area of illustrated section showing Sirius red staining for collagen (collagen proportionate area).

71
Standish R, et al., Gut 2006; 55:569–78.
 BMS Confidential – For Internal Use Only

The main diseases of the liver

A. Hepatitis
B. Fibrosis
C. Cirrhosis
D. Liver cancer

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Cirrhosis

• Definition
– Chronic liver disease due to prolonged injury,
leading to:
• Destruction of hepatocytes
• Tissue fibrosis Revealed by biopsy
• Regeneration nodules

• The most common causes are:

– Alcohol
– Chronic viral hepatitis (C and B)

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Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
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Cirrhosis
Bile ductules are compressed by the
fibrosis, contributing to jaundice

Damaged hepatocytes

Hepatocellular Blood is shunted away

insufficiency from the liver blood
vessels, leading to poor
perfusion and
hepatocellular
Jaundice insufficiency

Jaundice

Regenerating Proliferation of fibrous

nodules connective tissue

Fibrosis

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Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
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Cirrhosis

• Compensated cirrhosis
– May go unnoticed for months or years or be
discovered accidentally during a clinical or biological
examination

– Episodes of decompensation occur; the remaining

healthy hepatocytes can no longer perform hepatic
functions (rupture of oesophageal varicose veins,
ascites, hepatic encephalopathy)

Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999. 75
Andreoli T. Cecil Essentials of Medicine, 5th Ed. Philadelphia, PA: WB Saunders Co; 2001.
 BMS Confidential – For Internal Use Only

Cirrhosis

• Key point…
– Cirrhosis was previously thought to be irreversible
BUT recent clinical data have demonstrated that
effective antiviral therapy can lead to the regression of
fibrosis / cirrhosis

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Cirrhosis

• Cirrhosis may result in cancer

(most frequently hepatocellular carcinoma)
• Monitoring:
– Ultrasonography: detection of nodules <1 cm
– Alpha-foetoprotein (FP) assay:
• Liver cancer marker detected in 80% of cases

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Franca AVC. Braz J Med Biol Res 2004;37:1689–1705
 BMS Confidential – For Internal Use Only

The main diseases of the liver

A. Hepatitis
B. Fibrosis
C. Cirrhosis
D. Liver cancer

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Liver cancer

• Source: metastatic or primary

– The primary cancer is called hepatocellular carcinoma
(HCC) and usually develops in a cirrhotic liver
• Epidemiology
– In Europe, 5 years after a diagnosis of chronic
hepatitis B, there is a 6% probability of HCC occurring
– Frequency varies according to continent: more
common in Africa and Asia (strong prevalence of
HBV) than in Europe

Franca AVC, et al. Braz J Med Biol Res 2004;37:1689–1705 79

Michielsen PP, et al. World J Surg Oncol 2005;3:27
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Liver cancer

• Clinical
– HCC is asymptomatic for long periods
– When the tumour grows, non-specific clinical signs or
complications occur:
• Weight loss
• Asthenia
• High temperature
• Sometimes painful hepatomegaly

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Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
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Liver cancer

• Clinical
– HCC can be focal, multi-focal or diffuse (harder to
diagnose with imaging)
Solitary tumour

Nodular tumours

Diffuse tumour

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Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
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Liver cancer

• Diagnosis confirmed by:

– Abdominal ultrasonography: displays hepatomegaly
and tumour
– Abdominal CT scan (more accurate than
ultrasonography)
– Plasma alpha-foetoprotein (α-FP) assay
• Also routine screening test
• Can also be used to monitor tumour progression under
treatment

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Cotran RS, et al. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: WB Saunders Co; 1999.
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Liver cancer

• Progression
– Metastases generally involve the skeletal and
pulmonary systems
– The 5-year survival rate is 10%

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Schiff ER, et al. Schiff’s Diseases of the Liver, 9th Ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2003.