Q4 LONG ANSWER 10M ★ High-yield

Define cirrhosis. Describe its causes, pathogenesis and morphological types. Add a note on portal hypertension.

Pathology · 2nd Professional — Para-Clinical

Definition

Cirrhosis is a diffuse process characterised by fibrosis and the conversion of normal liver architecture into structurally abnormal regenerative nodules.

All three features are required — it must be diffuse (not focal scarring), there must be fibrous septa, and there must be regenerative nodules. Fibrosis alone is not cirrhosis
It is the end stage of chronic liver disease, and was long considered irreversible; early cirrhosis is now known to regress if the cause is removed

Causes

Cause	Notes
Alcohol	The commonest in the West; typically MICROnodular
Chronic viral hepatitis B and C	The commonest worldwide and in India; typically MACROnodular
Non-alcoholic fatty liver disease (NAFLD/NASH)	Rising rapidly with obesity and diabetes; now a leading cause
Biliary	Primary biliary cholangitis (anti-mitochondrial antibody), primary sclerosing cholangitis, secondary biliary cirrhosis from chronic obstruction
Metabolic and inherited	Haemochromatosis (iron), WILSON disease (copper), alpha-1 antitrypsin deficiency, galactosaemia, glycogen storage disease
Autoimmune hepatitis	Anti-smooth muscle and anti-nuclear antibodies; young women
Vascular	Chronic venous congestion — "cardiac cirrhosis"; BUDD–CHIARI syndrome
Drugs and toxins	Methotrexate, amiodarone, isoniazid
Cryptogenic	10–15%; many are now recognised as burnt-out NAFLD

Morphological Classification

Type	Nodule size	Typical causes
MICROnodular	Uniform, under 3 mm	Alcohol, haemochromatosis, biliary obstruction, chronic venous congestion
MACROnodular	Variable, over 3 mm	Chronic viral hepatitis, Wilson disease, alpha-1 antitrypsin deficiency
Mixed	Both patterns	Micronodular cirrhosis tends to become macronodular over time as nodules enlarge

Pathogenesis

Chronic injury to hepatocytes — viral, toxic, metabolic or immune → Kupffer cells and damaged hepatocytes release cytokines, chiefly TGF-beta, PDGF and TNF → hepatic stellate (ITO) cells in the space of Disse are activated → They lose their vitamin A stores and transform into myofibroblasts → These secrete collagen types I and III into the space of Disse → capillarisation of the sinusoids — loss of fenestrations, so exchange between blood and hepatocytes fails → Fibrous septa link portal tracts and central veins → Regenerating hepatocytes form nodules without normal vascular relationships → Increased resistance to portal flow → portal hypertension

The stellate cell is the central player, and is the target of antifibrotic research
The architectural disorder matters as much as the fibrosis — blood bypasses hepatocytes through shunts, so the liver fails even where cells survive

Portal Hypertension

Portal hypertension is a portal venous pressure above 10–12 mmHg (normal 5–10), or a hepatic venous pressure gradient above 5 mmHg.

Site of obstruction	Causes
Pre-hepatic	Portal vein thrombosis, splenic vein thrombosis, extrahepatic portal venous obstruction — an important cause in Indian children
Intra-hepatic	Cirrhosis (much the commonest); schistosomiasis (major worldwide); non-cirrhotic portal fibrosis, which is well recognised in India; massive fatty change; sarcoidosis
Post-hepatic	BUDD–CHIARI syndrome (hepatic vein thrombosis), constrictive pericarditis, right heart failure, veno-occlusive disease

Consequences — portosystemic anastomoses

Oesophageal varices (left gastric to azygos) — the most dangerous; rupture causes torrential haematemesis and is a leading cause of death
Caput medusae around the umbilicus (paraumbilical to epigastric veins)
Haemorrhoids (superior to middle and inferior rectal veins)
Retroperitoneal and splenorenal collaterals
Splenomegaly with hypersplenism — pancytopenia
Ascites — from portal hypertension, hypoalbuminaemia, splanchnic vasodilatation and secondary hyperaldosteronism acting together

CLINICAL PEARL

Ascites in cirrhosis has at least four mechanisms, which is why one treatment is never enough. Raised sinusoidal pressure drives fluid out; low albumin reduces oncotic pull; splanchnic vasodilatation reduces effective circulating volume, activating the renin–angiotensin–aldosterone system to retain sodium; and hepatic lymph weeps from the surface. This is why treatment combines salt restriction, spironolactone and a loop diuretic.

Clinical Features of Cirrhosis

Group	Features
Hepatocellular failure	Jaundice, hypoalbuminaemia with oedema, coagulopathy and easy bruising, encephalopathy, fetor hepaticus
Endocrine (failure to metabolise oestrogen)	Spider naevi, palmar erythema, gynaecomastia, testicular atrophy, loss of body hair, amenorrhoea
Portal hypertension	Splenomegaly, ascites, varices, caput medusae
Other signs	Clubbing, Dupuytren contracture, leuconychia, parotid enlargement, asterixis
Compensated versus decompensated	Many patients are asymptomatic for years; decompensation is marked by ascites, jaundice, variceal bleeding or encephalopathy and changes the prognosis sharply

Complications and Applied Aspects

Hepatic encephalopathy — from ammonia and other nitrogenous products bypassing the liver; asterixis, confusion, coma; precipitated by gastrointestinal bleeding, infection, constipation, sedatives and electrolyte disturbance. Treated with lactulose and rifaximin
Spontaneous bacterial peritonitis — infection of ascitic fluid without a perforated viscus; diagnosed by an ascitic neutrophil count above 250/mm3; must be actively sought, since fever may be absent
Hepatorenal syndrome — functional renal failure with histologically normal kidneys, from intense renal vasoconstriction; the kidneys work normally if transplanted
Hepatocellular carcinoma — the risk is about 1 to 5% a year in cirrhosis, justifying six-monthly ultrasound surveillance
Serum-ascites albumin gradient (SAAG) — a gradient above 1.1 g/dL indicates portal hypertension; below that suggests peritoneal disease such as tuberculosis or malignancy. More reliable than the old transudate/exudate distinction
Child–Pugh and MELD scores grade severity and guide transplantation; treatment of the underlying cause — abstinence, antivirals, weight loss — can allow substantial recovery
Variceal bleeding is managed by resuscitation, terlipressin, antibiotics and endoscopic band ligation; beta-blockers or banding prevent a first or further bleed
Avoid sedatives, NSAIDs and aminoglycosides in cirrhosis — they precipitate encephalopathy, bleeding and renal failure respectively
Paracentesis of new ascites should always include a cell count and culture, since spontaneous bacterial peritonitis is common, frequently silent, and lethal if missed
Liver biopsy is no longer always required — non-invasive elastography and serum fibrosis panels now stage fibrosis adequately in many patients

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