Cirrhosis is characterized by diffuse fibrosis and conversion of liver architecture into abnormal nodules. The main morphological features include bridging fibrous septa linking portal tracts, parenchymal nodules containing hepatocytes, and disruption of the liver architecture. Cirrhosis can be caused by chronic liver diseases and has different classifications including micronodular, macronodular, and mixed patterns as well as etiologies such as alcoholic, postnecrotic, and biliary cirrhosis. The pathogenesis involves hepatocyte death, extracellular matrix deposition, and vascular reorganization leading to fibrosis and nodular transformation.

1. CIRRHOSIS

2. 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. 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.

4. 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

5. 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.

6. 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.

7. -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.

8. -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.

9. 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.

10. Classification of cirrhosis
A) Morphologic B) Etiologic
1)Micronodular(<3mm) 1)Alcoholic cirrhosis (60-
2)Macronodular(>3mm) 70%)
3) Mixed 2)Post necrotic cirrhosis
3)Biliary cirrhosis
4)Cardiac cirrhosis
5)Indian childhood cirrhosis
6)Cryptogenic cirrhosis
7)Cirrhosis in metabolic
disorders.
8)Miscellaneos form of
cirrhosis.

11. Micronodular Cirrhosis-
Nodules are regular and less than 3mm.
Regular and diffuse involvement of hepatic
lobules.
Include alcoholic cirrhosis, nutritional
cirrhosis.

12. 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.

13. 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

14. 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.

15. Alcoholic Cirrhosis-
Also called as -Laennec’s cirrhosis
-Portal cirrhosis
-Hobnail cirrhosis
-Nutritional cirrhosis
-Diffuse cirrhosis
-Micronodular cirrhosis

16. 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.

17. Alcoholic cirrhosis

18. -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.

20. 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.

21. 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.

22. 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.

23. • 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

24. • 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.

25. • 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.

26. 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.

27. 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.

28. • MDA- malon
dialdehyde –
acetaldehyde.
• HNE-
Hydroxyethyl
ether.
• HNE- 4–hydroxy–
2–nonenal.
• MAA- mixed
MDA
acetaldehyde–
protein adducts

29. 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

30. Macroscopic features
Liver is small ,<1kg, have distorted
shape with irregular and coarse scars
and nodules of varying sizes.

32. 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.

33. 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.

35. Primary Biliary Cirrhosis-
Characterized by clinical ,biochemical
and morphological features of continued
Cholestasis of intrahepatic bile ducts.
Etiology is not known.

36. Macroscopic features-
Initially liver is enlarged greenish yellow.
Later becomes smaller, firmer and
coarsely micronodular.

37. Fine nodularity & bile staining of end stage
biliary cirrhosis

38. 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

39. Stage 3-Fibrous scarring interconnecting
the portal areas.
Reduced no of bile ducts.
Stage 4-Well formed micronodular cirrhosis
develop in few years.

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

41. Fibrous septa dividing parenchyma in to
micronodules. Bile duct proliferation

42. 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.

43. • 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

44. • 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.

45. • 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.

46. 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.

47. 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.

48. • MDA- malon
dialdehyde –
acetaldehyde.
• HNE-
Hydroxyethyl
ether.
• HNE- 4–hydroxy–
2–nonenal.
• MAA- mixed
MDA
acetaldehyde–
protein adducts

49. Secondary Biliary cirrhosis-
It is characterized by clinical, biochemical
and morphological features of long
continued cholestasis of extrahepatic bile
ducts.

50. Etiology-
-Extrahepatic cholelithiasis (MC)
-Biliary atresia
-Cancer of biliary tract and head of
pancreas.
-Postoperative strictures with
superimposed ascending cholangitis

51. Macroscopic features-
Initially liver is enlarged and greenish
yellow in appearance, later become
smaller,firmer,and coarsely
micronodular.

52. 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.

53. 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.

54. 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.

55. Etiology-
Idiopathic
May be associated with
1) IBD (inflammatory bowel disease)
(Ulcerative colitis in 70% pf cases)
2) AIDS
3) Multi focal fibrosclerosis

56. Macroscopic features-
Characteristic beading of ducts due to
irregular strictures and dilatation.
Microscopic features-
1) Fibrosing cholangitis with lymphocytic
infiltrate around bile ducts.

57. Beaded appearance of bile ducts

58. 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.

59. Onion skin fibrosis

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

61. 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.

62. 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.

63. 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.

64. (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.

65. 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.

66. 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.

67. 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.

68. Deficiency of antitrypsin results in
-Emphysema
-Panniculitis
-Arterial aneurysm
-Bronchiectasis
-Wegener’s granulomatosis

69. -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

70. 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.

71. 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.

72. PAS stain of liver showing red cytoplasmic
granules

73. Electron micrograph showing dilatation of
the endoplasmic reticulum

74. 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.

75. Neonatal hepatitis due to alpha1 antitrypsin
deficiency. Note severe cholestasis

76. Haemochromatosis-
Iron storage disorder
Classical triad consists of
1) Micronodular cirrhosis
2) Diabetes mellitus
( Bronze Diabetes)
3) Skin pigmentation

77. Types-
1) Idiopathic (primary, genetic)-
-Autosomal Recessive
-Mutation of gene HFE on
chromosome 6 (Near HLA locus)
-Defect in intestinal absorption of
dietary iron.

78. 2) Secondary (acquired) haemochromatosis
or Haemosidrosis-
-Gross iron overload with tissue
injury secondary to diseases like
thalassemia, sideroblastic anaemia,
alcoholic cirrhosis or multiple transfusions.

79. -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

80. 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.

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

82. -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.

83. Iron deposition in hepatocytes is blue in
Prussian-blue stain

84. -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.

85. 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

86. Macroscopic features-
The liver is enlarged, tender and firm with stretched
Glisson’s capsule.
Microscopic features-
In acute stage hepatic sinusoids are dilated and
Congested with haemorrhagic necrosis of
centrilobular hepatocytes (central haemorrhagic
necrosis). Fibrous septa are delicate and radiate from
central veins.

87. 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.

88. Pathological features-
1)Ballooning degeneration of hepatocytes
2)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.

89. There is marked increase in hepatic
copper content since milk consumed by
such infants is often boiled and stored in
copper vessel.

90. Complication of cirrhosis-
1)Portal Hypertension-Ascites
Splenomegaly
Caput medusae
Spider naevi
Esophageal varices
2)Progressive Hepatic failure
3)Hepatocellular carcinoma
4)Chronic relapsing pancreatitis

91. 5)Steatorrhoea
6)Gallstones
7)Infections
8)Haematological derangements-anaemia
-Bleeding d/o
9)Atherosclerosis
10)Musculoskeletal abnormalities-Clubbing
Hypertophic osteodystrophy
Dupuytren’s contracture

92. 11)Endocrine disorders- Gynaecomastia
Testis atrophy
Amenorrhoea
Impotence
12)Hepatorenal Syndrome