The document discusses various liver diseases including Budd Chiari Syndrome, Post Necrotic Cirrhosis, and Cholangiocarcinoma. It provides details on the clinical features, pathogenesis, histopathological findings, grading systems, and case reports for each condition. The document serves as an overview on these liver diseases for medical practitioners.

1. Budd Chiari Syndrome,
Post Necrotic Cirrhosis,
Cholangiocarcinoma
Presented by: Dr. Shubhi Saxena
Moderator: Dr. M.L. Yadav

2. The Right Lobe The Left Lobe
VIII
V
IV
IV
III
II
VII
VI
• Each segment receives its own portal
pedicle (triad of portal vein, hepatic
artery, and bile duct).
Liver Segments
• composed of 4
lobes (left, right,
caudate, quadrate)
and divided into 8
segments

4. HEPATOCYTES
• Hepatocytes are the large polyhedral cells with round nuclei with
peripherally dispersed chromatin and prominent nucleoli.
• The may be tetraploid or polyploid.
• Binucleate cells are also common in normal liver.
• The cytoplasm is strongly eosinophilic due to numerous
mitochondria with a fine basophilic granularity due to extensive free
ribosomes and rough endoplasmic reticulum.
• Fine brown granules of ‘wear and tear’ pigment lipofuscin are
present in variable amount.
• The sinusoids are lined by flat endothelial lining cells.

5. PORTAL TRACT
• Portal tract contains three main structures :
 Largest is a terminal branch of hepatic portal vein.
 Small diameter thick walled vessels are terminal branches of
hepatic artery.
 A network of bile canaliculi is located with in each plate of
hepatocytes. These drain into bile collecting ducts known as Canals
of Hering which in turn drain into bile ductules.
 The bile ductules merge to form larger more centrally located
trabecular ducts which drain via intrahepatic ducts into right and
left hepatic ducts, the common hepatic duct and then to duodenum
via common bile duct.

6. Portal tracts are triangular to round structures which contain pre-terminal and terminal portal veins
(arrowhead), terminal branches of hepatic artery (arrow with tail), and bile ducts (big arrow)
embedded in fibrous connective tissue. The portal tract is bounded by a discontinuous lining of
hepatocytes called the limiting plate (curved arrow).

8. Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of
the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply.
Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located
around central veins, where oxygenation is poor. Zone 2 is located in between.

9. BUDD CHIARI
SYNDROME

11. • Also called hepatic vein thrombosis.
• Common form of venous outflow obstruction
• BCS is further separated into –
o Primary BCS when related to a primarily venous disease
(thrombosis or phlebitis).
o Secondary BCS when related to compression or invasion by a
lesion originating outside the veins (benign or malignant tumor
abscess, cyst, etc.)
• Obstruction of the hepatic venous outflow tract can be classified
according to its location: small hepatic veins (HVs), large HVs,
inferior vena cava (IVC), and combined obstruction of large HVs and
IVC.

12. CAUSES:
1. Idiopathic (one-third of cases)
2. Congenital:
▫ web in the hepatic vein
▫ interruption of the diaphragm
3. Venous thrombosis secondary to:
▫ Dehydration
▫ Septicemia
▫ Polycythemia rubra vera
▫ Antiphospholipid antibody syndrome
▫ Pregnancy
▫ Oral contraceptive pill
▫ Sickle cell disease
▫ Thrombocytosis
▫ Paroxysmal nocturnal hemoglobinuria

13. 4. Injury and/or inflammation secondary to:
▫ Phlebitis: bone marrow transplant and chemoradiotherapy
▫ Autoimmune disease
▫ Tumour invasion, e.g. renal cell carcinoma, hepatocellular
carcinoma, adrenal carcinoma.
▫ leiomyosarcoma of inferior vena cava

14. CLINICAL FEATURES :
• Acute symptoms :
o Hepatomegaly
o RUQ abdominal pain
o Nausea and vomiting
o Ascites
• Chronic symptoms :
o Sequelae of cirrhosis and portal hypertension
o Variceal bleeding
o Bacterial peritonitis
o Encephalopathy

15. •Gross-
▫Swollen liver with red-purple, tense capsule
•Microscopy-
▫Severe centrilobular congestion/necrosis, progressing
to centrilobular fibrosis.
▫Large regenerative nodules, focal nodular hyperplasia
and hepatocellular adenomas can be seen.

16. CASE HISTORY :
• A 22 year old hindu male, presented to the OPD with chief complaints
of pain abdomen, nausea, vomiting, fatigue, malaise, low grade fever and
yellowish discoloration of urine since around 1 month. On physical
examination their was icterus, pallor present. Per abdomen examination
show distension of abdomen ?ascites, tenderness in right hypochondrium.
Hematological parameters were normal with mild anemia. Biochemical
parameters show abnormal LFT. CT Scan show homogeneous mottled
liver with delayed enhancement in the periphery of the liver and around
the hepatic veins (nutmeg liver) along with caudate lobe enlargement.
The surgeons kept the differential diagnosis as chronic liver disease ?
Budd chiari syndrome with cholelithiasis.
• The liver was transplanted and the diseased liver of recepient came for
histopathological examination.

17. • On Gross examination, formalin fixed specimen consists of
liver measuring 17x16x7cm. Falciparum ligament and
caudate lobe was identified. Right lobe was markedly
hypertrophied and left lobe appears to be ?slighly
hypertrophied. External surface was grey brown, cut surface
was grey white to pale brown. Attached gall bladder
measures 6x2.5cm, its external surface was grey white,
luminal surface was greenish velvety with wall thickness of
0.2cm. No stones were present.
• The sections were given from different areas of liver
parenchyma, portal area and gall bladder

18. • On microscopy, various sections given from different areas
shows marked congestion with dilated central vein and
sinusoids. Their was loss of hepatic architecture with
extensive fibrosis involving portal areas and centrilobular
area. Their was also intra lobular fibrosis. The portal area
show marked infilteration by chronic inflammatory cells with
focal proliferation of bile ductules. Their was extensive areas
of fatty change.
• Gall bladder shows chronic cholecystitis.
• Overall, picture was suggestive of cirrhosis and morphology
is consistent with Budd chiari syndrome.

24. POST necrotic CIRRHOSIS

25. CIRRHOSIS
• Term was 1st coined by Laennec in 1826
• Many definitions but common theme is injury, repair,
regeneration and scarring
• NOT a localized process; involves entire liver
• Cirrhosis is a pathological diagnosis, characterized by
widespread fibrosis with nodular regeneration.
• Its presence implies previous or continuing hepatic cell damage.
• The three main characteristics of cirrhosis are:
▫ Bridging fibrous septa
▫ Parenchymal nodules containing replicating hepatocytes
▫ Disruption of the architecture of the entire liver

27. 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.
•Pathophysiology-
Broad bands of scar tissue resulted from viral, toxic, or
autoimmune hepatitis

28. ETIOLOGY
• Viral hepatitis - About 25% of patients give history of recent or remote
attacks of acute viral hepatitis followed by chronic viral hepatitis. Most
common association is with hepatitis B and C; hepatitis A is not known
to evolve into cirrhosis.
• Drugs and chemical hepatotoxins. - such as phosphorus, carbon
tetrachloride, mushroom poisoning, acetaminophen and α-methyl dopa.
• 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 a picture of post-necrotic cirrhosis.
• Idiopathic - etiology is unknown.

29. Signs
•Loss of hair (alopecia)
•Icterus
•Pallor
•Fetor hepaticus
•Loss of axillary & pubic hair
•Spider nevi
•Gynecomastia

30. Signs
• Glossitis
• Palmar erythema
• Clubbing
• Dupuytren’s contracture
• Ascites
• In 70 % cases liver is enlarged, firm
• Splenomegaly
• Caput medusae

31. Signs
•Fever
•Hyperpigmentation
•Edema
•Testicular atrophy
•Delirium
•Flapping tremors
•Nail changes:
▫ Muehrcke's nails
▫ Terry’s nails
▫ Clubbing

32. Pathogenesis of the features of liver cirrhosis
•Due to:
▫Portal hypertension
▫Liver cell dysfunction

33. Normal Liver
Hepatic
vein
Sinusoid
Portal
vein
Liver
Splenic
vein
Coronary
vein
THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW

34. Portal
systemic
collaterals
Distorted
sinusoidal
architecture
leads to
increased
resistance
Portal
vein
Cirrhotic Liver
Splenomegaly
ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT
LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE

35. Complications
• Upper gastrointestinal hemorrhage
• Hepatic encephalopathy
• Infection
• Hepatorenal syndrome
• Hepatopulmonary Syndrome
• Primary carcinoma of the liver
• Disturbance of electrolyte and acid-base balance

36. • GROSS :
The liver is usually small, weighing less than 1 kg, having distorted
shape with irregular and coarse scars and nodules of varying size.
Sectioned surface shows scars and nodules varying in diameter from 3
mm to a few centimeters.

38. MICROSCOPY
• Nodular pattern: The normal lobular architecture of hepatic parenchyma
is mostly lost and is replaced by nodules larger than those in alcoholic
cirrhosis. However, uninvolved portal tracts and central veins in the
hepatic lobules can still be seen in some parts of surviving parenchyma.
• Fibrous septa: The fibrous septa dividing the variable sized nodules are
generally thick.
• Necrosis, inflammation and bile duct proliferation: Active liver cell
necrosis is usually inconspicuous. Fibrous septa contain prominent
mononuclear inflammatory cell infiltrate. Often there is extensive
proliferation of bile ductules derived from collapsed liver lobules.
• Hepatic parenchyma: Liver cells vary considerably in size and multiple
large nuclei are common in regenerative nodules. Fatty change may or
may not be present in the hepatocytes.

40. Staging and Liver Fibrosis
Two important concepts for consideration:
• Stage is more than histologic fibrosis:
An integrated clinical/pathophysiologic approach is needed to
accurately stage the disease
• Cirrhosis is not the “end” of the story:
Histologic scoring may need to evolve to identify regression or
remodeling of cirrhosis, and evaluate for very advanced
nonreversible, or “end-stage” cirrhosis, based on degree of
fibrosis

41. Patterns of Fibrosis
Two major patterns for early scarring of the liver
• Portal-based Fibrosis: Injury begins in periportal
area
• Central-based Fibrosis: Injury begins in
centrilobular zone

42. GRADING AND SCORING
• Knodell System
▫ The first chronic hepatitis scoring system to systematically
categorize liver inflammation and fibrosis
▫ Three categories of necroinflammatory activity (periportal injury
with or without bridging necrosis, lobular injury and portal
inflammation) and degree of fibrosis
▫ These are assigned numeric values, which are added to obtain a
Hepatic Activity Index (HAI) that ranges from 0 to 22
▫ Major criticism is the inclusion of fibrosis (stage) as a determinant
of activity (grade)

43. • Ishak Modification of Hepatitis Activity Index
▫ The major changes were eliminating the combined score, and
separating confluent necrosis, including bridging necrosis, into
a fourth category of necroinflammatory activity
▫ Also includes a stage of 'developing cirrhosis', which is
important to assess the progression of fibrosis
▫ A description of all aspects of viral injury is helpful
▫ However, because of its extensive details, it remains more
useful for research purposes than routine liver biopsy reporting

44. 0 No fibrosis
1 Expansion of some portal areas with or
without septa
2 Expansion of most portal areas with or
without septa
3 Expansion of most portal areas with
occasional portal to
portal bridging
4 Expansion of portal areas with marked
bridging (portalportal
and/or portal-central)
5 Marked bridging with occasional nodules
(incomplete
cirrhosis)
6 Cirrhosis, probable or definitive

45. • METAVIR System
▫ This grading system evaluates only 2 features (periportal
necrosis and lobular necroinflammatory activity)
▫ Portal inflammation is excluded because it is considered a
prerequisite for the diagnosis of chronic hepatitis, even
when there is no parenchymal activity
▫ It is a relatively simple system, providing scores of mild,
moderate or severe for activity and four stages of
progression of fibrosis

47. HISTOLOGICAL ACTIVITY FIBROSIS STAGE
No activity = A0 F0 = No fibrosis
Mild activity = A1 F1 = Portal fibrosis without septa
Moderate activity = A2 F2 = Portal fibrosis with rare septa
Severe activity = A3 F3 = Numerous septa without cirrhosis
F4 = Cirrhosis

48. • Scheuer System
▫ This also is a fairly simple system
▫ Only two categories are included (portal / periportal and lobular)
for evaluation of activity
• Batts-Ludwig System
▫ Uses five categories (0 to 4) separately for both grade and stage
▫ Grade is determined by evaluation of degree of interface activity,
lobular inflammation and necrosis
▫ Stage is scored from 0 (no fibrosis) to 4 (cirrhosis)
▫ It provides a pictorial description of each grade and stage of the
disease

49. Comparative scoring system for Histological Grade
(Inflammation)
IASL BATTS-LUDWIG METAVIR
Minimal chronic hepatitis Grade 1 A1
Mild chronic hepatitis Grade 2 A2
Moderate chronic hepatitis Grade 3 A3
Severe chronic hepatitis Grade 4 A4

51. REPORTING
• Each diagnosis in a liver biopsy for chronic hepatitis should include:
▫ A statement that it is chronic hepatitis
▫ The grade of necroinflammatory activity (name of the scoring system used)
▫ The stage of activity (name of the scoring system used)
▫ The known or suspected etiology
• Examples:
▫ Chronic hepatitis B, Metavir, grade 2/4 and stage 2/4 (fibrous septa)
▫ Chronic hepatitis, Batts-Ludwig, grade 2/4 and stage 4/4 (cirrhosis),
compatible with hepatitis C

53. • Pathological hallmark of cirrhosis is :
oDevelopment of scar tissue that replaces normal parenchyma, blocking the
portal flow of blood through the organ and disturbing normal function.
oRecent research shows the pivotal role of a stellate cell, a cell type that
normally stores vitamin A, in the development of cirrhosis.
oDamage to the hepatic parenchyma leads to activation of the stellate cell,
which becomes contractile (called myofibroblast) and obstructs blood flow in
the circulation.
oIt secretes TGF-β1, which leads to a fibrotic response and proliferation of
connective tissue.
oIt disturbs the balance between matrix metalloproteinases and the naturally
occurring inhibitors (TIMP 1 and 2), leading to matrix breakdown and
replacement by connective tissue-secreted matrix.

54. CASE REPORT :
A 25 year old male was a known case of Hepatitis B related cirrhosis. The
cirrhotic liver of recepient came for histopathological examination.
GROSS-
Formalin fixed specimen consists of liver with gall bladder. Liver measuring
11.5x10x5 cm. External surface is grey white and micronodular. Cut surface is
grey white with areas of congestion. Gall bladder measures 6x2.5 cm. external
surface is grey white, cut surface is grey brown with wall thickness of 0.7cm. No
stones were present.
The sections were given from different areas of liver and gall bladder.

55. Microscopy:
Multiple sections were studied and show complete loss of hepatic
archietecture with formation of pseudolobules of varying sizes. The
portal and intralobular areas show extensive fibrosis by loose fibrous
tissue and infiltration by chronic non specific inflammatory cells. The
portal area show … proliferation. The periportal show only focal mild
interface … . Significant lobular infiltration and necrosis was not seen.
Overall, picture indicates cirrhosis. The morphology is suggestive of
Post-Necrotic Cirrhosis.
METAVIR Score: Histological activity score :- 1 (mild)
Fibrosis score :- 4 (cirrhosis)

59. PAS stained section (10x)

60. PAS stained section (40x)

61. Reticulin stained section (40x)

62. Van Gieson stained section (40x)

63. CHOLANGIOCARCINOMA

64. • Cholangiocarcinoma is the designation used for
malignancy of the biliary tree, arising from bile
ducts within and outside of the liver.
•It is the second most common primary malignant
tumor of liver after HCC.

65. • It is of two types:
1.Intrahepatic
2.Extrahepatic
• Extrahepatic: it includes perihilar tumor known as Klatskin Tumors, which are
located at junction of right and left hepatic ducts. 50-60% are perihilar, 20-30%
are distal tumor arising from common bile ducts. Patients presents with
symptoms of biliary obstruction, cholangitis and RUQ pain.
• Intraheaptic: accounts 10%. The median time from diagnosis to death is 6
months. Patients comes to attention beacause of obstruction of bile flow and
symptomatic liver mass.

66. • Tumors of intrahepatic bile duct are less common than those of
hepatocytes.
• Risk factors-
▫ HCV related cirrhosis
▫ Caroli’s disease (congenitally dilated intrahepatic bile ducts)
▫ Clonorchis sinensis and opisthorchis infestation (parasitic)
▫ Anabolic steroid administration
• Occurs after 60 yrs of age
• Presents as abdominal pain & weight loss.
• Cholangiocarcinoma spread locally into portal area and metastasise
to both regional lymph nodes and to distant organs.

67. •Grossly-
▫firmer & whiter than Liver Cell Carcinoma
because of their greater amount of fibrous
stroma.
▫Arise close to the hilar region, but can occur
anywhere, including subsapsular region.
•Multicentricity is common.

69. Microscopically-
• Its an adenocarcinoma, the duct like structures being lined
by cuboidal or columnar cells.
• A cribriform pattern may be present.
• Tumor has a tendency to spread b/w hepatocyte plates,
along duct wall, and in relation to nerves.
• Stroma is abundant, is sometimes arranged circumferentially
around the neoplastic glands.
• The prominent sinusoidal pattern of liver cell carcinoma is
absent.
• Mucin stains is nearly always positive.

70. • Morphologic variants-
▫ Mucinous cholangioCA
▫ Signet ring variety
▫ Adenosquamous
▫ Clear cell
▫ Lymphoepithelioma like
▫ Sarcomatoid
Cytogenetics-
• Overexpress MET, hepatocyte Growth factors, c-ERBB-2, Claudin-4,
cyclin D1, P21, TP53, mutation in KRAS gene.
• HepPar-1 is negative.

71. IHC-
• Reactive for keratin, EMA, CEA
• A diagnostically useful difference in keratin immunoprofile between
intra hepatic and extra hepatic cholangiocarcinoma is that, the
former is positive for CK7+/CK20+ whereas latter is CK7+/CK20-.
• The tumour also stains for tissue polypeptide antigen, amylase
isoenzymes and PTH related peptides.
Treatment-
partial or total hepatic resection, followed by liver transplantation.

75. Case presentation:
Left lobe of liver with gall bladder and lymph nodes of a 55 year old female came for
histopathological examination.
GROSS-
Formalin fixed specimen consists of partial specimen of liver with gall bladder
collectively measuring 18x10x8 cm. Falciparum ligament was identified. External
surface is grey brown with multiple projecting nodules ?satellite nodules. On
cutting, grey white growth is seen in left lobe measuring 4x2.5 cm. Multiple grey
white area is seen in liver parenchyma ranging in size from 0.2 to 0.6 cm in
diameter. Gall bladder measures 7x3.5 cm. External surface is grey white to grey
brown. Luminal surface is greenish velvety with wall thickness of 0.2 cm. No
stones were present.
?Lymph node- Formalin fixed specimen consists of several grey white to grey brown
soft tissue pieces collectively measuring 2x1.5 cm.

76. • Various sections were taken from resected margins, margins from deeper tissue,
resected end of hilum, growth, satellite nodules, gall bladder and lymph nodes.
MICROSCOPY-
Liver shows moderately differentiated adenocarcinoma. The features are
suggestive of cholangiocarcinoma. Sections from satellite nodules show
moderately differentiated adenocarcinoma. The associated nerve bundle show
focal infiltration by tumor cells. The lymphovascular invasion was not seen. The
section from resected margins show focal infiltration by tumor cells. Section from
hilar area appears to be free from tumor invasion. The hepatic parenchyma show
marked infiltration by chronic non specific inflammatory cells, congested
sinusoids and bile stasis.
Gall bladder show chronic cholecystitis.
All the five lymph nodes resected show reactive hyperplasia. No evidence of
malignancy seen.

80. FEATURES LIVER CELL
CARCINOMA
CHOLANGIOCARCINOMA
Cell of origin Hepatocyte Bile duct cells
Spread Venous Lymphatics
Age Young Older
Sex Males None
Presence of cirrhosis Common Exceptional
Liver cell dysplasia May be present Absent
Alpha-fetoprotein Present Absent
Bile production May be present Absent
Mucin secretion Absent Present
Gross Soft & h’gh Hard & whitish