Definition/General
Introduction:
Hepatic cirrhosis is end-stage chronic liver disease with architectural distortion and fibrosis
FNAC is rarely performed due to bleeding risk and sampling issues
When performed, shows regenerative hepatocytes with inflammatory background
It represents irreversible liver damage with nodular regeneration.
Origin:
Results from chronic liver injury with progressive fibrosis
Hepatocyte necrosis triggers inflammatory response
Stellate cell activation leads to collagen deposition
Architectural distortion with nodule formation
Portal-central bridging fibrosis disrupts normal liver architecture.
Classification:
Morphologic classification: micronodular (<3mm nodules) vs macronodular (>3mm nodules)
Etiology-based: viral hepatitis (HBV, HCV)
Alcoholic cirrhosis
NASH cirrhosis
Autoimmune hepatitis
Primary biliary cholangitis
Wilson disease
Hemochromatosis
Cryptogenic cirrhosis.
Epidemiology:
Major cause of mortality worldwide
Male predominance in alcoholic cirrhosis
Peak incidence in 5th-6th decades
Leading causes in India: viral hepatitis B/C
Alcohol-related cirrhosis increasing
NASH cirrhosis emerging with lifestyle changes
High prevalence in developing countries.
Clinical Features
Presentation:
Compensated cirrhosis: may be asymptomatic
Portal hypertension: splenomegaly, varices
Hepatic insufficiency: jaundice, ascites
Spider nevi and palmar erythema
Hepatomegaly (early) progressing to atrophy
Decompensated cirrhosis: ascites, encephalopathy.
Symptoms:
Fatigue and weakness (most common)
Abdominal distension (ascites)
Jaundice (bilirubin elevation)
Pruritus (cholestasis)
Confusion (hepatic encephalopathy)
Gastrointestinal bleeding (varices)
Muscle wasting and weight loss.
Risk Factors:
Chronic viral hepatitis (HBV, HCV, HDV)
Chronic alcohol consumption
Non-alcoholic steatohepatitis (NASH)
Autoimmune hepatitis
Primary biliary cholangitis
Metabolic disorders (Wilson, hemochromatosis)
Drug-induced liver injury
Cryptogenic causes.
Screening:
High-risk patients: chronic liver disease
Liver function tests: elevated enzymes, bilirubin
Albumin decrease, PT prolongation
Platelet count decrease (hypersplenism)
Imaging: nodular liver surface, portal hypertension
Elastography: increased stiffness
Endoscopy for varices.
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Gross Description
Appearance:
FNAC (rarely performed) shows variable cellularity
Regenerative hepatocytes with nuclear enlargement
Inflammatory cells (lymphocytes, plasma cells)
Fibrous tissue fragments
Hemosiderin-laden macrophages
Background may show bile pigment.
Characteristics:
Mixed cellular population
Hepatocytes showing regenerative changes
Chronic inflammatory infiltrate
Fibroblasts and myofibroblasts
Ductular proliferation
Kupffer cells with pigment
Necrotic debris variable
Blood contamination common.
Size Location:
Diffuse process affecting entire liver
Micronodular pattern: uniform small nodules
Macronodular pattern: variable-sized larger nodules
Mixed pattern common in advanced disease
Surface irregularity grossly visible
Capsular thickening.
Multifocality:
Diffuse liver involvement
Regenerative nodules throughout parenchyma
Portal tract distortion
Bridging fibrosis connecting portal areas
Central vein involvement
Extrahepatic manifestations: splenomegaly, varices.
Microscopic Description
Histological Features:
Regenerative hepatocytes with nuclear enlargement and binucleation
Chronic inflammatory infiltrate (lymphocytes, plasma cells)
Fibrous tissue proliferation
Ductular proliferation
Mallory bodies (in alcoholic cirrhosis)
Hemosiderin deposits variable
Bile duct loss in advanced cases.
Cellular Characteristics:
Hepatocytes: enlarged nuclei with prominent nucleoli
Binucleated forms increased
Cytoplasmic changes: steatosis, ballooning
Inflammatory cells: chronic pattern predominant
Fibroblasts: activated stellate cells
Ductular epithelium: reactive proliferation
Kupffer cell hyperplasia.
Architectural Patterns:
Loss of normal architecture
Nodular regeneration pattern
Fibrous septa dividing parenchyma
Portal-central bridging fibrosis
Pseudolobule formation
Ductular reaction at interface
Sinusoidal capillarization.
Grading Criteria:
Fibrosis staging (F0-F4, F4=cirrhosis)
Inflammatory activity (minimal to severe)
Interface hepatitis presence
Lobular inflammation extent
Hepatocyte ballooning
Mallory bodies (alcoholic cases)
Portal inflammation severity.
Immunohistochemistry
Positive Markers:
Hepatocyte marker (positive in hepatocytes)
CK7 (ductular reaction, bile duct proliferation)
CK19 (cholangiocyte proliferation)
Smooth muscle actin (activated stellate cells)
Collagen I/III (fibrosis)
CD68 (Kupffer cells, macrophages).
Negative Markers:
Reticulin stain (loss of normal pattern)
Trichrome stain (highlights fibrosis)
Iron stain (hemochromatosis cases)
Copper stain (Wilson disease)
α1-antitrypsin (deficiency cases)
PAS (glycogen content variable).
Diagnostic Utility:
Limited utility in FNAC setting
CK7/19 highlight ductular proliferation
SMA shows stellate cell activation
Reticulin stain demonstrates architectural collapse
Trichrome highlights extent of fibrosis
Special stains for etiology determination
Histology preferred for staging.
Molecular Subtypes:
Viral etiology: HBV, HCV markers
Autoimmune markers: ANA, ASMA, anti-LKM
Metabolic markers: iron, copper studies
Alpha-1 antitrypsin deficiency
Genetic testing: Wilson disease, hemochromatosis
NASH-related: metabolic syndrome markers.
Molecular/Genetic
Genetic Mutations:
Etiology-specific genetic alterations
HFE mutations (hereditary hemochromatosis)
ATP7B mutations (Wilson disease)
SERPINA1 mutations (α1-antitrypsin deficiency)
Viral genome integration (HBV)
Fibrosis-related genes: PDGF, TGF-β pathways.
Molecular Markers:
TGF-β pathway (fibrosis progression)
PDGF signaling (stellate cell activation)
Collagen gene expression (COL1A1, COL3A1)
Matrix metalloproteinases (MMP family)
TIMP expression (tissue inhibitors)
Angiogenesis factors: VEGF.
Prognostic Significance:
Fibrosis stage most important prognostic factor
Etiology influences progression rate
Age at onset and gender effects
Viral load (in viral hepatitis)
Continued alcohol use (poor prognosis)
Metabolic factors: diabetes, obesity
Genetic background influences progression.
Therapeutic Targets:
Antiviral therapy (viral hepatitis)
Alcohol cessation
Anti-fibrotic agents (experimental)
Immunosuppression (autoimmune hepatitis)
Chelation therapy (Wilson, hemochromatosis)
Lifestyle modification (NASH)
Liver transplantation (end-stage).
Differential Diagnosis
Similar Entities:
Chronic hepatitis (without cirrhosis)
Regenerative nodular hyperplasia
Congenital hepatic fibrosis
Focal nodular hyperplasia
Hepatocellular carcinoma (in cirrhotic liver)
Metastatic disease
Portal hypertension without cirrhosis.
Distinguishing Features:
Cirrhosis: complete architectural distortion, bridging fibrosis
Chronic hepatitis: preserved architecture, portal fibrosis only
RNH: large regenerative nodules, portal hypertension
FNH: central scar, normal liver function
HCC: malignant cytology, AFP elevation
Metastases: space-occupying lesions.
Diagnostic Challenges:
Early cirrhosis vs advanced chronic hepatitis
Inactive cirrhosis vs resolved hepatitis
Dysplastic nodules vs regenerative nodules
Small HCC in cirrhotic liver
Etiology determination from FNAC alone
Activity assessment in established cirrhosis.
Rare Variants:
Primary biliary cirrhosis
Congenital hepatic fibrosis
Cardiac cirrhosis
Veno-occlusive disease
Granulomatous cirrhosis
Drug-induced cirrhosis
Cryptogenic cirrhosis.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Clinical Information
Patient with [chronic liver disease history], etiology: [known/unknown]
Specimen Adequacy
Adequate with [cellularity description] and inflammatory background
Cytomorphological Features
Shows [regenerative hepatocytes] with chronic inflammatory changes
Background
Background shows [chronic inflammation, fibrous tissue, bile pigment]
Hepatocyte Features
Hepatocytes show [nuclear enlargement, binucleation, regenerative changes]
Differential Diagnosis
Differential includes [chronic hepatitis, malignancy, other chronic conditions]
Final Cytological Diagnosis
Chronic liver disease with regenerative changes, consistent with cirrhosis
Recommendations
Recommend [tissue biopsy for staging, clinical correlation, avoid repeat FNAC]