---

Cirrhosis of the Liver

---

1. Definition

---

2. Etiology

"There are also some instances in which cirrhosis arises without any clear cause; the term cryptogenic cirrhosis is sometimes applied to such cases." — Robbins & Kumar Basic Pathology, p. 598

---

3. Pathogenesis

3.1 Core Mechanism: Hepatic Stellate Cell Activation

• Synthesize large amounts of type I and III collagen
• Produce TGF-β, which amplifies fibrogenesis
• Contract, increasing sinusoidal vascular resistance

3.2 Steps in Fibrosis Progression

1. Chronic hepatocellular injury (by viral proteins, alcohol/acetaldehyde, lipotoxicity, bile acids, immune-mediated damage)
2. Kupffer cell and macrophage activation → cytokine release (TGF-β, PDGF, TNF)
3. Stellate cell activation and proliferation → excessive ECM deposition
4. Ductular reaction — stem/progenitor cell activation gives rise to ductular structures, particularly prominent in advanced fibrosis
5. Disruption of normal lobular architecture → formation of regenerative nodules separated by fibrous septa (portal-to-portal, or portal-to-central bridging)

3.3 Nodule Classification

• Micronodular cirrhosis (nodules < 3 mm): typical of alcohol and biliary disease
• Macronodular cirrhosis (nodules > 3 mm, up to several cm): typical of viral hepatitis

3.4 Reversibility

---

4. Methods for Examining Patients

4.1 History

• Duration and quantity of alcohol consumption
• Risk factors for viral hepatitis (IV drug use, transfusions, sexual contacts)
• Metabolic risk factors (obesity, diabetes, dyslipidaemia)
• Family history (Wilson disease, haemochromatosis, α1-AT deficiency)
• Drug and herbal supplement use

4.2 Physical Examination

• Hepatomegaly (early) or small, shrunken liver (late)
• Splenomegaly (portal hypertension)
• Ascites (shifting dullness, fluid thrill)
• Jaundice, scleral icterus
• Spider angiomas (>5 is significant), palmar erythema
• Caput medusae (dilated periumbilical veins)
• Gynaecomastia, testicular atrophy (hyperestrogenism)
• Dupuytren's contracture (alcohol)
• Asterixis (flapping tremor — hepatic encephalopathy)
• Fetor hepaticus (sweet, musty breath — encephalopathy)

4.3 Laboratory Investigations

• FIB-4 index (age × AST / platelets × √ALT)
• APRI (AST-to-platelet ratio)
• FibroScan (transient elastography) — liver stiffness measurement in kPa

4.4 Imaging

• Ultrasound (first-line): nodular liver surface, increased echogenicity, splenomegaly, ascites, portal vein diameter, Doppler flow assessment
• CT (triphasic): nodular morphology, varices, HCC detection
• MRI/MRCP: superior HCC characterisation, biliary anatomy
• Endoscopy (EGD): grading of oesophageal/gastric varices — mandatory in all cirrhotic patients at diagnosis

4.5 Liver Biopsy

• Still the gold standard for staging fibrosis (METAVIR, Ishak scales)
• Used when non-invasive testing is inconclusive
• Provides aetiology, activity grade, and fibrosis stage simultaneously

---

5. Clinical Presentation

5.1 Compensated Cirrhosis

• ~40% of patients are asymptomatic at diagnosis
• Non-specific: fatigue, anorexia, weight loss, malaise
• Detected incidentally on imaging or blood tests

5.2 Decompensated Cirrhosis

---

6. Complications

6.1 Portal Hypertension

• Increased sinusoidal resistance: contraction of stellate cell myofibroblasts, fibrotic scarring, nodule formation
• Increased portal inflow: arterial vasodilation (NO-mediated) → increased splanchnic blood flow → increased venous return to portal system

6.2 Oesophageal/Gastric Varices

• Develop in ~40% of patients with advanced cirrhosis
• Result from portosystemic collateralisation (left gastric/coronary vein → oesophageal plexus → azygous system)
• Variceal haemorrhage is the most immediately life-threatening complication: massive haematemesis with mortality 15–20% per episode

6.3 Ascites

• Present in ~85% of cases of ascites overall; most common decompensating event in cirrhosis
• Mechanism: portal hypertension → splanchnic vasodilation → reduced effective arterial blood volume → RAAS and SNS activation → Na and water retention → fluid transudation into peritoneum
• Fluid is a transudate: protein < 30 g/L, serum-to-ascites albumin gradient (SAAG) ≥ 1.1 g/dL
• Complicated by spontaneous bacterial peritonitis (SBP): fever, abdominal pain, ascitic PMN count > 250/mm³ — a life-threatening infection (E. coli, Klebsiella most common)

6.4 Hepatic Encephalopathy (HE)

• Spectrum from subtle cognitive impairment (minimal HE) to coma
• Caused by gut-derived toxins (particularly ammonia) reaching systemic circulation via portosystemic shunts and bypassing hepatic detoxification
• Precipitants: GI bleeding, infection, constipation, hyponatraemia, sedatives, large protein load

6.5 Hepatorenal Syndrome (HRS)

• Functional renal failure in the absence of intrinsic renal pathology
• Pathogenesis: hepatic failure → vasodilators (nitric oxide) → splanchnic vasodilation → reduced effective renal perfusion → RAAS/SNS-mediated afferent arteriolar vasoconstriction → GFR falls
• Rising creatinine, oliguria — HRS-1 (rapid, formerly "type 1") carries ~50% 30-day mortality without treatment

6.6 Hypersplenism

• Congestive splenomegaly from portal hypertension → splenic sequestration of blood cells
• Thrombocytopenia, anaemia, leukopenia (pancytopenia)

6.7 Coagulopathy

• Reduced synthesis of factors II, V, VII, IX, X, fibrinogen (all except factor VIII, produced by endothelium)
• Prolonged PT/INR — increased bleeding risk

6.8 Hepatopulmonary Syndrome (HPS)

• Intrapulmonary vascular dilatations → right-to-left shunting → hypoxaemia
• Classic finding: platypnoea (dyspnoea worsening when upright, improving supine)

6.9 Hepatocellular Carcinoma (HCC)

• Most chronic liver diseases predispose to HCC development
• Risk particularly high in HBV (even without cirrhosis), HCV, alcohol-related, NAFLD-related cirrhosis, haemochromatosis
• Surveillance: AFP + liver ultrasound every 6 months in all cirrhotic patients

6.10 Hepatic Hydrothorax

• Transudative pleural effusion (usually right-sided) due to passage of ascitic fluid through diaphragmatic defects

---

7. Staging and Prognosis

Child-Pugh Score

• Class A (5–6): compensated; 1-year survival ~100%
• Class B (7–9): significant compromise
• Class C (10–15): decompensated; 1-year survival ~45%

MELD Score

• MELD = 9.57 × ln(creatinine) + 3.78 × ln(bilirubin) + 11.2 × ln(INR) + 6.43
• Used for liver transplant waitlist prioritisation (higher score = higher urgency)
• MELD ≥ 15: benefit from transplantation outweighs risk

---

8. Surgical Treatment

8.1 Management of Variceal Haemorrhage

• Haemodynamic resuscitation, blood transfusion (target Hb 70–80 g/L)
• Vasopressin analogues (terlipressin) or somatostatin analogues (octreotide) to reduce portal inflow
• Prophylactic antibiotics (norfloxacin or ceftriaxone) to prevent SBP and reduce mortality
• Urgent endoscopic variceal ligation (EVL) — first-line endoscopic treatment, superior to sclerotherapy
• Balloon tamponade (Sengstaken-Blakemore tube) as bridge to definitive treatment

• Interventional radiology procedure: metallic stent placed between hepatic vein and portal vein via transjugular approach
• Reduces portal pressure directly
• Highly effective for refractory variceal bleeding and refractory ascites
• Main complication: worsening hepatic encephalopathy (blood bypasses liver)
• Acts as a bridge to liver transplantation

• Distal splenorenal shunt (Warren shunt): selective decompression of gastrosplenic varices while preserving mesenteric flow to the liver — lower encephalopathy rate than total shunts
• Mesocaval shunt: superior mesenteric vein to inferior vena cava
• Portocaval shunt (end-to-side or side-to-side): high effectiveness but high encephalopathy rate; largely replaced by TIPS
• Shunt surgery is generally reserved for Child-Pugh Class A/B patients with adequate hepatic reserve; contraindicated in advanced disease

8.2 Surgical Management of Ascites

• Peritoneovenous shunts (LeVeen/Denver shunt): now rarely performed due to complications (DIC, shunt thrombosis)
• Large-volume paracentesis (LVP): with albumin infusion (8 g/L ascites removed) — standard of care for tense/refractory ascites
• TIPS: effective for refractory ascites — reduces need for repeated paracentesis

8.3 Splenectomy / Partial Splenic Embolisation

• Occasionally performed for severe hypersplenism causing refractory cytopenias
• Usually avoided as a standalone procedure in cirrhosis due to operative risk and potential acceleration of portal hypertension

8.4 Liver Transplantation — Definitive Treatment

• Decompensated cirrhosis (Child-Pugh C or MELD ≥ 15)
• Complications refractory to medical management (SBP, HRS, HE)
• HCC within Milan criteria (single nodule ≤ 5 cm, or up to 3 nodules none > 3 cm, no macrovascular invasion, no extrahepatic spread)

• Active extrahepatic malignancy
• Uncontrolled infection/sepsis (except SBP)
• Severe cardiac or pulmonary disease
• Active alcohol/drug use (requires documented abstinence period)
• Irreversible neurological disease

• Orthotopic liver transplantation (OLT) from deceased donor — standard
• Living donor liver transplantation (LDLT) — right lobe donation; reduces waitlist time
• Split liver transplantation — one donor liver for two recipients

---

Summary Table: Surgical Options by Complication

---