cirrhosis
DESCRIPTION
Dr bimalTRANSCRIPT
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
Macroscopic features-
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
Macroscopic features-
Characteristic beading of ducts due to
irregular strictures and dilatation.
Microscopic features-
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
Pathological features-
-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
Macroscopic features-
The liver is enlarged, tender and firm with stretched Glisson’s capsule.
Microscopic features-
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.
Pathological features-
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