Cirrhosis

CIRRHOSIS

Definition-

A diffuse process (i.e. the whole liver

is involved) characterized by fibrosis and

conversion of liver architecture in to

abnormal nodules.

It is end stage of chronic liver disease.

Account for most of liver-related

deaths.

3 Main Morphological features-

1) Bridging fibrous septa linking portal

tracts with one another and portal tracts

with terminal hepatic vein. Fibrosis is

dynamic process of collagen deposition

and remodeling.

2) Parenchymal nodules contain hepatocytes

encircled by fibrosis.They vary from very

small(<0.3cm,micronodular) to

large (several centimeters,macronodular).

Nodularity results from cycles of

hepatocytes regeneration and scarring

3) Disruption of the architecture of the

entire liver. The parenchymal injury and

consequent fibrosis are diffuse extending

through out the liver.

Focal injury with scarring does not

constitute cirrhosis nor does diffuse

nodular transformation without

fibrosis.

Pathogenesis-

-The central pathogenic processes are

death of hepatocyte,extracellular matrix

deposition and vascular reorganization.

-In normal liver, type 1 and 3 collagen are

present in portal tracts and around central

vein, type 4 in space of Disse.In cirrhosis

Type 1 and 3 collagen get deposited in

space of Disse.

-Vascular Reorganization-New vascular

channels in the fibrotic septa develop that

connect vessels in the portal regions to

terminal hepatic veins causing shunting of

blood from parenchyma. This impairs delivery

of blood to hepatocytes.

-Loss of fenestration of sinusoidal endothelial

cells i.e. capillarization of sinusoids.

-Proliferation of hepatic stellate cells and

their transformation to myofibroblast which

produces collagen.

-Factors responsible for this transformation

are-

1) Expression of platelet derived growth

factor receptor B(PDGFR-B) on stellate

cell.

2) Transforming growth factor B(TGF-B),

metalloproteinase (MMP-2) and

tissue inhibitor of

metalloproteinase (TIMP1 and 2)

produced by kupffer cell and

lymphocytes.

3)Tumour necrosis

factor(TNF), lymphotoxin,interleukin 1B

and lipid peroxidation products.

Classification of cirrhosis

A) Morphologic 1)Micronodular(<3mm) 2)Macronodular(>3mm) 3) Mixed

B) Etiologic1)Alcoholic cirrhosis (60-

70%)2)Post necrotic cirrhosis3)Biliary cirrhosis4)Cardiac cirrhosis5)Indian childhood cirrhosis6)Cryptogenic cirrhosis7)Cirrhosis in metabolic

disorders.8)Miscellaneos form of

cirrhosis.

Micronodular Cirrhosis-

Nodules are regular and less than 3mm.

Regular and diffuse involvement of hepatic

lobules.

Include alcoholic cirrhosis, nutritional

cirrhosis.

Macronodular Cirrhosis-

Nodules are of variable size and

generally more than 3mm.

Pattern of involvement is more irregular

than in micronodular cirrhosis.

Include postnecrotic or post hepatitic

cirrhosis.

Mixed cirrhosis- -Some part show micronodular appearance while other show macronodular pattern.

-Some portal tracts and central veins are spared.

-It is a type of incomplete expression of micronodular cirrhosis

Micronodular,macronodular and mixed form Can be active or inactive-

Active Form-There is continuous hepatocellular necrosis and inflammation.

Inactive Form-No evidence of continuing hepatocellular necrosis. Liver has sharply defined nodules of surviving hepatic parenchyma without any significant inflammation.

Alcoholic Cirrhosis-

Also called as -Laennec’s cirrhosis

-Portal cirrhosis

-Hobnail cirrhosis

-Nutritional cirrhosis

-Diffuse cirrhosis

-Micronodular cirrhosis

Macroscopic features- -It begins with micronodular cirrhosis. The liver is large fatty and weighing >2kg.

-Over a span of years, liver shrinks to less than 1kg in weight become nonfatty having macronodular cirrhosis.

Alcoholic cirrhosis

-The surface of liver is studded with diffuse

nodules producing hobnail liver. Nodules are

tawny yellow due to their fat content.

-On cut section,spheroidal or angular nodules

of fibrous septa are seen.

Microscopic features- 1) Lobular architecture- No normal architecture can be identified.

2)Fibrous Septa-Initially delicate, later become dense and confluent.

3)Hepatic parenchyma-The surviving hepatocytes undergo proliferation and form regenerative nodules having disorganized masses of hepatocytes.

4)Necrosis,inflammation and bile duct

proliferation-

-Mallory bodies are hard to found.

-The fibrous septa contain sparse

infiltrate of mononuclear cells with

some bile duct proliferation.

Pathogenesis

• Ethanol is rapidly absorbed from stomach and small intestine.

• It is mainly metabolized in hepatocytes through 3 main pathways- catalase, alcohol dehydrogenase and microsomal ethanol oxidising system.

• It is a direct hepatotoxin and its effect depends on many factors.

- Amount of alcohol

- Hormonal status- women are prone

- Fat content of diet

- Fat stores of the body

- Gender – females are more prone

- HCV- Increases risk

- Malnutrition

• Metabolic effects of ethanol

1) Peripheral catabolism of fat- It causes increase mobilization of fatty acid from the peripheral stores by increasing lipolysis.

2) Excess generation of NADH by alcohol dehydrogenase – The excess substrate generated from increased lipolysis is shunted away from catabolism and is diverted to lipid synthesis by excess generation of NADH by alcohol dehydrogenase.

• 3) Mitochondrial and micro tubular function-

• Acetaldehyde is a major metabolite of alcohol metabolism. This is metabolized to acetate and then utilized outside the liver.

• Ethanol directly decreases the mitochondrial fatty acid oxidation and also decreases the microtubule function.

• Thus there is accumulation of triglycerides in smooth endoplasmic reticulum.

• Triglycerides are normally secreted in the form of lipoprotein. In ALD lipoprotein synthesis decreases and their transport and release is also reduced. This results in fatty change.

4)Lipid peroxidation-

Acetaldehyde also induces lipid peroxidation and causes formation of malon dialdehyde –acetaldehyde(MDA) adduct formation. This induces antibody formation ( Autoantibody). This cause hepatocyte injury.

5)Release of cytokine- Ethanol alongwith endotoxins acts on kupffer cells to produce cytokines TNF α, TNF b & IL-6 which results in inflamation.

6)Fibrosis and cirrhosis

Stellate cells can be stimulated by cytokine, malondialdehyde acetaldehyde adducts and aldehyde to lay down collagen and fibrosis which forms nodules.

7)Generation of free radicals- Ethanol is also metabilized by microsomal ethanol oxidising system. Free radicals are generated during microsomal etahnol oxidation which cause hepatocyte injury.

• MDA- malon dialdehyde –acetaldehyde.

• HNE- Hydroxyethyl ether.

• HNE- 4–hydroxy–2–nonenal.

• MAA- mixed MDA acetaldehyde–protein adducts

Post-necrotic cirrhosis- Also called as - Post hepatitic cirrhosis - Macronodular cirrhosis - Coarsely nodular cirrhosis Etiology- Viral hepatitis (B,C) Drugs e.g. paracetamol, Chemicals e,g,phosphorus, Brucellosis Clonorchiasis Wilson’s disease

Macroscopic features

Liver is small ,<1kg, have distorted

shape with irregular and coarse scars

and nodules of varying sizes.

Microscopic features- 1)Lobular architecture- Not completely

lost. Uninvolved portal tracts and central

vein can be still seen.

2)Fibrous septa- Generally thick.Contain

prominent mononuclear inflammatory

cells.

3)Necrosis,inflammation and bile duct

proliferation-Active liver cell necrosis is

present. Extensive proliferation of bile ducts

4)Hepatic parenchyma- Liver cells vary in size and multiple nuclei are common in regenerative nodules.

Primary Biliary Cirrhosis-

Characterized by clinical ,biochemical

and morphological features of continued

Cholestasis of intrahepatic bile ducts.

Etiology is not known.

Macroscopic features-

Initially liver is enlarged greenish yellow.

Later becomes smaller, firmer and

coarsely micronodular.

Fine nodularity & bile staining of end stage biliary cirrhosis

Microscopic features- Stage 1-Florid bile duct lesions. -Destruction of intrahepatic bile ducts. -Bile plugs present. -Infiltration with acute and chronic inflammatory cells. Stage 2- Extensive ductular proliferation. - Periportal Mallory bodies may present

Stage 3-Fibrous scarring interconnecting

the portal areas.

Reduced no of bile ducts.

Stage 4-Well formed micronodular cirrhosis

develop in few years.

A portal tract is expanded by infiltrate of lymphocytes and plasma cells.there is granulomatous reaction to a bile duct

(florid reaction)

Fibrous septa dividing parenchyma in to micronodules. Bile duct proliferation

Pathogenesis of alcoholic liver disease

• Ethanol is rapidly absorbed from stomach and small intestine.

• It is mainly metabolized in hepatocytes through 3 main pathways- catalase, alcohol dehydrogenase and microsomal ethanol oxidising system.

• It is a direct hepatotoxin and its effect depends on many factors.

- Amount of alcohol

- Hormonal status- women are prone

- Fat content of diet

- Fat stores of the body

- Gender – females are more prone

- HCV- Increases risk

- Malnutrition

• Metabolic effects of ethanol

1) Peripheral catabolism of fat- It causes increase mobilization of fatty acid from the peripheral stores by increasing lipolysis.

2) Excess generation of NADH by alcohol dehydrogenase – The excess substrate generated from increased lipolysis is shunted away from catabolism and is diverted to lipid synthesis by excess generation of NADH by alcohol dehydrogenase.

• 3) Mitochondrial and micro tubular function-

• Acetaldehyde is a major metabolite of alcohol metabolism. This is metabolized to acetate and then utilized outside the liver.

• Ethanol directly decreases the mitochondrial fatty acid oxidation and also decreases the microtubule function.

• Thus there is accumulation of triglycerides in smooth endoplasmic reticulum.

• Triglycerides are normally secreted in the form of lipoprotein. In ALD lipoprotein synthesis decreases and their transport and release is also reduced. This results in fatty change.

4)Lipid peroxidation-

Acetaldehyde also induces lipid peroxidation and causes formation of malon dialdehyde –acetaldehyde(MDA) adduct formation. This induces antibody formation ( Autoantibody). This cause hepatocyte injury.

5)Release of cytokine- Ethanol alongwith endotoxins acts on kupffer cells to produce cytokines TNF α, TNF b & IL-6 which results in inflamation.

6)Fibrosis and cirrhosis

Stellate cells can be stimulated by cytokine, malondialdehyde acetaldehyde adducts and aldehyde to lay down collagen and fibrosis which forms nodules.

7)Generation of free radicals- Ethanol is also metabilized by microsomal ethanol oxidising system. Free radicals are generated during microsomal etahnol oxidation which cause hepatocyte injury.

• MDA- malon dialdehyde –acetaldehyde.

• HNE- Hydroxyethyl ether.

• HNE- 4–hydroxy–2–nonenal.

• MAA- mixed MDA acetaldehyde–protein adducts

Secondary Biliary cirrhosis-

It is characterized by clinical, biochemical

and morphological features of long

continued cholestasis of extrahepatic bile

ducts.

Etiology-

-Extrahepatic cholelithiasis (MC)

-Biliary atresia

-Cancer of biliary tract and head of

pancreas.

-Postoperative strictures with

superimposed ascending cholangitis


Initially liver is enlarged and greenish

yellow in appearance, later become

smaller,firmer,and coarsely

micronodular.

Microscopic features-

1)Bile stasis, degeneration and focal areas

of centrilobular necrosis of hepatocyte.

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 bile

ducts.

4) Progressive expansion of the portal tracts

by fibrosis and evolution in to

micronodular cirrhosis.

Primary Sclerosing Cholangitis-

It is characterized by nonspecific inflammation and obliterative fibrosis of intra and extra hepatic bile ducts with dilatation of preserved segments.

Occur in 3rd to 5th decade of life.

More common in males.

Etiology-

Idiopathic

May be associated with

1) IBD (inflammatory bowel disease)

(Ulcerative colitis in 70% pf cases)

2) AIDS

3) Multi focal fibrosclerosis


Characteristic beading of ducts due to

irregular strictures and dilatation.


1) Fibrosing cholangitis with lymphocytic

infiltrate around bile ducts.

Beaded appearance of bile ducts

2) Periductal fibrosis (onion skin fibrosis) with

eventual obliteration of lumen of affected

bile ducts.

3) Intervening bile ducts are dilated, tortuous

and inflammed.

4) Late cases show cholestasis and full blown

picture of biliary cirrhosis.

Onion skin fibrosisOnion skin fibrosis

A bile duct undergoing degeneration is entrapped in a dense “onion skin” concentric

scar

Antibodies found in PSC

1)Anti smooth muscle antibody

2)Anti-nuclear antibodies

3)Rheumatoid factor

4)Atypical p-ANCA (perinuclear

antineutrophilic cytoplasmic antibody) in

80% of cases.

Wilson’s Disease- -Autosomal Recessive

-Mutation in ATP7B gene on chromosome 13,which cause decrease in copper transport in to bile, impairs its incorporation into ceruloplamin and inhibits ceruloplasmin secretion in to the blood.

Pathological features-

Liver shows varying degree of changes

that include fatty change, acute and

chronic active hepatitis, submassive liver

necrosis and macronodular cirrhosis.

Mallory hyaline bodies may present.

Copper is usually deposited in periportal

hepatocytes.

(Stain for copper is Rhodamine and for

copper associated protein is orcein.)

Hepatic copper content >250ug/gram dry

weight is helpful in diagnosis.

In brain copper is mainly deposited in basal

ganglia especially putamen which shows

atrophy and cavitations.

Deposition of copper in brain lead to neuro-

psychiatric symptoms which include mild

behavioral changes,frank psychosis,tremors.

Eye lesion is called as Kayser Fleisher rings

which are green to brown deposits of copper

in Descemet membrane of cornea.

Biochemical Abnormalities-

1)Decreased ceruloplasmin.

2)Increased hepatic copper (most sensitive and accurate test for diagnosis)

3)Increased urinary excretion of copper. (most specific for screening)

4)Serum copper- may be low/high/normal So not diagnostic.

Alpha1- antitrypsin deficiency-

-Autosomal Recessive -Alpha1-antitrypsin is 394 amino acid plasma glycoprotein synthesized by hepatocytes. Its main function is to inhibit proteases like elastase, cathepsin G, proteinase 3 which are produced by neutrophill at the sites of inflammation.

Deficiency of antitrypsin results in

-Emphysema

-Panniculitis

-Arterial aneurysm

-Bronchiectasis

-Wegener’s granulomatosis

-Most common genotype is - PiMM (Pi stands for Protease inhibitor)

-PiS variant have moderate reduction of alpha1-antitrypsin

-Pi-null have no detectable serum alpha1antitrypsin

-PiZZ have only 10% of normal antitrypsin

Pathogenesis-

The deficient variants show selective defect

in migration of alpha1antitrypsin from endo-

-plasmic reticulum to golgi apparatus.So

there is accumulation of antitrypsin in

endoplasmic reticulum of hepatocytes. This

create stress on hepatocytes and lead to

apoptosis of hepatocytes.

Pathological features- It is characterized by the presence of round to oval cytoplasmic globular inclusions in periportal hepatocytes which are acidophilic, PAS positive and diastase resistant.

Ultrastructurally these globules consists of dilated rough endoplasmic reticulum.

PAS stain of liver showing red cytoplasmic granules

Electron micrograph showing dilatation of the endoplasmic reticulum

Mallory bodies and fatty change are

present infrequently.

In neonates, histological features consists of

neonatal hepatitis that may be acute or pure

Cholestasis.

Micronodular or macronodular cirrhosis may

Appear in childhood or in adolescence.

Neonatal hepatitis due to alpha1 antitrypsin deficiency. Note severe cholestasis

Haemochromatosis-

Iron storage disorder

Classical triad consists of

1) Micronodular cirrhosis

2) Diabetes mellitus

( Bronze Diabetes)

3) Skin pigmentation

Types-

1) Idiopathic (primary, genetic)-

-Autosomal Recessive

-Mutation of gene HFE on

chromosome 6 (Near HLA locus)

-Defect in intestinal absorption of

dietary iron.

2) Secondary (acquired) haemochromatosis

or Haemosidrosis-

-Gross iron overload with tissue

injury secondary to diseases like

thalassemia, sideroblastic anaemia,

alcoholic cirrhosis or multiple transfusions.

-More common & earlier in males.

-Total body iron may exceed >50gm.

(normal body iron is 2-6 gm)

-Disease manifest when body iron is >20gm


-Excessive iron in form of ferritin and

haemosiderin get deposited in liver,

pancreas, heart, endocrine glands ,skin,

synovium, joints and testis.

-Ferritin and haemosiderin appear as golden –yellow granules in cytoplasm of

parenchymal cells of affected organ.

Iron deposition in hepatocytes is dark brown in H&E stain

-Haemosiderin stains positively with Prussian blue.

-In liver ,iron get deposited in periportal hepatocytes. Eventually micronodular cirrhosis develop. -Pancreas become intensely pigmented has diffuse interstitial fibrosis. Haemosiderin is found in both acinar and islets cells.

Iron deposition in hepatocytes is blue in Prussian-blue stain

-Heart is enlarged and has interstitial

fibrosis.

-Skin pigmentation is due to increased

epidermal melanin production.

Haemosiderin deposition also contribute partially.

-Testis may undergo atrophy not due to pigment

deposition but due to derangement in

hypothalamic-pituitary axis.

Cardiac Cirrhosis-

Etiology-

1)Cor pulmonale

2)Tricuspid insufficiency

3)Constrictive pericarditis

Pressure in right ventricle is elevated which is

transmitted to liver via IVC and hepatic veins


The liver is enlarged, tender and firm with stretched Glisson’s capsule.


In acute stage hepatic sinusoids are dilated andCongested with haemorrhagic necrosis of centrilobular hepatocytes (central haemorrhagic necrosis). Fibrous septa are delicate and radiate from central veins.

Indian childhood cirrhosis-

-Seen in 6months -3years of age.

-Etiology is not clear but abnormalities

of copper metabolism is suspected.

-Death occur due to hepatic failure

within a year of diagnosis.


1)Ballooning degeneration of hepatocytes2)No fatty change.3)Neutrophilic infiltration.4)Prominent Mallory bodies.5)Creeping pericellular fibrosis which lead to micro-macronodular cirrhosis.6)Deposition of copper and associated protein in hepatocytes.

There is marked increase in hepatic

copper content since milk consumed by

such infants is often boiled and stored in

copper vessel.

Complication of cirrhosis-

1)Portal Hypertension-Ascites Splenomegaly Caput medusae Spider naevi Esophageal varices2)Progressive Hepatic failure3)Hepatocellular carcinoma4)Chronic relapsing pancreatitis

5)Steatorrhoea

6)Gallstones

7)Infections

8)Haematological derangements-anaemia

-Bleeding d/o

9)Atherosclerosis

10)Musculoskeletal abnormalities-Clubbing

Hypertophic osteodystrophy

Dupuytren’s contracture

11)Endocrine disorders- Gynaecomastia

Testis atrophy

Amenorrhoea

Impotence

12)Hepatorenal Syndrome

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Cirrhosis