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CHRONIC LIVER DISEASE (CLD) - COMPREHENSIVE CLINICAL NOTE

Sources: Harrison's Principles of Internal Medicine 22nd Ed. (2025) | Sleisenger & Fordtran's Gastrointestinal and Liver Disease | Robbins & Kumar Pathologic Basis of Disease | Bailey & Love's Short Practice of Surgery 28th Ed. | Medical Physiology (Boron & Boulpaep) | Yamada's Textbook of Gastroenterology 7th Ed. | Goldman-Cecil Medicine | Kumar & Clark's Clinical Medicine 11th Ed. (referenced throughout)

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1. DEFINITION

• Bailey & Love 28th Ed., Ch. 69: "Liver disease is the third leading cause of premature death in the UK, and since 1970 deaths have increased by 400%. Liver disease is potentially preventable in 90% of cases, and 75% of patients present with late-stage disease."

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2. ETIOLOGY

Common Causes (>90% of cases)

Less Common / Rare Causes

• Primary biliary cholangitis (PBC) - anti-mitochondrial antibody (AMA M2), cholestatic pattern
• Primary sclerosing cholangitis (PSC) - associated with IBD (especially UC); "beaded" ducts on MRCP
• Hereditary hemochromatosis - HFE gene mutation (C282Y homozygote); iron overload in parenchymal cells
• Wilson's disease - ATP7B mutation; copper accumulation; Kayser-Fleischer rings
• Alpha-1 antitrypsin deficiency - PiZZ phenotype; PAS-positive diastase-resistant globules in hepatocytes
• Drug-induced - methotrexate, amiodarone, isoniazid, methyldopa
• Cardiac/congestive hepatopathy - chronic right heart failure ("cardiac cirrhosis")
• Budd-Chiari syndrome - hepatic vein thrombosis
• Cryptogenic cirrhosis - ~5-10% after full workup; often "burned-out" MASLD

Sleisenger & Fordtran, Ch. 93: "Cirrhosis is the result of a prolonged process, usually more than 20 years, of progressive liver inflammation and fibrosis in response to chronic injury (e.g., alcohol consumption, chronic viral hepatitis, NAFLD)."

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3. PATHOLOGY

3.1 Macroscopic

• Micronodular cirrhosis (nodules <3 mm): uniform, small nodules; typical of alcohol, hemochromatosis, Wilson's disease, biliary cirrhosis
• Macronodular cirrhosis (nodules >3 mm): irregular large nodules; typical of viral hepatitis
• Mixed cirrhosis: features of both

3.2 Microscopic (Histopathology)

1. Hepatocyte necrosis - ballooning degeneration, Mallory-Denk bodies (in ALD/MASLD), interface hepatitis (in AIH/viral)
2. Inflammation - periportal (piecemeal necrosis = "interface hepatitis"), lobular, or portal tract infiltration
3. Fibrosis - perisinusoidal (Disse space), periportal, bridging fibrosis, ultimately complete replacement
4. Regenerative nodules - loss of normal lobular architecture; nodules surrounded by fibrous septa

• F0: No fibrosis
• F1: Portal fibrosis without septa
• F2: Portal fibrosis with few septa
• F3: Bridging fibrosis (many septa without cirrhosis)
• F4: Cirrhosis

3.3 Cellular Mechanisms of Fibrosis

• At rest, HSCs store vitamin A (lipocytes/Ito cells) in the perisinusoidal space of Disse
• On injury, they undergo transdifferentiation/activation triggered by:
  • TGF-β1 (the principal profibrogenic cytokine)
  • PDGF (potent HSC mitogen)
  • Reactive oxygen species (ROS)
  • Angiotensin II
• Activated HSCs produce type I and III collagen, matrix metalloproteinase inhibitors (TIMPs), and contract sinusoids (increasing intrahepatic resistance)
• With resolution of injury, HSCs may revert to quiescence or undergo apoptosis - the basis for fibrosis reversibility

Yamada's Textbook of Gastroenterology 7th Ed.: "Fate of activated stellate cells - reversion of liver fibrosis" - activated HSCs can undergo apoptosis or revert to an inactive phenotype, providing a therapeutic window for anti-fibrotic agents.

Robbins & Kumar Pathologic Basis of Disease: Progressive collagen deposition and formation of nodules lead to architectural distortion of sinusoidal blood flow, resulting in increased intrahepatic resistance.

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4. PHYSIOLOGY AND PATHOPHYSIOLOGY

4.1 Normal Liver Functions Impaired

• Gluconeogenesis reduced → hypoglycemia
• Lipid metabolism impaired → hypertriglyceridemia, low cholesterol (in end-stage)
• Amino acid metabolism impaired → aromatic amino acids accumulate (relevant to HE)

• Albumin ↓ → hypoalbuminemia → reduced oncotic pressure → edema/ascites
• Coagulation factors (II, V, VII, IX, X) ↓ → coagulopathy, elevated PT/INR
• Complement proteins ↓ → immunodeficiency

• Ammonia not converted to urea → hyperammonemia → hepatic encephalopathy
• Drug metabolism impaired → altered pharmacokinetics

• Conjugation and excretion impaired → jaundice (conjugated > unconjugated)

4.2 Portal Hypertension Pathophysiology

1. Increased intrahepatic resistance (fixed + dynamic):
   • Fixed: collagen deposition, nodule formation, architectural distortion
   • Dynamic: HSC contraction, sinusoidal vasoconstriction (reduced nitric oxide, increased endothelin-1)
2. Hyperdynamic splanchnic circulation:
   • Portal hypertension → gut-derived bacteria and PAMPs translocate systemically
   • Endotoxins + bacterial DNA → splanchnic endothelial NO overproduction → splanchnic arterial vasodilation
   • Splanchnic vasodilation → "effective arterial hypovolemia" → activation of RAAS + sympathetic nervous system + ADH
   • This leads to Na+ and water retention → ascites, dilutional hyponatremia
   • Systemic vasodilation → hyperdynamic circulation (raised CO, low SVR)

Medical Physiology (Boron & Boulpaep): "The scarring that accompanies cirrhosis causes increased resistance to blood flow through the liver. When the portal venous pressure rises, the signs and symptoms of portal hypertension can appear."

Sleisenger & Fordtran, Ch. 93 (Fig. 93.1): "Splanchnic arterial vasodilatation is the key mechanism leading to renal function abnormalities in cirrhosis. The development of effective arterial hypovolemia triggers activation of vasoconstrictor and antinatriuretic systems."

4.3 Ascites Formation

• Splanchnic vasodilation → underfilling → RAAS activation → Na+ retention
• Reduced plasma oncotic pressure (low albumin) - secondary contributing factor
• Increased lymphatic production from hepatic sinusoids

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5. CLINICAL FEATURES

5.1 Compensated Cirrhosis

• Fatigue and lethargy (most common early symptom)
• Right upper quadrant discomfort
• Spider naevi (>5 is significant) in SVC territory
• Palmar erythema
• Subtle loss of secondary sexual characteristics

5.2 Cutaneous and Peripheral Signs

5.3 Endocrine Signs

• Gynecomastia - increased estrogen (impaired hepatic clearance)
• Testicular atrophy - reduced testosterone
• Loss of axillary/pubic hair (in males)
• Menstrual irregularities (in females)
• Hypothyroidism association; adrenal insufficiency in advanced disease

5.4 Abdominal Signs

• Hepatomegaly: firm, irregular, non-tender liver (though liver may shrink in end-stage)
• Splenomegaly: due to portal hypertension; associated with hypersplenism (thrombocytopenia, leukopenia, anemia)
• Ascites: shifting dullness, fluid thrill (massive)
• Fetor hepaticus: sweet, musty breath (dimethyl sulfide, mercaptans); portosystemic shunting

5.5 Decompensation Features (ABCDE)

• Ascites (with or without spontaneous bacterial peritonitis)
• Bleeding varices (esophageal, gastric)
• Coagulopathy (elevated PT/INR)
• Dencephalopathy (hepatic encephalopathy)
• Edema (peripheral), jaundice

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6. INVESTIGATIONS

6.1 Liver Function Tests (LFTs)

Bailey & Love 28th Ed.: "The standard method of monitoring liver function in patients with chronic liver disease is serial measurement of bilirubin, albumin and PT."

6.2 Blood Count

• Thrombocytopenia: hypersplenism + reduced thrombopoietin synthesis
• Anemia: multifactorial - blood loss, hypersplenism, folate deficiency (alcohol), hemolysis
• Leukopenia: hypersplenism

6.3 Specific Serology / Biochemistry

6.4 Non-Invasive Fibrosis Assessment

• FIB-4 index: (Age × AST) / (Platelets × √ALT) - validated and widely used
• APRI score: AST/platelet ratio index
• Fibroscan (transient elastography): liver stiffness in kPa; F4 (cirrhosis) typically >12.5 kPa
• MR elastography: most accurate; reserved for discordant cases

6.5 Imaging

• Ultrasound abdomen: First-line; coarsened echo texture, nodular surface, splenomegaly, ascites, portal vein diameter >13 mm
• CT abdomen (triphasic): Assess liver morphology, portal hypertension, HCC screening, vascular anatomy
• MRI liver (with contrast): Best for HCC characterization (LI-RADS system)
• Upper GI endoscopy: Variceal screening

6.6 Liver Biopsy

• Gold standard for diagnosis and staging
• Indications: uncertain diagnosis, assessing inflammation grade, confirming cirrhosis, monitoring treatment
• Minimum core size: 15 mm; at least 10 portal tracts
• Percutaneous (most common) vs. transjugular (if coagulopathy/ascites)
• Complications: bleeding (1:100-200), biliary peritonitis, death (~1:10,000)

6.7 Prognostic Scores

• Class A: 5-6 (compensated; 1-year survival ~95%)
• Class B: 7-9 (moderate compromise; ~75%)
• Class C: 10-15 (decompensated; ~50%)

• MELD = 3.78 × ln[bilirubin mg/dL] + 11.2 × ln[INR] + 9.57 × ln[creatinine mg/dL] + 6.43
• Range 6-40; higher = worse prognosis
• MELD-Na now preferred (incorporates serum sodium)
• Used for liver transplant priority ranking

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7. COMPLICATIONS

7.1 Portal Hypertension and Varices

• Develop in ~50% of cirrhotics
• Annual risk of first bleed: 5-15% (prophylaxis-naive)
• Each bleed: 30-day mortality ~20%
• Graded by size: Small (<5 mm) / Large (>5 mm) / with red wale marks (high bleeding risk)

• Less common; more difficult to treat
• Sarin classification: GOV1, GOV2, IGV1, IGV2

7.2 Ascites

• Most common decompensation event (occurs in ~50% within 10 years)
• Diagnostic paracentesis: serum-ascites albumin gradient (SAAG) ≥ 1.1 g/dL confirms portal hypertension
• Spontaneous bacterial peritonitis (SBP): PMN >250/mm³ in ascitic fluid; organisms: E. coli, Klebsiella, S. pneumoniae; treat with 3rd generation cephalosporins + albumin infusion (1.5 g/kg day 1; 1 g/kg day 3)
• Refractory ascites: Non-responsive to maximal diuretics (spironolactone 400 mg + furosemide 160 mg/day)

7.3 Hepatic Encephalopathy (HE)

Sleisenger & Fordtran, Ch. 94: "HE develops in 50%-70% of patients with cirrhosis; 1- and 3-year survival rates of 42% and 23%, respectively, without liver transplantation."

• Ammonia (principal neurotoxin) produced by colonic bacteria and gut epithelial glutaminase
• Ammonia bypasses liver via portosystemic shunts → crosses blood-brain barrier
• Astrocytes swell (Alzheimer type II astrocytosis) → cerebral edema
• Additional factors: inflammatory cytokines, benzodiazepine-like GABA agonists, zinc deficiency, manganese

• Portein excess, Renal failure, Electrolyte imbalance (hypokalemia), Constipation
• Infection (SBP), Paracetamol/drugs, Itching drugs (sedatives), Transjugular shunt (TIPS), Alcohol, Thrombosis (portal vein), Intestinal bleed, Opiates, Neurotoxins

7.4 Hepatorenal Syndrome (HRS)

• Functional renal failure in advanced cirrhosis + ascites
• Pathogenesis: extreme splanchnic vasodilation → renal hypoperfusion → renal vasoconstriction
• HRS Type 1 (now HRS-AKI): Rapid deterioration; creatinine doubles to >2.5 mg/dL in <2 weeks; median survival 2-4 weeks without treatment
• HRS Type 2 (now HRS-CKD): Slower deterioration; refractory ascites; median survival 6 months
• Diagnosis: Exclude other causes of AKI; no improvement after 48h albumin challenge (1 g/kg/day × 2 days)

7.5 Hepatopulmonary Syndrome (HPS)

• Pulmonary vascular dilation → intrapulmonary shunting
• Clinical: dyspnea, platypnea (worse sitting up), orthodeoxia (SpO2 drops on standing)
• Diagnosis: positive bubble echocardiogram (microbubbles in left heart after 3-8 beats)
• PaO2 <80 mmHg qualifies for liver transplant listing

7.6 Spontaneous Bacterial Peritonitis (SBP)

• Bacterial translocation from gut → peritoneal fluid
• Presentation: fever, abdominal pain, worsening HE, rising creatinine
• Diagnosis: ascitic fluid PMN >250/mm³
• 30-day mortality if untreated: ~80%

7.7 Hepatocellular Carcinoma (HCC)

• Occurs in 1-4% of cirrhotics per year
• Risk highest: HCV cirrhosis > HBV > ALD > MASLD
• Surveillance: 6-monthly ultrasound ± AFP in all cirrhotics
• Diagnosis: LI-RADS criteria on multiphasic CT/MRI (arterial enhancement + portal washout)

7.8 Other Complications

• Coagulopathy: Low production of factors II, V, VII, IX, X + thrombocytopenia; paradoxically, also hypercoagulable (low protein C, S)
• Bone disease (hepatic osteodystrophy): Osteoporosis >> osteomalacia; cholestatic disease (PBC, PSC) at highest risk
• Cirrhotic cardiomyopathy: Impaired contractile response to stress; prolonged QT interval; diastolic dysfunction
• Hyponatremia (dilutional): Due to ADH excess (non-osmotic stimulation)
• Malnutrition / sarcopenia: Near-universal in advanced CLD; independently predicts mortality

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8. PHARMACOLOGY

8.1 Drugs to Treat Underlying Disease

8.2 Drugs to Manage Portal Hypertension / Varices

8.3 Drugs to Manage Ascites and HRS

8.4 Drugs to Manage Hepatic Encephalopathy

Harrison's 22nd Ed.: "The mainstay of therapy is elimination of the precipitating event and excess ammonia. LT generally reverses HE."

8.5 Drugs to Manage Spontaneous Bacterial Peritonitis

• Treatment: Cefotaxime 2g IV 8-hourly × 5 days (or ceftriaxone); always add albumin 1.5 g/kg day 1 + 1.0 g/kg day 3 (reduces HRS risk and mortality)
• Secondary prophylaxis (lifelong): Norfloxacin 400 mg/day OR ciprofloxacin 500 mg/day OR rifaximin
• Primary prophylaxis (ascitic protein <1.5 g/dL + renal/hepatic dysfunction): Norfloxacin 400 mg/day

8.6 Drugs Contraindicated / Used with Caution in CLD

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9. MANAGEMENT PRINCIPLES

9.1 General Approach

1. Identify and treat the underlying cause - most important step; can arrest or reverse fibrosis
2. Assess disease severity (Child-Pugh, MELD-Na)
3. Screen for and treat complications
4. Nutritional support - target 35-40 kcal/kg/day; 1.2-1.5 g protein/kg/day; no protein restriction (outdated)
5. Avoid hepatotoxic agents (alcohol, NSAIDs, herbal remedies)
6. Vaccinate: HAV, HBV, pneumococcal, influenza, COVID-19
7. Consider liver transplant in appropriate candidates

9.2 Treatment of Varices

• Non-selective β-blockers: Propranolol 20-40 mg BD titrated to heart rate 55-60 bpm OR carvedilol 6.25-12.5 mg/day
• Endoscopic band ligation (EBL): Equally effective; used if β-blockers not tolerated
• Not recommended: prophylactic sclerotherapy, portosystemic shunts

1. Airway protection (intubation if GCS falling)
2. Resuscitation: target Hb 70-80 g/L (restrictive transfusion reduces portal pressure)
3. Pharmacological: Terlipressin 2 mg IV stat then 1-2 mg 4-6-hourly × 5 days OR octreotide 50 µg bolus + infusion
4. Antibiotics: Ceftriaxone 1g/day × 7 days (reduces mortality, SBP, rebleeding)
5. Endoscopy: Within 12 hours; EBL preferred over sclerotherapy
6. Sengstaken-Blakemore tube: Bridge to definitive treatment if bleeding uncontrolled
7. TIPS (Transjugular Intrahepatic Portosystemic Shunt): For refractory/recurrent bleeding; also rescue therapy if above fails; reduces portal pressure by creating an intrahepatic shunt

• EBL every 2-4 weeks until varices obliterated + ongoing β-blocker therapy

9.3 Management of Ascites

1. Sodium restriction: 2g (88 mmol) per day (not severe fluid restriction unless Na+ <125)
2. Spironolactone: Start 100 mg OD, titrate to 400 mg max
3. Add furosemide: 40 mg OD (maintain 100:40 ratio with spironolactone)
4. Therapeutic paracentesis (LVP): >5L with albumin replacement (8g per litre removed)
5. TIPS: For refractory ascites not responding to maximal diuretics
6. Peritoneovenous shunt (LeVeen): Rarely used; high complication rate
7. Liver transplant: Definitive treatment

9.4 Management of Hepatic Encephalopathy

1. Identify and treat precipitant (infection, bleeding, constipation, electrolytes)
2. Lactulose titrated to 2-3 soft stools per day
3. Rifaximin 550 mg BD for secondary prevention
4. Nutritional support - do NOT restrict protein
5. Zinc supplementation if deficient
6. For refractory HE → consider TIPS reduction or occlusion; liver transplant evaluation

9.5 Management of HRS

1. Stop nephrotoxic drugs, remove precipitants, avoid diuretics
2. Volume challenge: Albumin 1 g/kg/day × 2 days (up to 100 g/day)
3. Terlipressin + albumin (0.5-1 mg IV 4-6 hourly, titrate to 2 mg if creatinine not falling)
4. Continue until creatinine <133 µmol/L or maximum 14 days
5. Bridge to liver transplant - most effective definitive treatment

9.6 HCC Treatment (Barcelona Clinic Liver Cancer - BCLC Staging)

9.7 Liver Transplantation

• MELD-Na ≥ 15 (benefit from transplant exceeds waiting-list mortality)
• Recurrent/refractory ascites
• HRS
• Recurrent variceal bleeding despite all measures
• Grade III-IV HE refractory to treatment
• HPS (PaO2 <60 mmHg)
• HCC within Milan criteria (single ≤5 cm or ≤3 nodules each ≤3 cm)

• Extrahepatic malignancy (outside Milan for HCC)
• Active alcohol/substance use (usually 6 months abstinence required)
• Uncontrolled sepsis
• Severe cardiopulmonary disease

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10. FOLLOW-UP

10.1 Compensated Cirrhosis

• 6-monthly ultrasound + AFP for HCC surveillance
• Upper GI endoscopy: Every 2-3 years if no varices; annually if small varices
• 6-monthly clinical review: LFTs, FBC, electrolytes, PT, renal function
• Bone densitometry (DEXA scan): Annually (especially PBC, PSC, ALD)
• Dietitian review: Nutritional status; muscle mass assessment

10.2 Decompensated Cirrhosis

• Monthly blood tests: LFTs, FBC, U&E, coagulation, AFP
• Ascitic tap if new / increasing ascites to exclude SBP
• MELD-Na reassessment at each visit
• Transplant listing review - update MELD, assess criteria
• Rifaximin - continue indefinitely post-HE
• Lactulose - monitor response
• Ongoing variceal surveillance even post-EBL

10.3 After Liver Transplant

• Immunosuppression: Tacrolimus-based (calcineurin inhibitor) ± mycophenolate ± prednisolone
• Monitor: Tacrolimus levels, renal function, LFTs
• HCC recurrence surveillance: CT/MRI 3-6 monthly
• HCV: DAA treatment if recurrence (SVR12 >95%)
• HBV prophylaxis: Lamivudine + hepatitis B immunoglobulin (HBIG) to prevent graft reinfection
• Metabolic complications: Hypertension, diabetes, dyslipidemia, renal impairment (tacrolimus nephrotoxicity)
• Skin cancer screening: Annual (immunosuppression increases risk 100-fold)

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11. PROGNOSIS

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KEY CLINICAL MEMORY AIDS

• Alcohol, Autoimmune
• Bviral (Hepatitis B)
• Cviral (Hepatitis C)
• Drugs, Dysmetabolic (MASLD)
• Endocrine / metabolic
• Wilson's, Wegener's (rare)
• Hemochromatosis
• Alpha-1-antitrypsin deficiency

• Bilirubin, Albumin, Time (PT), Ascites, Encephalopathy (5 parameters)

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REFERENCES

1. Kumar & Clark's Clinical Medicine, 11th Edition - Forrest et al.; Elsevier 2023 (standard reference throughout)
2. Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw Hill) - Kasper et al. - Chapters on Cirrhosis, Hepatic Encephalopathy, HRS, Viral Hepatitis, DAA therapy
3. Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 11th Edition - Feldman et al.; Elsevier - Chapters 74, 92, 93, 94 (Portal Hypertension, Ascites, HE, HRS)
4. Robbins & Kumar Pathologic Basis of Disease, 10th Edition - Kumar et al.; Elsevier - Chapter on Liver and Biliary Tract
5. Bailey and Love's Short Practice of Surgery, 28th Edition - Chapter 69 (Liver disease, CLD, investigation of LFTs)
6. Medical Physiology, 3rd Edition - Boron & Boulpaep; Elsevier - Chapter 24 (Portal Hypertension, Hepatic Encephalopathy)
7. Yamada's Textbook of Gastroenterology, 7th Edition - Chapter on Hepatic Fibrosis and HSC activation
8. Goldman-Cecil Medicine, International Edition - Chapter on Liver Disease, Cryptogenic CLD
9. EASL Clinical Practice Guidelines - Decompensated Cirrhosis (2018, updated 2023); Management of Ascites and HRS; Primary Prophylaxis of Variceal Bleeding
10. AASLD Practice Guidelines - Portal Hypertensive Bleeding (2022); Ascites Management; HCC (2023)
11. Recent PubMed evidence: Pharmacologic therapies for MASLD - Network meta-analysis (PMID 40211469, Diabetes Obes Metab 2025); Global prevalence of steatotic liver disease - meta-analysis (PMID 40204206, Clin Gastroenterol Hepatol 2025)

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1. Definition - CLD vs. cirrhosis distinction; >6 months, progressive
2. Etiology - Full table of common (ALD, HBV, HCV, MASLD, AIH) and rare causes (hemochromatosis, Wilson's, A1AT, PSC, PBC, drugs, cardiac)
3. Pathology - Macro (micro/macronodular), micro (METAVIR F0-F4), cellular mechanisms via hepatic stellate cells (HSC), TGF-β1, PDGF, fibrosis reversibility
4. Physiology/Pathophysiology - Portal hypertension mechanisms (fixed + dynamic resistance; hyperdynamic circulation; peripheral vasodilation theory); RAAS/SNS/ADH activation; ascites formation
5. Clinical Features - Compensated vs. decompensated; full sign table (spider naevi, palmar erythema, caput medusae, etc.); endocrine signs; ABCDE of decompensation
6. Investigations - LFTs (with ranges), fibrosis scoring (FIB-4, APRI, Fibroscan), Child-Pugh table, MELD score formula
7. Complications - Varices, ascites/SBP, hepatic encephalopathy (West Haven grading + precipitants), HRS (Type 1/2), HPS, HCC, coagulopathy, bone disease, cirrhotic cardiomyopathy
8. Pharmacology - Disease-specific drugs (DAAs, entecavir, UDCA, venesection), variceal drugs (terlipressin, β-blockers, octreotide), ascites/HRS drugs (spironolactone, furosemide, albumin, terlipressin), HE drugs (lactulose, rifaximin, LOLA, BCAAs), SBP treatment/prophylaxis, contraindicated drugs
9. Management - Step-wise protocols for varices (primary prophylaxis → acute bleed → secondary), ascites, HE, HRS; BCLC staging for HCC; Milan criteria for transplant
10. Follow-up - Compensated vs. decompensated schedules; post-transplant monitoring
11. Prognosis - Survival tables by Child-Pugh, MELD, and individual complications