Hepatic disorders

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DAWN V TOMY M.Pharm., Asst. Professor, Dept. of Pharmacology, ST.JOSEPH’S COLLEGE OF PHARMACY, CHERTHALA.
HEPATIC DISORDERS(H-596, R-603)
INTRODUCTION
• Liver weigh around 1400 - 1600gm.
• Parenchyma contains:
- Liver cells (hepatocytes) trabeculae 1 cell thick in adults.
- Kupffer cells in sinusoids are phagocytes.
- Hepatic stellate cells in space of Disse, store Vitamin A, transform into
collagen-producing myofibroblasts and regulate blood flow in sinusoids.
- Liver-associated lymphocytes.
• Biliary drainage system:
- Canaliculi (in center of liver cell plates).
- Canals of Hering & cholangioles.
- Intra-hepatic bile ducts.
- Extra-hepatic bile ducts.
• Vasculature (blood supply)
- Portal vein supplies 70% of the blood flow.
- Hepatic artery supplies 30% of the blood flow.
- Sinusoids lined by fenestrated endothelium.
- Hepatic venules, hepatic veins drain into the IVC.
• The functional unit of the liver parenchyma is the hepatic acinus with zones 1, 2 & 3.
Zone 1 is periportal, zone 3 is perivenular and zone 2 intermediate.
• Portal tracts composed of fibrous tissue form branches in the liver and contain 3
structures, portal vein, hepatic artery, bile duct (portal triad).
• The important functions of liver are:
- Metabolism of carbohydrate, protein, lipids.
- Protein synthesis (albumin, coagulation factors, complement factors etc).
- Storage of iron, copper, vitamins A, D & B12.
- Detoxification/drug metabolism.
- Bile production.
Investigation of liver diseases.
• Biochemical – enzymes (ALT/SGPT, AST/SGOT, Alkaline Phosphatase), proteins,
bilirubin.
• Hematological - coagulation factors (Prothrombin Time/INR, Albumin).
• Immunological - antibodies (viruses, autoimmune).
• Imaging - ultrasound, CT, MRI, ERCP, MRCP.
• Liver biopsy - percutaneous needle biopsy, trans-jugular biopsy, wedge biopsy at
laparoscopy or open surgery.

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Morphological patterns of liver injury.
1. Degeneration - ballooning degeneration (hydropic change) - feathery degeneration
(bile-induced damage). Intracellular accumulations - fat (steatosis), iron, copper, bile,
Mallory’s hyaline.
2. Necrosis - (coagulative or lytic) and apoptosis. Necrosis may be randomly focal (spotty
necrosis), zonal e.g. zone 3, bridging (bridging hepatic necrosis, e.g. portal to venular),
involve most or almost all of the liver (submassive and massive respectively). Zone 3 is
most prone to injury as it is farthest from the blood supply and is the area containing
most drug-metabolizing enzymes.
3. Inflammation - acute, chronic or granulomatous. May be portal, periportal (interface
hepatitis) or acinar (focal or panacinar).
4. Regeneration - hepatocytes have great ability to regenerate. Activation is described as
the ductular reaction.
5. Fibrosis forms in response to inflammation or direct toxic injury. Can be portal,
perivenular, form bridging fibrosis, finally cirrhosis.
JAUNDICE AND CHOLESTASIS
• Jaundice (icterus) is the deposition of bilirubin in the skin or sclera due to elevated
levels of bilirubin (high affinity for elastic tissue) in the blood (hyperbilirubinemia).
Normal ranges from 0.3-1.3 mg/dl (80% is unconjugated). If the total serum bilirubin
exceeds 2 mg/dl it causes jaundice. Between normal and 2 mg/dl is (asymptomatic
state) called latent jaundice.
• Cholestasis (arrest of bile flow). It is a condition in which there is an obstruction to the
flow of bile from liver cell microsomes to the duodenum.
Pathogenesis of jaundice and cholestasis.
• Increased bilirubin production resulting from excessive RBC destruction in intra and
extravascular hemolysis or due to ineffective erythropoiesis. Increased release of
hemoglobin leads to excess bilirubin. Hyperbilirubinemia develops when liver is unable
to conjugate large amount of bilirubin. In premature infants, the liver is deficient in
enzymes for conjugation results in icterus neonatorum (A severe condition in the
hemolytic disease of the newborn due to maternal isoantibodies). Hyperbilirubinemia
cause permanent brain damage in infants from kernicterus (serum level of unconjugated
bilirubin exceeds 20 mg/dl).
• Decreased uptake by hepatocytes: The uptake of bilirubin by the hepatocyte that
involves dissociation of the pigment from albumin and its binding to cytoplasmic
protein, GST or ligandin, may be deranged e.g. due to drugs, prolonged starvation and
sepsis.
• Impaired conjugation: This mechanism involves deranged hepatic conjugation due to
defect or deficiency of the enzyme, glucuronosyl transferase. Occurs in inherited
disorders of the enzyme (e.g. Gilbert’s syndrome and Crigler-Najjar syndrome), or
acquired defects in its activity (e.g. due to drugs, hepatitis, cirrhosis). The neonatal
jaundice occurs due to deficiency of UDP-glucuronosyl transferase in the neonatal liver
and partly as a result of increased rate of RBC destruction in neonates.
• Impaired excretion of bile in to urine (cholestasis):

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• Intrahepatic cholestasis: Intrahepatic cholestasis is due to impaired hepatic
excretion of bile and may occur from hereditary or acquired disorders.
i) Hereditary disorders e.g. in Dubin-Johnson syndrome, Rotor syndrome,
fibrocystic disease of pancreas, benign familial recurrent cholestasis,
intrahepatic atresia and cholestatic jaundice of pregnancy.
ii) Acquired disorders e.g. in viral hepatitis, alcoholic hepatitis, and drug-induced
cholestasis (administration of chlorpromazine and oral contraceptives).
• Extrahepatic: Extrahepatic cholestasis results from mechanical obstruction to large
bile ducts outside the liver or within due to gallstones, inflammatory strictures,
carcinoma head of pancreas, tumors of bile duct, sclerosing cholangitis and
congenital atresia of extrahepatic ducts.
Classification:
• Pre-hepatic – e.g. in hemolysis. Unconjugated bilirubin insoluble in water, not
excreted in urine. Risk of brain damage in neonates (kernicterus); pigment
gallstones in adults.
• Hepatic - e.g. hepatitis (hepatocyte damage and raised serum transaminases), intra-
hepatic bile duct damage, congenital hyperbilirubinemias e.g. Gilbert’s syndrome
(conjugated soluble in water resulting in dark urine).
• Post-hepatic - obstruction to extra-hepatic bile ducts by gallstone, stricture, tumor,
or congenital biliary atresia. Conjugated bilirubin.
LIVER FAILURE
• Classification.
• Acute - no pre-existing liver disease.
• Chronic - pre-existing liver disease.
• Causes.
• Acute - viral hepatitis, drugs, toxins, severe fatty change (e.g. fatty liver of
pregnancy, Reye syndrome), vascular.
• Chronic - cirrhosis, chronic hepatitis.
• Morphology.
• Acute - varying degrees of necrosis up to massive liver necrosis.
• Chronic - that of cirrhosis or chronic hepatitis.
Features of liver failure:
• Hepatic encephalopathy - a neuropsychiatric disturbance leading to coma. The
cardinal feature of acute liver failure, progressing over hours to days. More insidious in
chronic liver failure when it is a sign of worsening liver failure.
Pathogenesis:
Nitrogenous waste products derived from bacteria in the colon are not metabolized in the liver;
in addition shunting of portal blood to systemic circulation by-passes the liver. Compounds

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involved are ammonia and derivatives of aromatic amino acids (e.g. mercaptans, a cause of
foetor hepaticus).
Morphology:
• Brain - edema; Alzheimer type 2 astrocytic reaction.
• Jaundice - hyperbilirubinemia; deep jaundice.
• Hematological - decreased clotting factors (II, VII, IX, X) results in bleeding tendency.
• Cardiovascular - hyperkinetic circulation.
• Respiratory - hepatopulmonary syndrome.
• Renal - hepatorenal syndrome.
• Endocrine - in chronic failure - gonadal atrophy, gynecomastia, amenorrhea.
• Skin changes - in chronic failure - spider naevi, palmer erythema.
Laboratory investigations:
- Bilirubin.
- Prothrombin.
- Transaminases.
- Albumin.
Factors precipitating liver failure in chronic liver disease: - increase in liver injury due to virus
or alcoholic binge, infection, GIT hemorrhage (which can precipitate encephalopathy, as can
excess dietary protein, constipation, drugs, uremia, and hypokalemia).
VIRAL HEPATITIS:
It is the infection of liver caused by hepatotropic viruses, 6 types of virus causes viral hepatitis
and includes:
1. Hepatitis A virus (HAV), causing a faecal-spread self-limiting disease.
2. Hepatitis B virus (HBV), causing a parenterally transmitted disease that become
chronic.
3. Hepatitis C virus (HCV) involved chiefly in transfusion related hepatitis.
4. Hepatitis D virus (HDV) is sometimes associated as superinfection with hepatitis B
infection.
5. Hepatitis E virus (HEV), causing water-borne infection.
6. Hepatitis G virus (HGV), is a transfusion-transmitted hepatotropic virus but not known
to cause hepatitis.
All Human hepatitis viruses are RNA viruses except HBV (a DNA virus).
ETIOLOGIC CLASSIFICATION
Viral hepatitis classified into 6 etiologic types are hepatitis A, hepatitis B, hepatitis C, hepatitis
D, hepatitis E and hepatitis G.
Hepatitis A (infectious hepatitis):
Infection with hepatitis A virus (HAV) causes hepatitis A usually a benign, self-limiting
disease with an incubation period of 15-45 days. It occurs both as an epidemic and sporadically.

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It spreads by faecal-oral route and due to overcrowding, poor hygiene and poor sanitation. It
can infect at the age of 5-14 years and adults are infected from children.
HEPATITIS A VIRUS (HAV) is a single-stranded RNA virus. Virus can be killed by boiling
for 1 minute or by ultraviolet radiation, or by contact with formaldehyde and chlorine. The
virus is present in the liver cells, bile, stool and blood during the incubation period.
Pathogenesis:
Due to immunological basis. Infection is indicated by marker antibodies:
1. IgM anti-HAV antibody appears in the serum at the onset of symptoms of acute
hepatitis A.
2. IgG anti-HAV antibody is detected in the serum after acute illness and remains
detectable indefinitely. It gives life-long protective immunity against reinfection with
HAV.
Hepatitis B (serum hepatitis)
It caused by HBV. Infection has an incubation period of 30-180 days. It is transmitted
parenterally due to blood transfusion, intravenous drug abusers sharing needles, patients
undergoing renal dialysis and by physical contact (from mother to child and by sexual contact).
It may occur at any age. HBV infection causes acute hepatitis B, chronic hepatitis, progression
to cirrhosis, fulminant hepatitis and an asymptomatic carrier stage. It can also develop into
hepatocellular carcinoma.
HEPATITIS B VIRUS (HBV). The etiologic agent HBV is a DNA virus.
Pathogenesis:
Immunopathogenetic mechanism with hepatocellular damage occurs in HBV infection.
Hepatocytic damage is initiated by virus-infected CD8+T cytotoxic cells. Serologic and viral
markers in presence of HBV infection are:
1. HBsAg - first marker present in patients with active Hepatitis B infection.
2. HBcAg - core inner shell of virion, not seen in serum, does not circulate.
3. HBeAg - soluble protein secreted from hepatocytes, correlates with both quantity of
intact virus, infectivity and liver inflammation.
4. Anti-HBc: first Antibody to appear, primary IgM then IgG, persists for life, best marker
for previous exposure.
5. Anti-HBe: appears several weeks post illness.
6. Anti-HBs: indicates previous exposure to Hep B or the vaccine.
Hepatitis D
Infection with delta virus (HDV) in the hepatocyte nuclei of HBsAg-positive patients is termed
hepatitis D. HDV is a defective virus for which HBV is the helper. Hepatitis D develops with
coinfection with hepatitis B infection. HDV may infect a chronic HBsAg carrier causing
superinfection with an incubation period of 30-35 days. Chronic HBV infection can lead to

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chronic delta hepatitis or cirrhosis. HDV infection may occur in intravenous drug abusers,
homosexuals, transfusion recipients, and health care workers.
HEPATITIS DELTA VIRUS (HDV) is a small single-stranded RNA particle with double
shell, the outer shell consists of HBsAg and the inner shell consists of delta antigen provided
by a circular RNA strand. It is highly infectious and can induce hepatitis in any HBsAg-positive
host. HDV replication and proliferation takes place within the nuclei of liver cells. Markers for
HDV infections include:
1. HDV identification in the blood and in the liver cell nuclei.
2. HDAg detectable in the blood and on fixed liver tissue specimens.
3. Anti-HD antibody IgM type and later replaced by IgG type anti-HD antibody which
persists for life.
Pathogenesis:
HDV cause direct cytopathic effect on hepatocytes.
Hepatitis C
Hepatitis C infection is acquired by blood transfusions, blood products, haemodialysis,
parenteral drug abuse and accidental cuts and needle-pricks in health workers. Hepatitis C has
an incubation period of 20-90 days (mean 50 days). Persistence of infection and chronic
hepatitis are the key features of HCV. Occurrence of cirrhosis after 5 to 10 years and
progression to hepatocellular carcinoma are late consequences of HCV infection.
HEPATITIS C VIRUS (HCV) is a single-stranded, enveloped RNA virus. The viral proteins
markers for HCV infection are:
1. Anti-HCV antibodies:
i) First generation antibodies are against C100-3 region proteins and appear 1 to 3
months after infection.

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ii) Second generation antibodies are against C200 and C33c proteins and appear about
one month earlier than the first generation.
iii) Third generation antibodies are against C22-3 and NS-5 region proteins and are
detected even earlier.
2. HCV-RNA. HCV infection is confirmed by HCV-RNA which can be detected within a few
days after exposure to HCV infection.
Pathogenesis:
Cell-mediated immune mechanism and production of antiviral cytokines by T-lymphocytes
play a role in hepatocytic injury due to HCV. HCV infection of lymphoid cells may induce
immunologic injury to hepatocytes. HCV specific CD4+ T cells and HLA-restricted CD8+ T
cells have been identified. Cross reactivity between viral antigens and host autoantibodies to
liver-kidney microsomal antigen (anti-LKM) explains the association of autoimmune hepatitis
and HCV hepatitis.
Hepatitis E
Hepatitis E is an enterically-transmitted virus variant of non-A non-B hepatitis. The infection
occurs in young or middle-aged individuals. The infection is acquired by contamination of
water after monsoon flooding. Secondary person-to-person infection does not occur with HEV.
HEV infection has a high mortality in pregnant women otherwise self-limited disease and has
not been associated with chronic liver disease.
HEPATITIS E VIRUS (HEV) is a single-stranded, icosahedral non-enveloped virus. The
virus has been isolated from stools, bile and liver of infected persons. Serologic markers for
HEV include:
1. Anti-HEV antibodies of both IgM and IgG class.
2. HEV-RNA.
Hepatitis G
Hepatitis G occurs due to HGV infection. It has been found in blood donors, patients on
haemodialysis and as co-infection with HIV. HGV is cleared from the plasma while a small
percentage of cases have chronic HGV infection.
HEPATITIS G VIRUS (HGV) is a single-stranded RNA virus.
CIRRHOSIS
Definition. Cirrhosis occurs by fibrosis and regenerative parenchymal nodules result in
damage. It is the irreversible end-stage of hepatocellular injury and is characterised 4 features:
1. It involves the entire liver.
2. The normal lobular architecture of hepatic parenchyma is disorganised.
3. There is formation of nodules separated from one another by irregular bands of fibrosis.

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4. It occurs following hepatocellular necrosis of different aetiology there are alternate
areas of necrosis and regenerative nodules. The microvasculature of the liver is
markedly altered. Cirrhosis is the end stage of chronic liver disease.
It is classified according to etiology as:
• Infections. Viral hepatitis.
• Toxins and drugs. Alcohol, Therapeutic drugs.
• Autoimmune. Hepatitis, Primary biliary cirrhosis.
• Metabolic. Haemochromatosis. Wilson disease. Alpha-1-antitrypsin deficiency.
Glycogen storage disease and many others.
• Biliary obstruction. Congenital atresia. Sclerosing cholangitis.
• Hepatic outflow obstruction.
• Cryptogenic. The etiology of cirrhosis varies throughout the world. In the Western
world, alcohol is the most common factor at 60% and viral hepatitis 10%. Viral hepatitis
is the most common factor in Asia and Africa. Cryptogenic cirrhosis (cause unknown)
forms 10%.
Alcoholic Liver Disease and Cirrhosis Alcoholic liver disease causes liver injury associated
with acute and chronic alcoholism. The three sequential stages in alcoholic liver disease are:
alcoholic steatosis (fatty liver), alcoholic hepatitis and alcoholic cirrhosis.
ETHANOL METABOLISM. Alcohol undergo oxidation, chiefly in the liver. Ethanol after
ingestion and absorption from the small intestine circulates through the liver about 90% of it
is oxidised to acetate. In a two-step enzymatic process involving enzymes: alcohol
dehydrogenase (ADH) present in the cytosol, and acetaldehyde dehydrogenase (ALDH) in the
mitochondria of hepatocytes. The remaining 10% of ethanol is oxidised in other parts of the
body.
First step: Ethanol is catabolised to acetaldehyde in the liver by one major and two minor
pathways:
i) In the cytosol, by alcohol dehydrogenase (ADH).
ii) In the smooth endoplasmic reticulum, via microsomal P-450 oxidases (also called
microsomal ethanol oxidising system, MEOS), where only part of ethanol is
metabolised.
iii) In the peroxisomes, minor pathway via catalase such as H2O2.
Acetaldehyde is toxic and may cause membrane damage and cell necrosis. The cofactor
Nicotinamide adenine dinucleotide (NAD) which is a hydrogen acceptor, is reduced to NADH.
Second step: The second step occurs in the mitochondria where acetaldehyde is converted to
acetate with ALDH acting as a co-enzyme. Most of the acetate on leaving the liver is finally
oxidised to carbon dioxide and water, or converted by the citric acid cycle to other compounds
including fatty acids. The cofactor, NAD, is reduced to NADH resulting in increased NADH.
Pathogenesis:
The biomedical and cellular pathogenesis due to chronic alcohol includes:

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1. Direct hepatotoxicity by ethanol. Ethanol ingestion regularly cause direct hepatotoxic
effect on the liver and produce fatty change. Ethanol is directly toxic to microtubules,
mitochondria and membrane of hepatocytes.
2. Hepatotoxicity by ethanol metabolites chiefly acetaldehyde. Acetaldehyde produces
hepatotoxicity by forming 2 adducts:
i) Production of protein-aldehyde adducts which are extremely toxic and can cause
cytoskeletal and membrane damage and bring about hepatocellular necrosis.
ii) Formation of malon-di-aldehyde-acetaldehyde (MAA) adducts which produce
autoantibodies and initiate autoimmune response. Theses adducts have also a role
in hepatic fibrogenesis due to peroxisome proliferator-activated receptor (PPAR)-γ
on hepatocytes.
3. Oxidative stress. Oxidation of ethanol by the cytochrome-450 oxidases (MEOS) leads to
generation of free radicals which causes oxidative damage to the membranes and proteins.
4. Immunological mechanism. Cell-mediated immunity is impaired in alcoholic liver disease.
Ethanol causes direct immunologic attack on hepatocytes.
5. Inflammation. Chronic ethanol ingestion is not only injurious to hepatocytes but also
damages the intestinal cells. The injured intestinal cells elaborate endotoxins which release
proinflammatory cytokines, chiefly tumour necrosis factor-α, IL-1, IL-6 and TGF-β. These
cytokines and endotoxinaemia produce apoptosis and necrosis of hepatocytes and initiate
inflammatory reaction in the alcohol damaged liver.
6. Fibrogenesis. Main event facilitating hepatic fibrogenesis is activation of stellate cells by
various stimuli:
a. by damaged hepatocytes,
b. by malon-di-aldehyde-acetaldehyde adducts,
c. by activated Kupffer cells, and
d. Direct stimulation by acetaldehyde.
Morphology:
Three types of morphologic lesions in alcoholic liver disease are alcoholic steatosis (fatty
liver), alcoholic hepatitis and alcoholic cirrhosis.
1. ALCOHOLIC STEATOSIS (FATTY LIVER). Grossly, the liver is enlarged, yellow and
greasy, and firm with a smooth and glistening capsule. Microscopically, consist of initial
microvesicular droplets of fat in the hepatocyte cytoplasm followed by macrovesicular large
droplets of fat displacing the nucleus to the periphery. Fat cysts may develop due to coalescence
and rupture of fat-containing hepatocytes.
2. ALCOHOLIC HEPATITIS. Alcoholic hepatitis develops acutely, usually following heavy
drinking. The features of alcoholic hepatitis are:
i) Hepatocellular necrosis: Single or small clusters of hepatocytes, especially in the
centrilobular area (zone 3), undergo ballooning degeneration and necrosis.
ii) Mallory bodies or alcoholic hyalin: These are eosinophilic, intracytoplasmic
inclusions seen in perinuclear location within swollen and ballooned hepatocytes.
They represent aggregates of cytoskeletal intermediate filaments (prekeratin).

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iii) Inflammatory response: The areas of hepatocellular necrosis and regions of Mallory
bodies are associated with an inflammatory infiltrate, chiefly consisting of
polymorphs and scattered mononuclear cells.
iv) Fibrosis: Most cases of alcoholic hepatitis are accompanied by pericellular and
perivenular fibrosis, producing a web-like or chicken wire-like appearance. This is
also termed as creeping collagenosis.
3. ALCOHOLIC CIRRHOSIS. Alcoholic cirrhosis constituting of 60-70% of all cases of
cirrhosis. It is also known as Laennec’s cirrhosis, portal cirrhosis, hobnail cirrhosis, nutritional
cirrhosis, diffuse cirrhosis and micronodular cirrhosis. The liver shrinks to less than 1 kg in
weight, becomes non-fatty, having macronodular cirrhosis (nodules larger than 3 mm in
diameter), resembling post-necrotic cirrhosis. Liver cells show ballooning degeneration and
necrosis with some containing Mallory’s hyalin (Inbox). Fatty change and clusters of
neutrophils are also present.
Alcoholic cirrhosis is a progressive alcoholic liver disease which includes:
i) Nodular pattern: Normal lobular architecture is effaced in which central veins are
hard to find and is replaced with nodule formation.
ii) Fibrous septa: The fibrous septa that divide the hepatic parenchyma into nodules
are initially delicate and extend from central vein to portal regions, or portal tract to
portal tract, or both. As the fibrous scarring increases with time, the fibrous septa
become dense and more confluent.
iii) Hepatic parenchyma: The hepatocytes in the islands of surviving parenchyma
undergo slow proliferation. It shows nearly uniform-sized micronodules, devoid of
central veins and having thick fibrous septa dividing them. There is minimal
inflammation and some reactive bile duct proliferation in the septa.
iv) Necrosis, inflammation and bile duct proliferation: The fibrous septa usually
contain sparse infiltrate of mononuclear cells with some bile duct proliferation. Bile
stasis and increased cytoplasmic haemosiderin deposits due to enhanced iron
absorption in alcoholic cirrhosis are some other noticeable findings.
The laboratory findings in alcoholic liver disease generally presents the following biochemical
and haematological alterations:
1. Elevated transaminases: increase in SGOT (AST) is more than that of SGPT
(ALT).
2. Rise in serum γ-glutamyl transpeptidase (γ-GT).
3. Elevation in serum alkaline phosphatase.
4. Hyperbilirubinemia.
5. Hyperproteinaemia with reversal of albumin-globulin ratio.
6. Prolonged prothrombin time and partial thromboplastin time.
7. Anaemia.
8. Neutrophilic leucocytosis in alcoholic hepatitis and in secondary infections.

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Post-necrotic Cirrhosis:
Post-necrotic cirrhosis, also termed post-hepatitic cirrhosis, macronodular cirrhosis and
coarsely nodular cirrhosis, is characterised by large and irregular nodules with broad bands of
connective tissue and occurring most commonly after previous viral hepatitis.
Aetiology:
1. Viral hepatitis: Recent or remote attacks of acute viral hepatitis followed by chronic
viral hepatitis. Most common association is with hepatitis B and C known to evolve
into cirrhosis.
2. Drugs and chemical hepatotoxins: Chemicals and drugs such as phosphorus, carbon
tetrachloride, mushroom poisoning, acetaminophen and α-methyl dopa.
3. Others. Certain infections (e.g. brucellosis), parasitic infestations (e.g. clonorchiasis),
metabolic diseases (e.g. Wilson’s disease or hepatolenticular degeneration) and
advanced alcoholic liver disease may produce post-necrotic cirrhosis.
4. Idiopathic: Aetiology is unknown.
CLINICAL FEATURES. The patients may remain asymptomatic or may present with
prominent signs and symptoms of chronic hepatitis. Splenomegaly and hypersplenism are other
prominent features. The results of haematologic and liver function test are similar to those of
alcoholic cirrhosis. More frequently associated with hepatocellular carcinoma.
Biliary Cirrhosis:
Biliary cirrhosis is defined as a chronic disorder characterised by clinical, biochemical and
morphological features of long continued cholestasis of intrahepatic or extrahepatic origin.
Biliary cirrhosis is of following types:
 Primary biliary cirrhosis in which the destructive process of unknown etiology affects
intrahepatic bile ducts.
 Secondary biliary cirrhosis resulting from prolonged mechanical obstruction of the
extrahepatic biliary passages.
Aetiology:
A. Primary biliary cirrhosis:
1. The condition is predominant in middle-aged women (male: female ratio is 1:9)
and of a possible endocrine origin.
2. Familial incidence has been observed, genetic influence and certain HLA types.
3. There is elevated cholesterol level with appearance of xanthoma and
xanthelasma. Hepatomegaly and chronic liver disease are late features of the
disease.
B. Secondary biliary cirrhosis. Most cases of secondary biliary cirrhosis result from
prolonged obstruction of extrahepatic biliary passages. These causes include the
following:
i) Extrahepatic cholelithiasis, most common
ii) Biliary atresia

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iii) Cancer of biliary tree and of head of pancreas
iv) Postoperative strictures with superimposed ascending cholangitis.
C. Cirrhosis due to primary sclerosing cholangitis. Primary or idiopathic sclerosing
cholangitis is a chronic cholestatic syndrome of unknown etiology. It is characterised
by progressive, inflammatory, sclerosing and obliterative process affecting the entire
biliary passages, both extrahepatic and intrahepatic ducts. Although etiology remains
unknown, various mechanisms have been postulated which include viral and bacterial
infections, immunologic injury, toxins, and genetic predisposition.
The salient features of various forms of biliary cirrhosis are:
A. Primary biliary cirrhosis:
The diagnostic histologic feature is a chronic, non-suppurative, destructive cholangitis
involving intrahepatic bile ducts. The disease evolves through the following 4 histologic states:
i) Stage I: There are florid bile duct lesions confined to portal tracts. The changes in
the affected area consist of destruction of bile ducts, presence of bile plugs,
infiltration with acute and chronic inflammatory cells and sometimes formation of
granulomas and lymphoid follicles.
ii) Stage II: There is ductular proliferation. The ductal involvement is quite widespread
with very few normal bile ducts.
iii) The inflammatory infiltrate too extends beyond the portal tracts into surrounding
hepatic parenchyma. Periportal Mallory bodies may be present.
iv) Stage III: This stage is characterised by fibrous scarring interconnecting the portal
areas. There is diminished inflammatory infiltrate and reduced number of bile ducts.
v) Stage IV: Well-formed micronodular pattern of cirrhosis develops in a period of a
few years.
B. Secondary biliary cirrhosis:
Prolonged obstruction of extrahepatic bile ducts may produce the following histologic changes:
1. Bile stasis, degeneration and focal areas of centrilobular necrosis of hepatocytes.
2. Proliferation, dilatation and rupture of bile ductules in the portal area with formation of
bile lakes.
3. Cholangitis, sterile or pyogenic, with accumulation of polymorphs around the bile
ducts.
4. Progressive expansion of the portal tract by fibrosis and evolution into micronodular
cirrhosis.
C. Cirrhosis due to primary sclerosing cholangitis:
Following changes are seen:
1. Fibrosing cholangitis with lymphocytic infiltrate around bile ducts with segmental
involvement.
2. Periductal fibrosis with eventual obliteration of lumen of affected bile ducts.
3. Intervening bile ducts are dilated, tortuous and inflamed.

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4. Late cases show cholestasis and full-blown picture of biliary cirrhosis.
Miscellaneous Forms of Cirrhosis
Cirrhosis associated with different diseases includes:
1. Metabolic disorders e.g. in galactosaemia, hereditary fructose intolerance, glycogen
storage diseases.
2. Infectious diseases e.g. in brucellosis, schistosomiasis, syphilis (hepar lobatum) and
toxoplasma infection.
3. Gastrointestinal disorders e.g. in inflammatory bowel disease, cystic fibrosis of the
pancreas and intestinal bypass surgery for obesity.
4. Infiltrative diseases e.g. in sarcoidosis.
Cryptogenic Cirrhosis:
Patients with cirrhosis of unknown cause is called cryptogenic cirrhosis (crypto =concealed).

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