1. Jaundice

1.1 Epidemiology

• Global occurrence: Jaundice is a common clinical finding worldwide. It can affect all ages from neonates to the elderly, though causes differ by age group and setting.
• Significance: Jaundice often prompts urgent evaluation due to its association with potentially serious liver, biliary, or haemolytic disorders.

1.2 Aetiology

Broadly, jaundice results from an imbalance in bilirubin production, metabolism (conjugation), or excretion.

1.2.1 Classification by Pathophysiology

1. Pre-Hepatic (Unconjugated Hyperbilirubinaemia)
   • Excess production of bilirubin (e.g., haemolysis, ineffective erythropoiesis).
   • Reduced hepatic uptake of unconjugated bilirubin (drugs such as rifampicin).
   • Impaired conjugation in the liver (e.g., Gilbert’s syndrome, Crigler–Najjar syndrome).
2. Hepatocellular
   • Hepatocyte dysfunction leading to a mix of unconjugated and conjugated bilirubin elevation (viral hepatitis, alcoholic hepatitis, cirrhosis, drug-induced liver injury).
3. Cholestatic or Obstructive (Conjugated Hyperbilirubinaemia)
   • Intrahepatic cholestasis (e.g., primary biliary cholangitis, certain drugs).
   • Extrahepatic obstruction (e.g., gallstones in the common bile duct, cholangiocarcinoma, pancreatic head cancer).

1.2.2 Classification by Type of Bilirubin

• Unconjugated (Indirect) Bilirubin
  • Overproduction (haemolysis).
  • Reduced hepatic uptake.
  • Impaired conjugation (Gilbert’s, Crigler–Najjar).
• Conjugated (Direct) Bilirubin
  • Hepatocellular damage (hepatitis, toxins).
  • Cholestatic/obstructive processes (stones, strictures, tumours).

1.3 Pathophysiology

1.3.1 Normal Bilirubin Metabolism

1. Production: Senescent red cells are broken down by reticuloendothelial macrophages, releasing haem. The haem moiety is converted into protoporphyrin and then to unconjugated bilirubin (UCB).
2. Transport: UCB is not water-soluble; it binds albumin for transport to the liver.
3. Conjugation: In hepatocytes, the enzyme uridine-diphosphoglucuronate glucuronosyltransferase (UGT) conjugates UCB → conjugated bilirubin (CB).
4. Excretion: CB is secreted into bile canaliculi → stored in the gallbladder → delivered to the small intestine.
5. Conversion: Intestinal bacteria convert CB → urobilinogen. Some is reabsorbed (enterohepatic circulation) and excreted renally (urobilin: yellow urine); some is converted to stercobilin (brown stool).

1.3.2 Mechanisms Causing Jaundice

• Pre-hepatic: Increased bilirubin load (haemolysis) → elevated UCB.
• Hepatic: Impaired uptake, conjugation, or excretion in liver pathology → mixed or predominantly conjugated hyperbilirubinaemia.
• Post-hepatic: Obstruction in bile ducts → conjugated bilirubin reflux into blood; absent excretion into gut → pale stools, dark urine.

1.4 Signs and Symptoms / Clinical Features

• Yellowish discolouration of sclera, mucous membranes, and skin (earliest sign is scleral icterus).
• Unconjugated hyperbilirubinaemia: No bilirubin in urine (as unconjugated bilirubin is water-insoluble).
• Conjugated hyperbilirubinaemia: Dark (‘tea-coloured’) urine, pale/clay-coloured stools, potential pruritus if cholestatic.
• Associated clues:
  • Pruritus in cholestatic/obstructive causes.
  • Right upper quadrant pain if gallstones or acute cholangitis.
  • Fever in cholangitis or hepatitis.
  • Spider naevi, palmar erythema (chronic liver disease).
  • Splenomegaly (portal hypertension, haemolysis).
  • Signs of haemolysis (e.g., pallor, gallstones).
  • Red flags: Weight loss, mass on examination, suggest malignancy.

1.5 Complications

Untreated or severe jaundice may lead to:

1. Progression of underlying liver disease (e.g., acute liver failure, cirrhosis).
2. Cholestatic pruritus → skin excoriations, secondary infection.
3. Fat malabsorption if prolonged cholestasis → deficiency of fat-soluble vitamins (A, D, E, K).
4. Hepatic encephalopathy if severe hepatic dysfunction.
5. Renal impairment (hepatorenal syndrome in advanced disease).
6. Bleeding (coagulopathy from decreased vitamin K absorption in cholestasis).

1.6 Immediate Management

1.6.1 General Approach

• History and Examination: Enquire about risk factors (alcohol, drugs, foreign travel, family history, high-risk sexual behaviour, IV drug use, transfusions). Examine for stigmata of chronic liver disease, scratch marks from pruritus, organomegaly.
• Investigations (initial):
  1. Liver function tests (LFTs): Bilirubin (total, direct), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), albumin, prothrombin time (PT/INR).
  2. Full blood count: Haemolysis clues (Hb, reticulocyte count).
  3. Coagulation profile: PT, INR.
  4. Imaging: Ultrasound of liver/biliary tree (bile duct dilation, gallstones, structural lesions).
  5. Viral serology: If suspect acute hepatitis.
  6. Autoimmune markers: If suspect autoimmune hepatitis or primary biliary cholangitis.
  7. Detailed medication history: Potential drug-induced liver injury.

1.6.2 Specific Interventions

• Cholestatic/obstructive jaundice:
  • If cholangitis is suspected, intravenous antibiotics and potential urgent endoscopic or radiological drainage.
  • Endoscopic Retrograde Cholangiopancreatography (ERCP) or MRCP if ductal obstruction is suspected.
• Haemolysis:
  • Treat underlying cause (e.g., transfusion if severe anaemia, steroid therapy for autoimmune haemolysis).
• Severe hepatic dysfunction:
  • Supportive management with fluid balance, avoidance of hepatotoxic drugs, urgent referral to a hepatologist if acute liver failure is likely.

1.7 Long-Term Management

1. Address Underlying Cause
   • Hepatitis therapies (antivirals for chronic viral hepatitis).
   • Stopping hepatotoxic drugs.
   • Cholecystectomy for recurrent gallstones.
2. Nutritional Support
   • Adequate protein intake, vitamin supplementation, especially fat-soluble vitamins in cholestatic disease.
3. Monitoring
   • Ongoing LFTs, imaging if needed, tumour markers (AFP for HCC, CA 19-9 for cholangiocarcinoma in some contexts).
   • Screening for complications (portal hypertension, varices, encephalopathy).
4. Lifestyle Factors
   • Alcohol cessation if relevant.
   • Weight management in non-alcoholic fatty liver disease.

1.8 Practical Table: Common Aetiologies of Jaundice

2. Alcoholic Liver Disease

2.1 Epidemiology

1. Global impact
   • Alcohol misuse is a significant public health issue worldwide, with an estimated 140 million people suffering from alcohol dependence.
   • Alcoholic liver disease is among the most common causes of cirrhosis in the West.
2. Demographic patterns
   • Male-to-female ratio: Around 11:4 in ALD.
   • Female susceptibility: Women have a lower threshold for alcohol-induced damage, partly due to differences in body water composition and hormone influences.
3. Disease spectrum
   • ALD covers fatty liver (steatosis), alcoholic hepatitis, and cirrhosis. Patients may present with overlapping or sequential features.

2.2 Aetiology

1. Quantity and duration of alcohol ingestion are the paramount risk factors.
2. Nutritional status:
   • Poor diet can exacerbate alcohol-induced damage.
3. Genetic predisposition:
   • Polymorphisms in aldehyde dehydrogenase, alcohol dehydrogenase, and CYP450 enzymes affect alcohol metabolism and susceptibility to liver injury.
4. Oxidative stress is central to liver injury from alcohol, influenced by:
   • Mitochondrial damage and reduced antioxidants in hepatocytes.
   • Inflammatory cytokines, hormonal imbalances, and adipokines.

2.3 Pathophysiology

Alcoholic liver disease typically evolves through three key histopathological stages, although these may overlap clinically:

1. Fatty Liver (Steatosis)
   • Macrovesicular steatosis: Large fat droplets within hepatocytes displace the nucleus.
   • Microvesicular steatosis: More associated with mitochondrial dysfunction.
   • This stage is reversible with abstinence from alcohol.
2. Alcoholic Hepatitis
   • Involves hepatic inflammation and necrosis on top of fatty liver changes.
   • Hepatocellular ‘balloon degeneration’ – the cytoplasm becomes swollen and granular.
   • Mallory (alcoholic) hyaline bodies: Tangled aggregates of cytokeratin intermediate filaments in hepatocytes.
   • Inflammatory infiltration (neutrophils) and necrosis.
   • May present acutely with significant morbidity and mortality.
3. Cirrhosis
   • Advanced, irreversible scarring of the liver with nodular regeneration.
   • Typically micronodular in ongoing alcohol misuse, but macronodular changes can appear if there is abstinence and partial healing.
   • Portal hypertension and risk of variceal bleeding, hepatic decompensation, and hepatocellular carcinoma.

Zieve’s Syndrome

• A particular combination of alcoholic hepatitis, haemolysis, jaundice, abdominal pain, and hyperlipidaemia.
• Considered a distinct clinical entity separate from the usual steatosis→hepatitis→cirrhosis progression.

2.4 Signs and Symptoms / Clinical Features

2.4.1 Fatty Liver (Steatosis)

• Often asymptomatic.
• Possible mild RUQ discomfort, anorexia, nausea (often after heavy, prolonged alcohol intake).

2.4.2 Alcoholic Hepatitis

• Spectrum: mild, moderate, or severe.
• Mild–moderate:
  • 2–3 weeks of fatigue, anorexia, nausea, weight loss.
  • Mild fever, jaundice, tender hepatomegaly.
  • Malnutrition is common.
• Severe:
  • Follows significant binge or prolonged heavy ingestion, often combined with poor nutrition.
  • Marked jaundice, high fever, ascites, encephalopathy (in advanced cases).
  • Signs of hyperdynamic circulation (e.g., pronounced palmar erythema, spider naevi).
  • Hypoglycaemia, coagulopathy (INR elevation) common.
  • GI bleeding risk from associated gastritis or coagulopathy.

2.4.3 Cirrhosis

• Shared features with other cirrhosis aetiologies (see other cirrhosis references).
• Additional alcohol-related manifestations:
  1. Neurological: Peripheral neuropathy, Wernicke’s encephalopathy, Korsakoff’s psychosis.
  2. Endocrine: Hypogonadism, feminisation in men (testicular atrophy, gynaecomastia).

2.5 Complications

1. Acute complications
   • Fulminant hepatic failure from severe alcoholic hepatitis.
   • Variceal haemorrhage if portal hypertension develops.
   • Spontaneous bacterial peritonitis in advanced cirrhosis with ascites.
   • Renal failure (hepatorenal syndrome).
2. Chronic complications
   • Cirrhosis with associated portal hypertension (ascites, varices, splenomegaly).
   • Hepatocellular carcinoma: ~10% incidence in stable cirrhotics, especially after partial recovery with macronodular changes.
   • Malnutrition, vitamin deficiencies (B vitamins, folate).

2.6 Immediate Management

1. Recognition and stabilisation
   • Evaluate severity of acute alcoholic hepatitis (clinical signs: encephalopathy, coagulopathy, jaundice).
   • Treat potential GI bleeding, infection, or acute-on-chronic hepatic decompensation.
2. Hospital admission
   • For severe alcoholic hepatitis (e.g., encephalopathy, marked coagulopathy, deep jaundice).
   • Provide intravenous fluids, correct electrolyte imbalances, manage or prevent withdrawal (e.g., benzodiazepines).
   • Nutritional support (monitor glucose carefully, especially if poor intake).
   • High-dose vitamins (especially thiamine) to prevent Wernicke’s encephalopathy; B-vitamin supplementation in the first days.
3. Assess severity
   • Maddrey’s discriminant function (DF):DF=(4.6×(PTpatient−PTcontrol))+bilirubin (mg/dl)DF=(4.6×(PTpatient​−PTcontrol​))+bilirubin (mg/dl)
     • A value >32 indicates severe disease and potential benefit from corticosteroids.
4. Pharmacotherapy
   • Corticosteroids (e.g., prednisolone) in severe alcoholic hepatitis, if no contraindications.
   • Pentoxifylline may be considered if steroids are contraindicated, though the benefit is uncertain.

2.7 Long-Term Management

• Absolute Abstinence
  • Cornerstone therapy to prevent progression or allow partial reversibility in earlier stages.
  • Ongoing psychosocial support: consider referral to addiction services, self-help groups (e.g., Alcoholics Anonymous), or cognitive behavioural therapy.
• Nutritional Support
  • High-calorie diet, adequate protein (contrary to older low-protein regimens).
  • Regular vitamin supplementation (especially B vitamins, folate).
  • Monitor for deficiencies (magnesium, phosphate).
• Specific Therapies
  • Steroids or pentoxifylline in selected patients with severe acute alcoholic hepatitis.
  • Monitoring for complications: varices, ascites, encephalopathy.
• Liver transplantation:
  • Option for end-stage disease with 6 months of documented abstinence, robust social support, and psychological stability.
  • 50% risk of relapse post-transplant if insufficient social/psychological support.
• Prognosis
  • Up to 40% 5-year survival in cirrhotic patients who continue drinking vs 60–70% in abstainers.
  • Poor prognostic indicators: encephalopathy, low albumin, high INR, persistent jaundice, elevated creatinine (hepatorenal risk).

3. Non‐Alcoholic Fatty Liver Disease (NAFLD)

3.1 Epidemiology

• Prevalence and Demographics:
  • NAFLD is the most common liver disorder in Western countries and now the leading cause of chronic liver disease worldwide.
  • Estimated prevalence in the general population is approximately 30%.
  • Affects all age groups, including children.
  • Equal sex distribution.
  • In individuals with normal weight, the prevalence is around 10–15%, but in obese individuals it may be as high as 80%.
• Association with Metabolic Syndrome:
  • NAFLD is considered the hepatic manifestation of metabolic syndrome.
  • It is commonly associated with obesity, insulin resistance, type 2 diabetes mellitus, dyslipidaemia, and hypertension.
• Subcategories:
  • Simple Steatosis (Fatty Liver): Fat accumulation in hepatocytes without significant inflammation.
  • Non‐Alcoholic Steatohepatitis (NASH): Fat accumulation with inflammation and hepatocyte injury, which may progress to fibrosis and cirrhosis.
  • Fibrosis and Cirrhosis: Advanced stages that result from persistent inflammation in NASH.

3.2 Aetiology and Risk Factors

• Primary (Idiopathic) NAFLD:
  • Occurs in the absence of significant alcohol intake or other identifiable causes of liver disease.
• Secondary Causes:
  • Rare disorders of lipid metabolism and insulin resistance (e.g. abetalipoproteinaemia, lipoatrophic diabetes, Mauriac syndrome, Weber–Christian syndrome).
  • Iatrogenic factors, including:
    • Parenteral nutrition.
    • Acute starvation.
    • Intravenous glucose therapy.
    • Abdominal surgery.
    • Drugs (e.g. amiodarone, tamoxifen, synthetic oestrogens, glucocorticoids).
• Key Risk Factors:
  • Obesity: Central (abdominal) obesity is particularly significant.
  • Insulin Resistance and Type 2 Diabetes Mellitus: Hyperinsulinaemia increases hepatic free fatty acid uptake.
  • Dyslipidaemia and Hypertension: Often part of the metabolic syndrome.
  • Lifestyle Factors: Sedentary lifestyle and a diet high in saturated fats and low in fibre.

3.3 Pathophysiology

NAFLD is widely explained by a “two‐hit” hypothesis:

3.3.1 First Hit – Hepatic Steatosis

• Insulin Resistance:
  • Resistance in muscle and adipose tissue leads to compensatory hyperinsulinaemia.
  • The liver remains sensitive to insulin, resulting in increased uptake of free fatty acids (FFAs).
• Triglyceride Synthesis and Fat Accumulation:
  • FFAs are esterified into triglycerides, which accumulate within hepatocytes as macrovesicular fat droplets.
  • This accumulation forms the basis of simple steatosis.
• Vicious Cycle:
  • Excess FFAs further impair insulin signalling, perpetuating fat deposition.

3.3.2 Second Hit – Progression to NASH and Fibrosis

• Oxidative Stress:
  • Enhanced FFA oxidation in mitochondria generates reactive oxygen species (ROS) leading to cellular damage.
• Inflammatory Response:
  • ROS and lipid peroxidation products stimulate the release of pro-inflammatory cytokines (e.g. tumour necrosis factor‑α [TNF‑α]).
• Mitochondrial Dysfunction:
  • Pre-existing or acquired mitochondrial abnormalities further contribute to hepatocellular injury.
• Activation of Fibrogenic Pathways:
  • Cytokines and other mediators (e.g. defects in peroxisome proliferator‑activated receptors [PPARs] and leptin resistance) promote stellate cell activation.
  • Activated stellate cells deposit collagen, leading to fibrosis and, eventually, cirrhosis.
• Additional Factors:
  • The “second hit” may also include gut-derived endotoxins and genetic predispositions that exacerbate inflammation and fibrosis.

3.4 Clinical Features

• Asymptomatic Presentation:
  • The majority of patients are asymptomatic, with NAFLD often discovered incidentally during routine blood tests or imaging.
• When Symptomatic:
  • Right Upper Quadrant Discomfort/Pain: Often vague and non-specific.
  • Fatigue and Malaise: Generalised tiredness is common.
  • Hepatomegaly: The liver may be enlarged on physical examination.
• Association with Metabolic Syndrome:
  • Patients frequently exhibit signs of obesity, hypertension, and other features of metabolic syndrome (e.g. acanthosis nigricans).
• Differentiation from Alcoholic Liver Disease:
  • A detailed alcohol history is essential; NAFLD is considered when alcohol consumption is below established thresholds (typically <18 units/week for men and <9 units/week for women).

3.5 Investigations

• Laboratory Tests:
  • Liver Function Tests (LFTs):
    • Mild to moderately elevated transaminases (ALT typically higher than AST, in contrast to alcoholic liver disease).
    • Fluctuating levels over time.
  • Metabolic Profile:
    • Fasting blood sugars, lipid profile, and markers of insulin resistance.
• Imaging:
  • Ultrasound:
    • A hyperechoic (bright) liver on ultrasound is suggestive of fatty infiltration, although sensitivity and specificity are limited.
  • Elastography or FibroScan:
    • Non‑invasive method to assess liver stiffness and approximate degree of fibrosis.
• Liver Biopsy:
  • Considered the gold standard for distinguishing simple steatosis from NASH.
  • Provides histological details on inflammation, ballooning degeneration, fibrosis, and steatosis.
• NAFLD Fibrosis Score:
  • A calculated score using the following parameters:
    • Age.
    • Presence of hyperglycaemia.
    • Body Mass Index (BMI).
    • Platelet count.
    • Serum albumin.
    • AST/ALT ratio.
  • This score aids in assessing the likelihood of significant fibrosis and may help to avoid biopsy in some cases.

3.6 Management

3.6.1 Immediate Management

• Diagnosis Confirmation:
  • Exclude significant alcohol consumption and other causes of liver disease.
  • Establish the diagnosis using a combination of laboratory tests and imaging.
• Supportive Measures:
  • Advise on lifestyle modification as soon as NAFLD is suspected.
  • Initiate basic counselling on diet and exercise.

3.6.2 Long‑Term Management

• Lifestyle Modification:
  • Weight Loss:
    • Aim for a moderate, sustained weight loss; even a 5–10% reduction in body weight can significantly improve hepatic steatosis.
    • Encourage increased physical activity.
    • Consider referral to a dietician.
  • Dietary Recommendations:
    • Increase dietary fibre (fruits, vegetables, whole grains).
    • Reduce intake of red and processed meats and saturated fats.
    • Limit refined sugars.
• Management of Metabolic Syndrome Components:
  • Glycaemic Control:
    • Optimise blood sugar levels in diabetic patients (target HbA1c <7%).
  • Lipid Management:
    • Address dyslipidaemia using lifestyle and pharmacological interventions.
  • Blood Pressure:
    • Control hypertension to lower cardiovascular risk.
• Pharmacological Therapy (When Indicated):
  • Antioxidants:
    • Vitamin E (800 IU/day) may improve histology in patients with NASH; note that higher doses may be associated with adverse outcomes.
  • Insulin Sensitisers:
    • Pioglitazone has shown benefits in improving inflammation and fibrosis, particularly in patients with concomitant diabetes.
  • Aspirin:
    • Daily low-dose aspirin might reduce the risk of progression from simple steatosis to NASH based on observational studies.
• Regular Monitoring and Follow-Up:
  • Liver Enzymes and Metabolic Parameters:
    • Regular LFTs, fasting blood glucose, and lipid profiles.
  • Assessment for Fibrosis:
    • Use non‑invasive fibrosis assessments (elastography) or the NAFLD Fibrosis Score.
  • Screening for Hepatocellular Carcinoma (HCC):
    • In patients who have developed cirrhosis, screen for HCC with ultrasound and serum alpha-fetoprotein (AFP) every six months.

3.7 Prognosis and Natural History

• Disease Progression:
  • The majority of patients with simple steatosis do not progress to NASH.
  • Estimates for progression from NASH to cirrhosis range between 8% and 15%.
  • Once cirrhosis develops, the risk of complications (such as portal hypertension and HCC) increases.
• Mortality:
  • Patients with NAFLD have a slightly higher mortality rate than the general population, largely due to cardiovascular events.
• Variability:
  • Fibrosis progression in NASH is heterogeneous:
    • Approximately one-third of patients experience progression,
    • One-third remain stable,
    • One-third show regression of fibrosis.

4. Viral Hepatitides

4.1 Hepatitis A

4.1.1 Epidemiology

• Global Distribution: Hepatitis A occurs worldwide with higher incidence in regions with poor sanitation.
• Outbreaks in Developed Countries: Frequently associated with daycare centres, sewage‐contaminated shellfish, men who have sex with men, and intravenous drug users.
• Rare Transmission: Blood transfusion transmission is very rarely reported.

4.1.2 Aetiology

• Virus Characteristics: The hepatitis A virus (HAV) is highly stable, resisting substantial heat, drying, low pH, and detergents.
• Transmission: Spread primarily via the faecal–oral route. The virus survives in foods and water and withstands the acidic environment of the stomach.
• Vaccine Development: Advances in cell‐line virus culture have led to the development of effective inactivated vaccines.

4.1.3 Pathophysiology

• Hepatocellular Injury: The liver damage is not due to direct viral cytotoxicity but rather the host’s immune response. The virus interferes with normal interferon (IFN)-β synthesis, prolonging the incubation phase.
• Immune Response: When hepatocellular injury begins, HLA-restricted, virus-specific cytotoxic CD8+ T cells secrete IFN-γ, recruiting additional inflammatory cells and contributing to liver damage.
• Antibody Production: Neutralising antibodies develop concurrently with the onset of liver injury and are critical for protective immunity.

4.1.4 Clinical Features

• Incubation Period: 15–50 days (average 28–30 days).
• Symptoms in Adults: Often present with an acute febrile illness, jaundice, anorexia, nausea, abdominal discomfort, malaise, and dark urine.
• Viral Shedding: Occurs extensively during the incubation phase and continues for 1–3 weeks after symptom onset in adults (longer in young children).
• Age-Related Presentation: Infants and preschool children are frequently asymptomatic or only mildly affected; symptoms tend to be more severe in adults.
• Rare Complications: Fulminant hepatitis is rare; chronic carrier states do not occur, and permanent hepatic damage is extremely unlikely.

4.1.5 Investigations

• Serology:
  • IgM Anti-HAV: Indicates recent infection, developing 5–10 days after exposure and may persist for up to 6 months.
  • IgG Anti-HAV: Appears shortly after IgM and remains detectable for life, providing long-term immunity.
• Virus Culture: Not used routinely in diagnosis.

4.1.6 Management

• Supportive Care: Treatment is mainly symptomatic.
• Vaccination:
  • Active Immunisation: Inactivated hepatitis A vaccine is effective in preventing both infection and disease.
  • Post-Exposure Prophylaxis: Immunoglobulin may be used in outbreak settings if administered within 2 weeks of exposure.
• Targeted Vaccination: Recommended for high-risk groups (e.g. patients with chronic hepatitis B or C, travellers to endemic areas, employees in early childhood settings, healthcare workers, IV drug users).

4.1.7 Prognosis

• Self-Limiting: The vast majority of infections are self‐limiting.
• Mortality Rates: Approximately 4 deaths per 1000 cases in the general population, rising to 17.5 per 1000 in those aged over 50 and in patients with pre‐existing liver disease.

4.2 Hepatitis E

4.2.1 Epidemiology

• Outbreaks and Endemic Areas: Hepatitis E virus (HEV) causes epidemics primarily in South-East Asia, Northern Africa, and the Indian subcontinent.
• Population Affected: Initially studied epidemics (e.g. Delhi 1955–56) showed high attack rates with a notable impact on 15–40-year-olds; children are also susceptible.
• Pregnancy: A very high risk of fulminant liver failure is observed in pregnant women, especially in the third trimester.

4.2.2 Aetiology

• Virus Classification: HEV is the prototype virus of the Hepeviridae family.
• Transmission: Primarily spread by the faecal–oral route; food-borne infections are increasingly recognised. Vertical transmission (mother-to-child) occurs in up to 50% of cases.
• Zoonotic Reservoirs: Domestic animals (such as pigs) are recognised as important reservoirs.

4.2.3 Pathophysiology

• Primary Replication: The virus replicates in the intestinal tract and then reaches the liver via the portal vein, where it infects hepatocytes.
• Hepatocellular Injury: Damage is mediated by the host’s immune response rather than direct cytopathic effects.
• Acid Resistance: The virus withstands a wide range of pH levels, aiding its transmission through the gastrointestinal tract.

4.2.4 Clinical Features

• Incubation Period: 15–60 days (mean approximately 40 days).
• Phases of Illness:
  • Pre-Icteric Phase: Lasts 1–10 days with gastrointestinal symptoms such as epigastric pain, nausea, and vomiting.
  • Icteric Phase: Characterised by the abrupt onset of jaundice, dark urine, and clay-coloured stools; two-thirds of patients also experience arthralgia.
• Course of Illness: An uncomplicated infection typically lasts 12–15 days with complete recovery within 1 month.
• Special Populations: In pregnant women, the mortality rate is significantly higher.

4.2.5 Investigations

• HEV RNA: Can be detected in stool during the pre-icteric phase and declines as the disease progresses.
• Serology:
  • Anti-HEV IgM: Appears at symptom onset and is detectable for 2 weeks to 3 months.
  • Anti-HEV IgG: Increases after IgM and persists for several years in approximately 50% of patients.
• Detection Methods: Enzyme immunoassays (EIAs) and immunochromatography are the most convenient methods.

4.2.6 Management

• Supportive Care: Mainstay is supportive treatment; no specific antiviral therapy is currently recommended for otherwise healthy individuals.
• Prevention: Improving sanitation, provision of clean drinking water, and proper sewage disposal are critical in endemic areas.
• Vaccination: A vaccine is available in China, but it is not currently available in Europe.

4.2.7 Prognosis

• Self-Limiting Course: In most individuals, hepatitis E is self-limiting.
• Case Fatality Rate: Overall case fatality is around 4%, but it rises to approximately 20% in pregnant women, particularly in the later trimesters.

4.3 Hepatitis B

4.3.1 Epidemiology

• Global Impact: Hepatitis B virus (HBV) infects an estimated 400 million people worldwide.
• Mortality: HBV is responsible for about 1 million deaths annually due to complications such as hepatocellular carcinoma (HCC) and cirrhosis.
• Transmission: Risk factors include transfusion, IV drug use, sexual transmission, perinatal transmission, and healthcare-associated exposures.
• Genotypes: Eight genotypes (A–H) exist, each with a distinct geographical distribution and clinical significance.

4.3.2 Aetiology

• Virus Characteristics: HBV is a hepatotropic DNA virus belonging to the Hepadnaviridae family.
• Transmission Routes: Includes percutaneous exposure (e.g. needlestick injuries), sexual contact, perinatal transmission, and close contact in endemic areas.
• Risk Factors: Include IV drug use, unprotected sex, healthcare exposures, and high-risk populations such as haemodialysis patients.

4.3.3 Pathophysiology

• Viral Replication: HBV replicates non‐cytopathically within hepatocytes until the adaptive immune response is activated.
• Immune Response: Virus-specific CD4+ T helper cells facilitate the induction of CD8+ cytotoxic T cells, leading to hepatocyte injury. An influx of non-specific inflammatory cells further exacerbates the damage.
• Phases of Infection:
  1. Replicative Phase: High viral replication with minimal liver injury.
  2. Inflammatory Phase: Elevated aminotransferases and histological evidence of chronic hepatitis.
  3. Inactive Carrier Phase: Low or absent viral replication, normal liver enzymes, and minimal inflammation.
• Role of Genotype: Certain genotypes (e.g. genotype C) are associated with a higher risk of advanced liver disease and HCC.

4.3.4 Clinical Features

• Acute Phase:
  • Often asymptomatic or presents with mild fatigue.
  • Subclinical or overt icterus; rarely fulminant hepatitis.
• Chronic Phase:
  • Ranges from asymptomatic liver enzyme abnormalities to chronic hepatitis, cirrhosis, and HCC.
  • Many patients remain asymptomatic until advanced disease develops.
• Extrahepatic Manifestations: May include cryoglobulinaemia, membranous nephropathy, and polyarteritis nodosa.

4.3.5 Investigations

• Serological Markers:
  • HBsAg: Positive within 1–6 months post-exposure; persistence for more than 6 months defines chronic infection.
  • HBeAg: Indicates high infectivity; present during active replication.
  • Anti-HBc: Suggests past or ongoing infection.
  • Anti-HBs: Indicates immunity due to vaccination or recovery.
• HBV DNA: Quantified by PCR; correlates with viral load and guides treatment.
• Liver Function Tests: ALT, AST, bilirubin, albumin, and INR to assess liver damage.
• Imaging: Ultrasound and CT/MRI may be used for staging and detection of cirrhosis or HCC.
• Liver Biopsy: May be used to assess the degree of liver damage if indicated.

4.3.6 Management

Prevention

• Vaccination: Universal childhood vaccination and targeted vaccination for high-risk groups.
• Infection Control: Safe sex, safe needle practices, proper sterilisation of equipment.

Treatment Options

• Interferon-α:
  • Administered for a finite period.
  • Limited by injection route and adverse effects.
• Oral Nucleos(t)ide Analogues:
  • Examples include entecavir and tenofovir.
  • Better tolerated with long-term use, though resistance can develop.
• Monitoring:
  • Regular assessment of HBV DNA, liver enzymes, and imaging for cirrhosis/HCC.
  • Treatment decisions are guided by viral load, HBeAg status, and liver histology.

4.3.7 Prognosis

• Acute Infection: 95% of adults clear the infection, whereas a minority develop chronic infection.
• Chronic Infection: Risk of progression to cirrhosis and HCC increases with higher HBV DNA levels.
• Survival: Compensated cirrhosis has a reasonably good 5-year survival (≈85%), but decompensated cirrhosis carries a poor prognosis.
• Risk Prediction: Serial HBV DNA measurements are critical for predicting disease progression.

4.4 Hepatitis D

4.4.1 Epidemiology

• Prevalence: Approximately 20 million of the over 400 million chronic HBV carriers worldwide are co-infected with hepatitis D virus (HDV).
• Risk Groups: Commonly seen in individuals with chronic HBV infection; geographical prevalence is higher in areas with early childhood transmission of HBV (e.g. Mediterranean, parts of Asia).

4.4.2 Aetiology

• Virus Characteristics: HDV is an incomplete RNA virus that requires HBV for its assembly and propagation.
• Transmission: Shared risk factors with HBV, including percutaneous exposure and sexual transmission.
• Dependency: HDV relies on HBV envelope proteins to form viral particles.

4.4.3 Pathophysiology

• Replication: HDV uses the HBV surface antigen (HBsAg) for encapsulation. Although HDV replication is not directly cytopathic, it amplifies the immune-mediated liver injury.
• Immune-Mediated Damage: The immune response against HDV (and HBV in co-infected patients) results in more rapid progression to liver injury.
• Impact on Liver Disease: Superinfection with HDV in patients with chronic HBV leads to accelerated progression of liver fibrosis and cirrhosis.

4.4.4 Clinical Features

• Acute Infection:
  • Co-infection with HBV and HDV may produce a severe acute hepatitis with a higher risk of fulminant hepatitis.
• Chronic Infection:
  • Chronic HDV infection is associated with rapidly progressing liver damage, leading to cirrhosis.
  • Patients may present with signs of decompensated liver disease earlier than those with HBV alone.

4.4.5 Investigations

• Serology:
  • Anti-HD Antibodies: Total anti-HD antibodies indicate exposure; IgM anti-HD antibodies suggest recent infection.
• Molecular Testing:
  • HDV RNA: Measured by RT-PCR, useful for monitoring chronic infection.
• Clinical Correlation: Always consider HDV testing in HBV-positive patients with a flare or unexpectedly severe liver disease.

4.4.6 Management

• Treatment Options:
  • Interferon-α Therapy: Prolonged interferon-α therapy is the current mainstay, although its efficacy is limited.
  • Liver Transplantation: Considered in severe, refractory cases.
• Prevention: HBV vaccination is crucial as it also prevents HDV infection.

4.4.7 Prognosis

• Accelerated Disease Course: HDV co-infection leads to a more rapid progression to cirrhosis compared with HBV monoinfection.
• Limited Treatment Options: Due to the lack of effective antiviral therapy, prognosis in chronic HDV is generally poorer than in chronic HBV.
• Overall Outcome: Many patients with chronic HDV infection progress to decompensated liver disease and may require liver transplantation.

4.5 Hepatitis C

4.5.1 Epidemiology

• Global Prevalence: Approximately 170 million people worldwide are infected with hepatitis C virus (HCV).
• Genotypes: There are six major genotypes (1–6), with their prevalence varying globally.
• Risk Factors: Include blood transfusions (prior to routine screening), intravenous drug use, tattoos, sexual contact, and incarceration.
• Co-infection: High rates of co-infection with HIV are observed, especially in high-risk populations.

4.5.2 Aetiology

• Virus Characteristics: HCV is an RNA virus belonging to the Flaviviridae family.
• Transmission: Mainly transmitted via blood; sexual transmission is less efficient.
• Chronic Infection: Approximately 85% of acute HCV infections progress to chronic infection, often asymptomatic until advanced liver disease develops.

4.5.3 Pathophysiology

• Immune Evasion: Both the innate and adaptive immune responses are inadequate to clear the virus in most cases, leading to chronic infection.
• Hepatocyte Injury: Enhanced hepatocyte apoptosis correlates with liver pathology and contributes to fibrosis.
• Fibrogenesis: Ongoing inflammation promotes the activation of hepatic stellate cells, leading to collagen deposition and fibrosis.
• Extrahepatic Manifestations: Chronic HCV is associated with systemic conditions such as cryoglobulinaemia, porphyria cutanea tarda, thyroiditis, and B-cell lymphoproliferative disorders.

4.5.4 Clinical Features

• Acute HCV Infection:
  • Typically asymptomatic or presents with mild, non-specific symptoms (fatigue, abdominal pain, anorexia, itching, flu-like symptoms).
  • Diagnosis is often incidental.
• Chronic HCV Infection:
  • Often remains asymptomatic until significant fibrosis develops.
  • Liver function tests are variably elevated and fluctuate.
  • May manifest with extrahepatic features (e.g. cryoglobulinaemia, thyroiditis, sicca syndrome).
  • Approximately 25% of chronically infected patients develop cirrhosis over 20 years; about 5% of cirrhotic patients develop hepatocellular carcinoma (HCC) annually.

4.5.5 Investigations

• Serology:
  • Anti-HCV Antibodies: Detect exposure; positive in >97% by 6 months after infection.
• Molecular Testing:
  • HCV RNA PCR: Confirms ongoing infection and is used for monitoring viral load.
• Genotyping: Determines the HCV genotype, which is important in guiding treatment duration and regimen.
• Liver Assessment: Liver biopsy or non-invasive elastography may be performed to assess the degree of fibrosis.

4.5.6 Management

Prevention

• Risk Reduction: Education on safe injection practices, screening of blood products, and harm-reduction strategies in high-risk groups.
• Vaccine: No effective vaccine is currently available.

Treatment

• Antiviral Therapy:
  • Traditional Regimens: Pegylated interferon-α with ribavirin; these regimens have been largely replaced.
  • Interferon-Free Regimens: Direct-acting antivirals (DAAs) targeting NS3 protease, NS5A, and NS5B RNA polymerase have revolutionised treatment, leading to higher sustained virological response (SVR) rates with improved tolerability.
• Tailoring Treatment: Treatment duration and choice depend on viral genotype and patient factors (e.g. co-infections, liver function).
• Monitoring: Regular assessment of viral load and liver enzymes during treatment.

4.5.7 Prognosis

• Acute Infection: Most adults clear the virus; however, if chronic infection develops, liver fibrosis may progress.
• Chronic Infection: The risk of cirrhosis is approximately 1% per year. Long-term complications include cirrhosis and HCC.
• Advances in Treatment: With the advent of DAAs, SVR rates have significantly improved, which is associated with reduced progression to cirrhosis and improved survival.
• Overall Mortality: Despite effective therapies, HCV remains a major cause of liver-related morbidity and mortality, particularly in patients who present late with advanced fibrosis.

Summary

• Viral hepatitides encompass a spectrum of liver diseases caused by different hepatitis viruses. Each virus has its unique epidemiological pattern, transmission route, and clinical course:
  • Hepatitis A is an acute, self-limiting infection transmitted via the faecal–oral route, with effective vaccination available.
  • Hepatitis E also follows a self-limiting course in most individuals but carries a high risk in pregnant women.
  • Hepatitis B is a globally prevalent infection that can progress to chronic hepatitis, cirrhosis, and hepatocellular carcinoma; vaccination and antiviral therapies are central to management.
  • Hepatitis D occurs only in the presence of HBV and accelerates liver damage.
  • Hepatitis C is a leading cause of chronic liver disease and has been revolutionised by interferon-free DAA regimens.

5. Other Viral Hepatitides

5.1 Epstein–Barr Virus (EBV) Hepatitis

5.1.1 Epidemiology

• Prevalence: Almost 95% of the population is seropositive by the end of childhood.
• Age Distribution: Infections in childhood are mostly asymptomatic; however, symptomatic infectious mononucleosis tends to occur in adolescents and adults.
• Geographical Variation: EBV infection is more common in developed countries where early childhood transmission is less frequent.

5.1.2 Aetiology

• Viral Characteristics: Epstein–Barr virus is a ubiquitous herpesvirus that primarily infects B lymphocytes and epithelial cells.
• Transmission: Spread through saliva (often termed the “kissing disease”) and close personal contact.

5.1.3 Pathophysiology

• Immune-Mediated Injury: Liver damage is believed to be predominantly due to the host’s immune response rather than direct cytolysis by the virus.
• Histological Findings:
  • Hepatocyte swelling and vacuolisation.
  • Periportal and sinusoidal infiltration by lymphocytes and monocytes.
  • Mild bile duct swelling without significant obstruction.
• Mechanism: The activation of virus-specific CD8+ T cells leads to the release of cytokines (e.g. IFN-γ) and recruitment of additional inflammatory cells, causing hepatocellular injury.

5.1.4 Clinical Features

• Infectious Mononucleosis: Characterised by fever, sore throat, and cervical adenopathy.
• Liver Involvement:
  • Non-specific abdominal discomfort and nausea occur in up to 15% of cases.
  • Splenomegaly is detected in up to 60% of patients.
  • Hepatomegaly is less common (about 15%).
• Rare Complications:
  • Splenic rupture.
  • Liver failure, particularly in immunocompromised patients or post-transplant.
  • Associations (controversial) with autoimmune hepatitis, hepatocellular carcinoma (especially in certain populations), and lymphoproliferative disorders.

5.1.5 Investigations

• Liver Enzymes:
  • Transaminases are typically elevated 2–3 times above the upper limit of normal.
  • Alkaline phosphatase is raised in around 60% of cases.
  • Bilirubin is elevated in approximately 45% of cases, though clinically apparent jaundice is uncommon (<5%).
• Serology:
  • EBV IgM Antibody: Indicates recent infection.
  • Heterophile Antibody Tests: Such as the monospot or Paul–Bunnell tests, although false positives can occur in conditions like HIV, endocarditis, or acute hepatitis A.
• Molecular Testing: Polymerase chain reaction (PCR) may be employed when clinical suspicion is high despite unremarkable serology.

5.1.6 Management

• Supportive Care: Most cases resolve spontaneously; treatment is largely supportive.
• Severe Disease:
  • In cases of fulminant hepatitis or in immunosuppressed patients, steroids and antiviral agents have been used, though their benefit remains unproven.
• Patient Advice:
  • Avoid hepatotoxins (e.g. alcohol).
  • Patients with splenomegaly should be advised to avoid abdominal trauma.

5.1.7 Prognosis

• General Outcome: The vast majority of EBV hepatitis cases are self-limiting.
• Complications: Although rare, severe cases (including fulminant hepatitis) can occur, particularly in immunocompromised individuals.

5.2 Cytomegalovirus (CMV) Hepatitis

5.2.1 Epidemiology

• Seroprevalence: Between 50% and 100% of adults are seropositive for CMV, depending on socioeconomic status and regional factors.
• Latent Infection: CMV remains latent in the host with periodic reactivation, often asymptomatic in immunocompetent individuals.

5.2.2 Aetiology

• Viral Characteristics: CMV is a member of the herpesvirus family (human herpesvirus 5) and is typically acquired through bodily fluids.
• Transmission: Common routes include blood transfusions, organ transplantation, and close contact, particularly in settings of immunosuppression.

5.2.3 Pathophysiology

• Immune Response: In immunocompetent individuals, the immune system controls viral replication, leading to asymptomatic or mild disease.
• In Immunocompromised Patients: Reactivation or primary infection can lead to severe multisystem disease including hepatitis, colitis, retinitis, and pneumonitis.
• Histological Findings: Liver biopsies may show focal necrosis, inflammatory infiltrates, and characteristic cytomegalic cells with intranuclear inclusions.

5.2.4 Clinical Features

• Immunocompetent Individuals:
  • Often asymptomatic or present with a mononucleosis-like syndrome.
  • Hepatitis may manifest with mild elevations in liver enzymes.
• Immunosuppressed Patients:
  • Can present with severe hepatitis, gastrointestinal involvement (e.g. colitis, oesophagitis), retinitis, and pneumonitis.
• Pregnancy: CMV infection in pregnancy can cause congenital abnormalities in the neonate.

5.2.5 Investigations

• Serology:
  • CMV IgM: Indicates recent infection in immunocompetent hosts.
• Quantitative Nucleic Acid Testing (QNAT):
  • Essential in immunosuppressed patients to monitor viral load.
• Histopathology:
  • Tissue biopsy with CMV inclusions may be necessary in cases of invasive disease.
• Other Tests: Liver function tests (LFTs) may be elevated; imaging can assist in assessing complications.

5.2.6 Management

• Treatment in Immunocompetent:
  • Often supportive, with most cases resolving spontaneously.
• In Immunosuppressed:
  • Antiviral therapy is required. Agents include ganciclovir (or its oral prodrug valganciclovir).
  • Pre-emptive treatment may be initiated in transplant patients based on QNAT results.
• Invasive Disease: May require prolonged antiviral therapy.

5.2.7 Prognosis

• Immunocompetent Patients: Generally have an excellent prognosis.
• Immunosuppressed Patients: Prognosis depends on the degree of immunosuppression and response to antiviral therapy; severe disease can be life-threatening.

5.3 Herpes Simplex Virus (HSV) Hepatitis

5.3.1 Epidemiology

• Prevalence:
  • HSV-1 infects approximately two-thirds of the world’s population (around 3.7 billion individuals under the age of 50).
  • HSV-2 infects approximately 11% of the population (around 400 million individuals).
• Lifelong Latency: Following primary infection, HSV establishes latency in sensory neurons.

5.3.2 Aetiology

• Viral Characteristics: HSV is a DNA virus that causes infections at mucosal surfaces, primarily in the orofacial (HSV-1) or genital regions (HSV-2).
• Transmission:
  • Direct contact with infected secretions.
  • Sexual transmission is common for HSV-2.
  • Primary infection may occur subclinically or with localized lesions.

5.3.3 Pathophysiology

• Primary Infection: The virus infects epithelial cells, causing cell lysis and formation of vesicles which evolve into shallow ulcers.
• Latency and Reactivation:
  • After primary infection, HSV becomes latent in sensory ganglia.
  • Reactivation can occur, leading to recurrent lesions.
• Disseminated Infection: In immunocompromised individuals, HSV can cause severe systemic infections including hepatitis, pneumonitis, and colitis.

5.3.4 Clinical Features

• Primary HSV Infection:
  • Often preceded by a prodrome of tingling or burning at the infection site.
  • Vesicular eruptions that may ulcerate.
  • Systemic symptoms (fever, malaise, lymphadenopathy) may occur in severe cases.
• Reactivation: Typically causes milder, localized lesions (e.g. cold sores, genital lesions).
• Severe Disease: In immunocompromised hosts, disseminated HSV can cause significant hepatitis and other visceral involvement.

5.3.5 Investigations

• Clinical Diagnosis: Based on typical vesicular lesions.
• Confirmatory Tests:
  • PCR testing from swabs or vesicle scrapings.
  • Viral culture or immunofluorescence studies.
  • Serology may be used but is less useful in acute diagnosis.

5.3.6 Management

• Supportive Care: For mild infections in healthy individuals.
• Antiviral Therapy:
  • Aciclovir is the treatment of choice, administered orally for uncomplicated cases.
  • Intravenous aciclovir is indicated in severe cases, in immunocompromised patients, or when central nervous system involvement (e.g. encephalitis) is suspected.
• Prevention:
  • In recurrent or severe cases, long-term suppressive therapy may be considered.
  • Patients should be counselled on avoiding triggers and contact precautions.

5.3.7 Prognosis

• General Outcome: Most primary and recurrent infections are self-limiting.
• Severe/Disseminated Disease: Can carry significant morbidity and mortality if not treated promptly, especially in immunocompromised patients.

5.4 Varicella Zoster Virus (VZV) Hepatitis

5.4.1 Epidemiology

• Primary Infection (Chickenpox):
  • Primarily affects children.
  • Transmitted by respiratory droplets.
  • Incubation period of 14–21 days.
• Reactivation (Shingles):
  • Occurs predominantly in older or immunocompromised individuals.
  • Presents as a painful, unilateral dermatomal rash.
• Transmission:
  • Primary infection is highly contagious.
  • Reactivation is generally not transmitted except in cases of disseminated infection.

5.4.2 Aetiology

• Viral Characteristics: VZV is a DNA virus belonging to the herpesvirus family.
• Mechanism of Infection:
  • Primary VZV infection results in chickenpox, followed by latency in sensory nerve roots.
  • Reactivation later in life causes shingles.

5.4.3 Pathophysiology

• Primary Infection:
  • Virus replicates in the respiratory mucosa and spreads via lymphatics, leading to widespread vesicular rash.
• Latency and Reactivation:
  • VZV remains dormant in dorsal root ganglia.
  • Reactivation is often due to a decline in cell-mediated immunity.
• Hepatic Involvement: Although primarily a skin and nerve pathogen, VZV can cause hepatitis, especially in immunosuppressed individuals.

5.4.4 Clinical Features

• Chickenpox:
  • Prodromal phase includes fever, malaise, headache, and abdominal pain lasting 1–2 days.
  • Rash appears as pruritic, erythematous macules that evolve into vesicles and then crust over within 48 hours.
• Shingles:
  • Presents as a painful, hyperaesthetic rash confined to a single dermatome.
  • May be accompanied by fever and malaise.
• Complications:
  • In immunocompromised patients, VZV may cause disseminated infection, encephalitis, pneumonia, or transverse myelitis.
  • Post-herpetic neuralgia is a common complication of shingles.

5.4.5 Investigations

• Clinical Diagnosis: Primarily based on history and characteristic rash.
• Confirmatory Tests:
  • PCR of lesion samples.
  • Viral culture or direct fluorescent antibody testing if necessary.
  • Serology may aid in atypical cases.

5.4.6 Management

• Treatment for Chickenpox and Shingles:
  • Oral aciclovir or valaciclovir for uncomplicated cases, ideally initiated within 72 hours of rash onset.
  • Intravenous aciclovir for severe or disseminated infection, immunocompromised patients, or cases involving the central nervous system.
• Pain Management: Particularly in shingles to reduce the risk of post-herpetic neuralgia.
• Prevention:
  • Varicella vaccination for children (where indicated) and shingles vaccination for older adults (typically from age 70).
  • Immunoglobulin prophylaxis for high-risk non-immune individuals after exposure may be considered.

5.4.7 Prognosis

• Chickenpox: Generally self-limiting in children; complications are rare in healthy individuals.
• Shingles: The majority recover with antiviral therapy; however, post-herpetic neuralgia can cause significant long-term pain.
• Severe Cases: In immunocompromised patients, the risk of complications including hepatitis and encephalitis is higher, affecting overall prognosis.

6. Drug-Induced Liver Injury (DILI)

6.1 Introduction and Classification

• Definition:
  Drug-induced liver injury (DILI) refers to liver damage caused by medications, herbal products, or other exogenous compounds. It is a major cause of drug development cessation and regulatory action.
• Types of DILI:
  • Idiosyncratic DILI:
    • Unpredictable and not clearly dose-dependent (although most reactions occur with doses above 50–100 mg/day).
    • Latency is variable (days to weeks).
    • May be mediated by metabolic factors, immune mechanisms, or a combination.
  • Intrinsic DILI:
    • Dose-dependent and predictable.
    • Occurs shortly after exposure (hours to days), e.g. acetaminophen toxicity.
• Patterns of Liver Injury:
  • Hepatocellular: Primarily characterised by elevated alanine transaminase (ALT) levels.
  • Cholestatic: Marked by increased alkaline phosphatase (ALP) and conjugated bilirubin.
  • Mixed: Features of both hepatocellular and cholestatic injury.

6.2 Epidemiology

• Incidence:
  • Approximately 20 new cases of DILI occur per 100,000 persons per year.
  • DILI is responsible for about 11% of acute liver failure cases in the USA.
• Detection Challenges:
  • Under-reporting is common due to the unpredictable nature and rarity of idiosyncratic cases.
  • Prospective population-based studies (e.g. from France and Iceland) report incidence rates that are higher than spontaneous reporting figures.
• Geographical Variations:
  • In Western countries, conventional pharmaceuticals (e.g. amoxicillin-clavulanate, chlorpromazine) are frequent causes.
  • In parts of Asia, herbal and dietary supplements (HDS) account for a significant proportion of DILI cases.
• Registry Contributions:
  • Networks such as the Spanish DILI Registry, US DILIN, and LATINDILIN have been instrumental in characterising clinical spectra, identifying implicated agents, and assessing outcomes.

6.3 Aetiology and Risk Factors

6.3.1 Host-Dependent Factors

1. Age:
   • Advanced age may reduce hepatic clearance and increase cumulative drug exposure.
   • Certain drugs (e.g. isoniazid) show increased risk in older individuals, whereas agents like valproate may affect younger patients more.
2. Sex:
   • Although overall incidence appears similar between sexes, some drugs (e.g. minocycline, nitrofurantoin) are associated with a higher risk in women.
   • Women may face an increased risk of progression to acute liver failure in some studies.
3. Ethnicity and Genetic Factors:
   • Genetic predisposition plays a central role; specific HLA alleles (e.g. HLA-DRB115:01, HLA-A02:01) are linked to higher susceptibility.
   • Polymorphisms in drug-metabolising enzymes (e.g. N-acetyltransferase 2 for isoniazid) contribute to risk.
   • Allele frequency differences among ethnic groups affect susceptibility profiles.
4. Alcohol Use and Pregnancy:
   • Chronic alcohol intake can modulate risk for certain drugs, sometimes enhancing hepatotoxicity.
   • In pregnancy, the differential diagnosis includes conditions such as intrahepatic cholestasis; drugs used during gestation may have unique hepatotoxic risks.
5. Underlying Diseases and Comorbidities:
   • Pre-existing liver conditions (e.g. chronic hepatitis, NAFLD) predispose to more severe DILI.
   • Metabolic syndrome, obesity, and diabetes may also increase susceptibility, particularly to drugs that cause fatty liver disease.

6.3.2 Drug-Dependent Factors

1. Dose and Lipophilicity:
   • Although idiosyncratic reactions are not strictly dose-dependent, drugs prescribed at doses above 50 mg/day are more frequently implicated.
   • Highly lipophilic drugs (often with LogP >3) require extensive hepatic metabolism, increasing the risk of forming toxic reactive metabolites.
   • The “rule-of-two” (dose >100 mg/day and high lipophilicity) is associated with a greater risk of DILI.
2. Metabolism and Reactive Metabolites:
   • Drugs that undergo cytochrome P450-mediated metabolism may generate reactive metabolites that can bind to cellular proteins, leading to oxidative stress, mitochondrial damage, and cell death.
   • Examples include acetaminophen (in overdose), diclofenac, and troglitazone.
3. Drug–Drug Interactions:
   • Concomitant medications may induce or inhibit cytochrome P450 enzymes, altering the metabolism of a potentially hepatotoxic drug.
   • For example, rifampicin can increase the risk of isoniazid hepatotoxicity, while other interactions may increase the serum levels of hepatotoxins.

6.4 Pathophysiology

• Metabolic Activation and Reactive Metabolites:
  • Lipophilic drugs are metabolised in the liver to reactive intermediates.
  • These metabolites may covalently bind to cellular proteins (haptenisation), triggering immune responses.
  • Reactive oxygen species (ROS) generated during metabolism lead to oxidative stress and mitochondrial injury.
• Immune-Mediated Injury:
  • In idiosyncratic DILI, reactive metabolites can act as haptens, inducing an adaptive immune response.
  • Virus-specific CD8+ T cells and other inflammatory cells are recruited, leading to hepatocellular injury.
  • Specific HLA associations suggest that genetic predisposition influences the risk of an immune-mediated response.
• Inhibition of Cellular Processes:
  • Certain drugs may impair bile transporters (e.g. BSEP inhibition), leading to cholestasis.
  • Disruption of cellular organelles such as the endoplasmic reticulum (ER) and mitochondria contributes to cell death via apoptosis.
• Dose-Related Toxicity:
  • Although idiosyncratic reactions are unpredictable, intrinsic toxicity (e.g. acetaminophen overdose) follows a clear dose–response relationship.

6.5 Clinical Features

• Presentation Patterns:
  • Acute Hepatitis:
    • May present with non-specific symptoms or with overt jaundice.
    • Patients can develop symptoms ranging from fatigue and nausea to severe abdominal pain.
  • Cholestatic Injury:
    • Characterised by jaundice, pruritus, dark urine, and pale stools.
    • Laboratory findings show elevated ALP and conjugated bilirubin with minimal transaminase elevation.
  • Mixed Injury:
    • Features both hepatocellular and cholestatic injury.
• Systemic Features:
  • Allergic features such as fever, rash, and eosinophilia may be present, particularly in immune-mediated cases.
  • In severe cases, signs of acute liver failure (encephalopathy, coagulopathy) may develop.

6.6 Investigations

• History and Clinical Assessment:
  • A thorough drug history is essential, including prescribed medications, over-the-counter drugs, herbal supplements, and recent changes in therapy.
  • Exclude alternative causes of liver injury (viral hepatitis, autoimmune hepatitis, metabolic diseases).
• Liver Function Tests (LFTs):
  • Hepatocellular Pattern: Elevated ALT (often >2× upper limit) with relatively lower ALP.
  • Cholestatic Pattern: Elevated ALP (>2× upper limit), increased conjugated bilirubin, with a lower rise in ALT.
  • Mixed Pattern: ALT/ALP ratio between 2 and 5.
• Causality Assessment Tools:
  • The CIOMS/RUCAM scale evaluates temporal relationships, dechallenge/rechallenge information, and risk factors.
• Imaging and Liver Biopsy:
  • Imaging is generally used to exclude other causes; liver biopsy may be considered in cases with diagnostic uncertainty or to assess the severity of injury.
• Emerging Biomarkers:
  • Research into genomic markers (e.g. HLA genotyping) and other biomarkers is ongoing; these may offer additional support for diagnosis and risk stratification in the future.

6.7 Management and Therapeutic Recommendations

• Immediate Measures:
  • Prompt discontinuation of the suspected hepatotoxic agent is the cornerstone of management.
  • Supportive care, including intravenous fluids and close monitoring of liver function, is essential.
• Specific Therapeutic Interventions:
  • N-Acetylcysteine (NAC):
    • The only specific antidote for intrinsic DILI (e.g. acetaminophen overdose); it replenishes glutathione stores and provides antioxidant effects.
  • Corticosteroids:
    • Generally reserved for cases where there is evidence of an immune-mediated mechanism (e.g. drug-induced autoimmune hepatitis). Use should be guided by a multidisciplinary team.
  • Rechallenge Considerations:
    • Re-exposure to the offending agent is generally discouraged. However, in exceptional circumstances (e.g. essential medications), a carefully monitored rechallenge may be considered.
• Monitoring:
  • Regular monitoring of liver enzymes, bilirubin, and coagulation profiles is crucial until recovery.
  • In cases of severe DILI, frequent reassessment (often daily in hospital) is required to identify progression to acute liver failure.

6.8 Prognosis and Outcomes

• Overall Recovery:
  • Most patients with symptomatic DILI recover completely after the offending drug is discontinued.
  • Even cases with significant enzyme elevation and jaundice generally have a favourable prognosis if managed promptly.
• Severe Cases:
  • Approximately 10% of patients with DILI presenting with jaundice may progress to acute liver failure, which carries high mortality and a risk for liver transplantation.
• Long-Term Follow-Up:
  • Some patients may develop chronic DILI, with persistent liver enzyme abnormalities or progression to cirrhosis.
  • Long-term monitoring is recommended for those with significant initial injury.

6.9 Special Considerations

• Herbal and Dietary Supplements (HDS):
  • These products are a rising cause of DILI in certain regions, particularly in Asia. Their hepatotoxicity is complicated by issues of contamination, mislabelling, and lack of standardisation.
• Immune Checkpoint Inhibitors (ICIs):
  • Increasing use of ICIs in oncology has led to a unique spectrum of immune-mediated liver injuries. Management involves immunosuppression (typically corticosteroids) under a multidisciplinary approach.
• Drug Development Implications:
  • Early in vitro assessment of hepatotoxic potential—including assays for reactive metabolite formation, mitochondrial toxicity, and transporter inhibition—is crucial.
  • Pharmacokinetic modelling (e.g. unbound C_max versus inhibitory constants) helps predict DILI risk before clinical use.
• Biomarker Development:
  • There is a strong need for reliable biomarkers to predict severe DILI and to differentiate it from other liver diseases. Current genetic markers (e.g. specific HLA alleles) have high negative predictive value but are not yet definitive diagnostic tools.

6.10 Summary of Recommendations

• Diagnosis:
  • Rely on a detailed medication history and a structured causality assessment (e.g. CIOMS/RUCAM).
  • Exclude other causes of liver injury through serological, imaging, and sometimes histological investigations.
• Management:
  • Discontinue the suspected causative agent immediately.
  • Provide supportive care, including NAC in cases of acetaminophen overdose.
  • Consider corticosteroids only in select immune-mediated scenarios.
  • Avoid rechallenge with the offending drug except under exceptional circumstances.
• Monitoring:
  • Regularly monitor liver function tests, bilirubin, and coagulation parameters.
  • Use serial testing to assess recovery or progression to acute liver failure.
• Special Populations:
  • Always inquire about herbal and dietary supplement use.
  • Manage immune checkpoint inhibitor-induced liver injury with a multidisciplinary approach.

7. Autoimmune Hepatitis (AIH)

7.1 Epidemiology

• Incidence and Prevalence:
  • Annual incidence: Approximately 1–2 per 100,000 individuals.
  • Prevalence: Ranges from 10 to 20 per 100,000.
  • AIH is classified as a rare autoimmune liver disease.
• Demographic Characteristics:
  • Predominantly affects young females, although all ages, sexes, and ethnic groups can be affected.
  • There is an increasing recognition of AIH in older patients and in children, albeit less frequently.
  • Recurrence or de novo disease after liver transplantation is common; therefore, AIH should be considered in transplanted patients with allograft dysfunction.
• Association with Other Immune Disorders:
  • AIH is frequently associated with other autoimmune conditions such as thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus.

7.2 Aetiology

• Unknown Primary Cause with Identified Triggers:
  • The exact cause is unknown; however, AIH is thought to result from a loss of immunological tolerance against hepatocytes.
  • Environmental triggers, including certain drugs (see Table 26.1 in the original text), may precipitate the condition in genetically predisposed individuals.
• Genetic Predisposition:
  • Strong association with specific HLA class II alleles, which vary between ethnic and geographical groups.
  • Genetic factors modulate the immune response and may influence both disease susceptibility and severity.
• Immunological Factors:
  • A central role is played by CD4+ and CD8+ T lymphocytes in mediating liver injury.
  • A notable feature is the reduced number and/or function of regulatory T cells (CD4+ CD25+), leading to unopposed cytotoxic T-cell activity.
  • Autoantibodies—such as antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and in some cases anti–liver kidney microsome-1 (anti-LKM1)—are characteristic, helping to classify the disease (e.g. Type 1 vs Type 2 AIH).
• Drug Associations:
  • Certain drugs (e.g., nitrofurantoin, minocycline, alpha‐methyldopa) have been implicated as triggers for an AIH-like syndrome.

7.3 Pathophysiology

• Immune-Mediated Hepatic Injury:
  • AIH is driven by an aberrant immune response in which hepatocytes become the target of autoreactive T cells.
  • Cytotoxic CD8+ T cells and helper CD4+ T cells infiltrate the liver, resulting in hepatocyte apoptosis.
• Failure of Regulatory Mechanisms:
  • Defective regulatory T cell function leads to unrestrained activation of the immune system, permitting continued liver inflammation.
• Histological Hallmarks:
  • Interface Hepatitis: Inflammatory cells (often plasma cells) infiltrate the limiting plate, causing damage at the portal-parenchymal interface.
  • Emperipolesis and Hepatocellular Rosettes: Occasionally observed as part of the injury pattern.
  • These features, along with varying degrees of fibrosis or cirrhosis in advanced disease, are essential for diagnosis.
• Potential Role of Molecular Mimicry:
  • Environmental antigens may share structural similarities with hepatocyte components, triggering cross-reactivity in susceptible individuals.

7.4 Clinical Features

• Acute Presentation:
  • May mimic acute viral or toxic hepatitis with rapid onset of symptoms including marked elevation in liver enzymes.
  • Occasionally fulminant hepatitis can occur, although this is less common.
• Chronic/Insidious Presentation:
  • Nonspecific symptoms such as fatigue, malaise, and anorexia are common.
  • Many patients may be asymptomatic initially and are diagnosed during work-up for abnormal liver function tests.
  • Associated symptoms may include arthralgia, amenorrhoea, and signs related to concomitant rheumatological disorders.
• Physical Examination Findings:
  • In severe disease, patients may present with jaundice, spider naevi, palmar erythema, and hepatosplenomegaly.
  • Signs of chronic liver disease (e.g. ascites, encephalopathy) may be present in advanced stages.
• Overlap with Other Immune Diseases:
  • The presence of concurrent autoimmune conditions (such as thyroid disease or systemic sclerosis) may obscure the diagnosis of AIH.

7.5 Complications

• Progression to Cirrhosis:
  • If untreated, AIH can rapidly progress to cirrhosis within 3–5 years.
• Liver Failure:
  • Severe cases may culminate in acute liver failure.
• Post-Transplant Recurrence:
  • AIH can recur or develop de novo after liver transplantation, complicating management.
• Extrahepatic Manifestations:
  • May include features of other autoimmune conditions; these can complicate the clinical picture and affect overall prognosis.
• Drug-Related Toxicities:
  • Long-term immunosuppressive therapy may lead to complications such as osteoporosis, metabolic disturbances, and an increased risk of infections or malignancies.

7.6 Investigations

7.6.1 Laboratory Tests

• Autoantibodies:
  • Antinuclear Antibodies (ANA) and Smooth Muscle Antibodies (SMA): Typically present in Type 1 AIH.
  • Anti–Liver Kidney Microsome-1 (Anti-LKM1): Seen in Type 2 AIH.
  • Anti–Soluble Liver Antigen (Anti-SLA/LP): Occasionally detected and highly specific.
• Immunoglobulin Levels:
  • Hypergammaglobulinaemia (Elevated IgG): Nearly universal in AIH and useful in monitoring disease activity and response to therapy.
• Liver Function Tests (LFTs):
  • Elevated transaminases (ALT and AST) with a hepatocellular injury pattern.
  • Reduced serum albumin may be seen in more advanced disease.

7.6.2 Liver Biopsy

• Histological Evaluation:
  • Interface Hepatitis: Infiltration of lymphocytes and plasma cells at the portal-parenchymal border.
  • Inflammation and Fibrosis: Varying degrees may indicate disease severity.
  • Exclusion of Other Liver Diseases: Biopsy helps differentiate AIH from conditions such as primary biliary cirrhosis (PBC) or drug-induced liver injury.

7.6.3 Additional Assessments

• Imaging:
  • While imaging is not diagnostic for AIH, ultrasound or elastography may be used to assess liver size and fibrosis.
• Exclusion of Differential Diagnoses:
  • Comprehensive screening to rule out viral hepatitis, metabolic liver diseases, and DILI is essential.

7.7 Immediate Management

• Initiation of Immunosuppressive Therapy:
  • Corticosteroids:
    • First-line induction therapy with high-dose prednisone (typically 40–60 mg/day) for 4–6 weeks.
    • Rapid improvement in liver enzymes is expected; monitor clinical and biochemical response closely.
• Supportive Measures:
  • Ensure adequate nutritional support, as malnutrition is common.
  • Manage any concurrent autoimmune conditions.
  • Consider hospitalisation for patients presenting with severe disease, fulminant hepatitis, or complications (e.g. encephalopathy).

7.8 Long-Term Management

• Maintenance Therapy:
  • Azathioprine:
    • Commonly added for its steroid-sparing effects and long-term maintenance, usually at doses of 1–2 mg/kg/day.
    • Monitor for drug toxicity (e.g., bone marrow suppression, hepatotoxicity) via regular blood tests.
  • Alternative Immunosuppressants:
    • Options such as 6-mercaptopurine, mycophenolate mofetil, or tacrolimus may be considered in cases of intolerance or refractory disease.
• Treatment Duration and Relapse Prevention:
  • AIH often requires lifelong treatment; a trial of withdrawal may be considered after at least 2 years of complete biochemical remission, though relapse is common.
• Monitoring:
  • Regular follow-up with LFTs, immunoglobulin levels (especially IgG), and clinical assessment to detect early relapse.
  • Periodic liver imaging or non-invasive fibrosis assessment is recommended in patients with cirrhosis.
• Liver Transplantation:
  • Indicated in patients who progress to end-stage liver disease or acute liver failure despite medical therapy.
  • Note that AIH may recur post-transplantation; continued monitoring and management of immunosuppression are required.

7.9 Special Considerations

• Post-Transplant Recurrence:
  • AIH can recur after liver transplantation. Vigilant post-transplant monitoring and potential reintroduction of immunosuppressive therapy are necessary.
• Quality of Life and Side Effects:
  • Long-term corticosteroid use can cause significant adverse effects (osteoporosis, metabolic disturbances, mood changes). Strategies to minimise these (such as using steroid-sparing agents) are important.
• Management in Special Populations:
  • Pregnancy:
    • AIH can be safely managed during pregnancy with continued immunosuppression (e.g. azathioprine) while avoiding teratogenic agents (e.g. mycophenolate mofetil).
  • Paediatric Patients:
    • Transition from paediatric to adult care requires careful coordination and monitoring, as disease behaviour and response to therapy may differ in children.
  • Emerging Therapies and Research:
    • Ongoing research into non-invasive biomarkers, refined diagnostic criteria, and novel immunomodulatory therapies (targeting cytokines or the microbiome) may further improve patient outcomes in the future.

8. Liver Tumours and Lesions

8.1 Epidemiology

• Global Incidence of Liver Cancer:
  • Liver cancer is the sixth most common cancer worldwide, with approximately 750,000 new cases diagnosed each year (representing about 6% of all cancers).
  • There is wide geographical variation: highest incidence in Eastern Asia and lowest in South‑Central Asia and Northern Europe, with more than a ten‑fold difference between countries.
• UK Statistics:
  • Lifetime risk in the UK is approximately 1 in 120 for men and 1 in 215 for women.
• Distribution of Primary Liver Cancers:
  • Approximately 50% of primary liver cancers are hepatocellular in origin (hepatocellular carcinoma [HCC], hepatoblastoma, angiosarcoma, and other sarcomas).
  • Intrahepatic bile duct carcinomas account for around 40% of cases.
  • A small proportion (≈9%) are classified as unspecified.
• Incidental Findings:
  • The vast majority of liver lesions are discovered incidentally on imaging performed for unrelated reasons.
  • Many lesions are asymptomatic at the time of discovery.

8.2 Aetiology

• Benign vs Malignant Lesions:
  • Liver lesions are first classified by their likelihood of malignancy:
    • Benign Lesions: Include haemangiomas, focal nodular hyperplasia (FNH), hepatocellular adenomas, and simple cysts.
    • Malignant Lesions: Include primary liver cancers (HCC, intrahepatic cholangiocarcinoma, angiosarcoma) and metastatic deposits (most commonly from colorectal, breast, lung, and other primary tumours).
• Risk Factors for Malignant Tumours:
  • Underlying chronic liver disease (cirrhosis, chronic hepatitis B or C, non‑alcoholic fatty liver disease, haemochromatosis, Wilson’s disease, α‑1 antitrypsin deficiency).
  • Exposure to aflatoxins (from Aspergillus), which induce p53 mutations.
  • Certain systemic conditions such as Budd–Chiari syndrome.
• Risk Factors for Benign Tumours:
  • Hepatic Adenoma: Strongly associated with oral contraceptive use, anabolic steroid use, and exposure to high oestrogen levels (including pregnancy).
  • Haemangioma and FNH: May have a female predominance; FNH is thought to be a hyperplastic response to an anomalous arterial supply.
• Secondary Liver Tumours:
  • Liver metastases are far more common than primary liver cancers.
  • Common primary sites include the colon, pancreas, lung, and breast.
  • Metastases typically present as multiple nodules, though some primaries (e.g. colorectal cancer or neuroendocrine tumours) can present as solitary metastases that may be amenable to resection.

8.3 Pathophysiology

• Development of Malignant Lesions:
  • Hepatocellular Carcinoma (HCC):
    • Often develops in the background of chronic liver injury and cirrhosis.
    • Pathogenesis is closely linked to persistent inflammation, regenerative nodules, and genetic alterations (e.g., p53 mutations, viral integration in HBV).
    • In non-cirrhotic livers, HCC can occur in the setting of chronic hepatitis B infection or metabolic syndrome.
  • Intrahepatic Cholangiocarcinoma:
    • Arises from the bile duct epithelium within the liver.
    • Often associated with chronic inflammation of the biliary tree (e.g. primary sclerosing cholangitis) or exposure to liver flukes in endemic regions.
• Benign Lesions:
  • Hepatic Haemangioma:
    • Represents a vascular malformation with aberrant angiogenesis.
    • Typically consists of proliferative endothelial cells forming blood-filled channels.
  • Focal Nodular Hyperplasia (FNH):
    • Considered a hyperplastic response to an abnormal vascular supply.
    • Characteristically exhibits a central stellate scar from which fibrous septa radiate.
  • Hepatocellular Adenoma (HCA):
    • A benign neoplasm of hepatocytes, influenced by hormonal factors.
    • Subtypes (e.g. HNF1A-inactivated, β‑catenin activated, inflammatory) differ in their molecular pathways and risk for haemorrhage or malignant transformation.
• Metastatic Lesions:
  • Occur via haematogenous spread from primary tumours.
  • The liver’s dual blood supply (portal venous and arterial) makes it a common site for metastatic deposits.

8.4 Clinical Features

• General Symptoms (Common to Most Liver Tumours):
  • Often asymptomatic; detected incidentally during imaging.
  • When symptomatic, patients may report:
    • Right upper quadrant (RUQ) pain or discomfort due to capsule stretching.
    • Fever, malaise, anorexia, and unintentional weight loss.
    • Jaundice is typically a late feature, except in cases where the biliary tree is involved (e.g., cholangiocarcinoma).
• Specific Presentations:
  • Hepatocellular Carcinoma (HCC):
    • May present with constitutional symptoms (fatigue, weight loss) and signs of advanced liver disease if cirrhosis is present.
    • A palpable mass or a bruit over the liver may be found on physical examination.
  • Intrahepatic Cholangiocarcinoma:
    • Often presents with a more insidious course.
    • Patients may have vague abdominal discomfort and weight loss.
    • Features of cholestasis (e.g., dark urine, pale stools) may be present.
  • Benign Lesions:
    • Haemangiomas: Typically incidental; large lesions might cause pain or rarely complications like rupture.
    • FNH: Usually asymptomatic; occasional mild discomfort.
    • Hepatic Adenoma: Can be asymptomatic but may present with pain or signs of haemorrhage (especially if large or subcapsular).
• Metastases:
  • May cause hepatomegaly with a nodular liver edge.
  • Systemic features will be dominated by the primary tumour’s behaviour.

8.5 Complications

• Malignant Lesions:
  • Local invasion and vascular invasion (common in HCC and cholangiocarcinoma).
  • Early spread via lymphatics and haematogenous routes, particularly to the liver, lungs, and bones.
  • Poor prognosis if diagnosed at an advanced stage.
• Benign Lesions:
  • Hepatic Adenoma: Risk of rupture and intraperitoneal haemorrhage, particularly during pregnancy or with rapid growth.
  • Haemangioma: Rarely, spontaneous rupture or the development of a coagulopathy (Kasabach–Merritt syndrome) may occur.
• General Considerations:
  • Lesions causing biliary obstruction may lead to cholangitis and secondary biliary cirrhosis.
  • Invasive procedures (biopsy) risk tumour seeding, particularly with suspected HCC or hydatid disease.

8.6 Investigations

• Initial Evaluation:
  • History and Physical Examination:
    • Focus on risk factors (e.g., viral hepatitis, alcohol use, metabolic syndrome, family history of cancer) and symptoms (pain, weight loss, jaundice).
    • Examination for signs of chronic liver disease, hepatomegaly, and a palpable mass.
• Laboratory Tests:
  • Liver Function Tests (LFTs):
    • May show mild to moderate enzyme elevation.
  • Tumour Markers:
    • Alpha-Fetoprotein (AFP): Elevated in 50–80% of HCC cases; not entirely specific.
  • Serology:
    • Screening for viral hepatitis and other chronic liver diseases should be performed.
• Imaging:
  • Ultrasound:
    • Often the first-line modality; useful for serial monitoring. It can detect hyperechoic or heterogeneous lesions.
  • Computed Tomography (CT) and Magnetic Resonance Imaging (MRI):
    • Employed when further characterisation is required.
    • CT/MRI can help differentiate benign from malignant lesions based on enhancement patterns (e.g., peripheral nodular enhancement with centripetal fill-in in haemangiomas; central scar in FNH).
  • Additional Modalities:
    • Endoscopic Retrograde Cholangiopancreatography (ERCP): If cholangiocarcinoma is suspected.
• Biopsy:
  • Role:
    • Reserved for cases where imaging and clinical data are inconclusive.
    • Contraindicated in cases where HCC or hydatid disease is strongly suspected, to avoid tumour seeding.
  • Procedure:
    • May be guided by imaging to target the lesion accurately.
• Differentiation of Lesion Types:
  • The diagnostic work-up aims to classify lesions as benign or malignant. This guides the need for further intervention versus conservative management.

8.7 Immediate Management

• For Incidentally Discovered Lesions (Benign):
  • Observation:
    • Most benign lesions (e.g., small haemangiomas, FNH) do not require treatment if asymptomatic.
  • Symptom Relief:
    • For lesions causing pain (due to mass effect or capsular stretching), symptomatic treatment may include analgesics and dietary adjustments.
• For Lesions Causing Biliary Obstruction or Other Acute Complications:
  • Supportive Care:
    • Intravenous fluids, management of pain, and correction of metabolic disturbances.
  • Interventional Procedures:
    • Endoscopic stenting or percutaneous drainage may be needed for biliary obstruction.
  • Urgent Intervention:
    • In cases of suspected rupture or haemorrhage, immediate surgical consultation is essential.

8.8 Long-Term Management

• Benign Lesions:
  • Regular Surveillance:
    • Serial imaging (usually with ultrasound) to monitor for changes in size or characteristics.
  • Intervention Criteria:
    • Surgical or interventional treatment is reserved for symptomatic lesions (e.g., those causing persistent pain or biliary obstruction) or for lesions that demonstrate significant growth.
• Malignant Lesions:
  • Surgical Resection:
    • The preferred treatment for resectable HCC or cholangiocarcinoma when liver function is adequate.
    • In the case of colorectal liver metastases, surgical resection may offer curative potential in a subset of patients.
  • Locoregional Therapies:
    • Techniques such as radiofrequency ablation, transarterial chemoembolization (TACE), or percutaneous ablation for lesions not amenable to surgery.
  • Systemic Therapies:
    • Neoadjuvant and adjuvant chemotherapy or targeted therapies (e.g., anti‑VEGF agents, sorafenib) may be used, particularly in metastatic disease.
  • Liver Transplantation:
    • Considered in select cases of HCC, particularly when lesions are small (within Milan criteria) and liver function is compromised.
• Follow-Up and Surveillance:
  • Regular Monitoring:
    • Follow-up imaging to assess for recurrence or progression of disease.
    • Serum tumour markers (e.g., AFP) can be monitored serially.
  • Management of Underlying Conditions:
    • In cases of HCC associated with chronic liver disease, ongoing surveillance for complications of cirrhosis is required.
• Multidisciplinary Approach:
  • Decisions regarding management are made in multidisciplinary team meetings, integrating the expertise of hepatologists, surgeons, radiologists, oncologists, and pathologists.

8.9 Special Considerations

• Risk of Seeding with Biopsy:
  • When HCC or hydatid disease is suspected, biopsy is generally avoided due to the risk of tumour seeding along the needle tract.
• Surveillance Programs:
  • For high-risk groups (e.g., patients with cirrhosis, chronic HBV infection), routine 6‑monthly ultrasound screening with AFP measurement is recommended to detect early HCC.
• Management of Metastatic Disease:
  • Liver metastases generally indicate advanced disease and are managed on a palliative basis unless the patient qualifies for resection (e.g., solitary metastases in colorectal cancer with no extrahepatic spread).
• Prevention and Risk Reduction:
  • In HCC, vaccination against HBV, safe needle practices, and reduction of aflatoxin exposure are critical preventive measures.
  • Lifestyle modifications (e.g., weight loss, exercise, avoidance of alcohol) are advised for patients with non‑alcoholic fatty liver disease (NAFLD), which is a risk factor for HCC in non-cirrhotic livers.

9. Vascular Liver Diseases

9.1 Overview and Background

• Vascular liver diseases refer to a group of conditions where altered blood flow—primarily in the venous system—leads to liver dysfunction.
• The spectrum ranges from acute hepatic failure to passive congestion.
• The main categories include:
  • Budd–Chiari syndrome (BCS) – obstruction of hepatic venous outflow
  • Hepatic Veno-occlusive Disease (VOD) – occlusion of small hepatic veins, often following haematopoietic stem cell transplantation or toxic ingestion
  • Congestive Hepatopathy/Cardiac Cirrhosis – liver changes due to chronic right-sided heart failure

Embryology and Vascular Anatomy

• Embryology: The liver develops from a ventral diverticulum of the gut. Early in development, two solid cellular buds—termed hepatic cylinders—branch and merge to form a meshwork. This network invades the vitelline and umbilical veins, fragmenting them into the sinusoids that eventually become the liver’s venous capillaries.
• Vascular Anatomy:
  • Inflow: Blood enters via the hepatic artery (providing oxygenated blood) and the portal vein (bringing nutrient-rich blood from the gut). These vessels travel together at the porta hepatis (with the bile duct lying to the right, the hepatic artery to the left, and the portal vein posteriorly).
  • Within the Liver: The blood is distributed through the portal canals, forming an interlobular plexus which then supplies the sinusoids in each lobule.
  • Outflow: The sinusoids coalesce into sublobular veins, which merge to form the hepatic veins that drain into the inferior vena cava (IVC).

9.2 Budd–Chiari Syndrome (BCS)

9.2.1 Epidemiology

• Incidence: Approximately 1 in 100,000 in the general population.
• Demographics: More common in women, typically presenting in the third or fourth decade of life.

9.2.2 Aetiology

• Primary Causes (Intraluminal):
  • Thrombosis: Most commonly due to underlying hypercoagulable states such as:
    • Primary myeloproliferative disorders (e.g. polycythaemia vera, essential thrombocythaemia, myelofibrosis)
    • Inherited deficiencies (protein C, protein S, antithrombin III) with factor V Leiden mutation being frequently implicated in pregnancy‐ and oral contraceptive–related cases
    • Paroxysmal nocturnal haemoglobinuria
  • Vascular Webs: Rare congenital or acquired intraluminal webs in the hepatic veins.
• Secondary Causes:
  • Intraluminal Invasion: By parasitic infections or malignant tumours invading the vessel lumen.
  • Extraluminal Compression: From abscesses, cysts, or solid tumours causing external compression.

9.2.3 Pathophysiology

• Obstruction of Outflow: Blockage of the hepatic veins causes a rise in sinusoidal pressure, leading to:
  • Portal Hypertension: Due to impaired outflow, which may eventually cause portal vein thrombosis (PVT) if collateral circulation is insufficient.
  • Hypoxic Injury: Reduced venous drainage and congestion result in hepatocyte hypoxia, especially in centrilobular areas, triggering oxidative stress and necrosis.
  • Fibrosis: Ongoing injury leads to centrilobular fibrosis, and in chronic cases, regenerative nodules may develop as part of cirrhotic transformation.

9.2.4 Clinical Features

• General Presentation:
  • Variable Onset: Ranges from asymptomatic cases (detected incidentally) to fulminant liver failure.
  • Symptoms:
    • Right upper quadrant (RUQ) abdominal pain
    • Hepatomegaly
    • Ascites
    • Mild jaundice may occur
  • Classification: Can be categorised into acute, subacute, or chronic presentations depending on the rapidity and extent of the obstruction.

9.2.5 Complications

• Portal Vein Thrombosis (PVT): Can develop from sustained high sinusoidal pressures.
• Hepatic Failure: In acute cases, rapid hepatocellular necrosis may lead to liver failure.
• Cirrhosis: Chronic congestion can ultimately cause bridging fibrosis and cirrhosis.

9.2.6 Immediate Management

• Stabilisation:
  • Ensure adequate fluid resuscitation and correct electrolyte imbalances.
  • Monitor vital signs and liver function tests closely.
• Anticoagulation:
  • Initiate systemic anticoagulation to prevent thrombus extension (often lifelong, unless contraindicated).
• Imaging:
  • Use Doppler ultrasound as the first-line imaging modality; if inconclusive, contrast-enhanced CT or MRI may be performed.
• Interventional Procedures:
  • Thrombolysis: Consider local or systemic thrombolytic therapy if a fresh thrombus is identified.
  • Percutaneous Angioplasty and Stenting: May be indicated for focal hepatic vein stenoses or webs.
  • Transjugular Intrahepatic Portosystemic Shunt (TIPS): Can be used to decompress the liver, particularly in acute settings or as a bridge to liver transplantation.

9.2.7 Long-Term Management

• Continued Anticoagulation: Lifelong therapy is usually required.
• Regular Surveillance: Monitor for signs of progressive liver dysfunction, development of varices, and portal hypertension complications.
• Interventional Follow-Up: Assess for restenosis or recurrent thrombosis with periodic imaging.
• Consideration of Liver Transplantation: In patients with progressive liver failure or decompensated cirrhosis unresponsive to other interventions.

9.2.8 Differential Diagnosis

• IVC Obstruction/Thrombosis: May produce similar features; imaging helps distinguish the two.
• Cardiac Causes: Right heart failure (tricuspid regurgitation, constrictive pericarditis) can cause hepatic congestion; a thorough cardiovascular examination is essential.

9.2.9 Prognosis

• Survival Rates:
  • Five-year survival is approximately 85% in isolated BCS, but falls to around 60% if associated with portal vein thrombosis.
• Prognostic Factors:
  • Severity of ascites, presence of encephalopathy, and elevated prothrombin time/serum bilirubin are associated with poorer outcomes.

9.3 Hepatic Veno‐Occlusive Disease (VOD)

9.3.1 Epidemiology

• Occurrence: Most frequently observed following haematopoietic stem cell transplantation (HSCT).
• Incidence Post-HSCT: Ranges from 5% to 50% depending on the conditioning regimen.
• Additional Causes: Ingestion of pyrrolizidine alkaloids (found in certain herbal remedies).

9.3.2 Aetiology

• HSCT-Related:
  • Chemotherapy regimens (notably those including cyclophosphamide, busulphan, and total body irradiation) are major risk factors.
• Toxin-Induced:
  • Exposure to pyrrolizidine alkaloids can result in VOD even outside of the transplant setting.

9.3.3 Pathophysiology

• Endothelial Injury:
  • Damage to the sinusoidal endothelial cells (SECs) results in the loss of fenestrae and the formation of gaps.
• Subendothelial Oedema and Obliteration:
  • The sublobular and central veins narrow due to oedema; in advanced cases, the lumina of sinusoids and veins become obliterated.
• Glutathione Depletion:
  • Decreased glutathione impairs the liver’s ability to detoxify hepatotoxic metabolites (e.g. acrolein from cyclophosphamide), further exacerbating injury.

9.3.4 Clinical Features

• Onset:
  • Typically develops within three weeks following HSCT.
• Symptoms:
  • Tender hepatomegaly
  • Fluid retention and ascites
  • Jaundice (often appearing after liver enzyme changes)
• Laboratory Findings:
  • Elevated bilirubin, often with increased alkaline phosphatase and ALT, though these may not be markedly high initially.

9.3.5 Complications

• Acute Liver Failure:
  • Severe VOD may progress to liver failure with a high risk of mortality.
• Refractory Ascites:
  • Can necessitate repeated paracentesis.
• Multiorgan Dysfunction:
  • In advanced cases, renal failure and coagulopathy may develop.

9.3.6 Immediate Management

• Supportive Care:
  • Fluid restriction, diuretics, and sodium reduction.
  • Repeated paracentesis with IV albumin replacement if required.
• Avoidance of Hepatotoxins:
  • Cease or avoid drugs that may further impair liver function.
• Anticoagulation:
  • May be considered in selected cases, although evidence is limited.
• Defibrotide:
  • Emerging therapy with antithrombotic and endothelial-protective properties; promising results in some HSCT patients.
• Transjugular Liver Biopsy/Measurement of Hepatic Venous Pressures:
  • Can be used in uncertain cases, though the diagnosis is primarily clinical using established criteria (e.g. Seattle/Baltimore criteria).

9.3.7 Long-Term Management

• Prevention:
  • Modify conditioning regimens in high-risk patients.
  • Prophylactic use of ursodeoxycholic acid and possibly low-molecular-weight heparin, although data are limited.
• Monitoring:
  • Serial liver function tests and imaging in patients post-HSCT.
• Consideration for Liver Transplantation:
  • Reserved for patients with end-stage liver disease, though this option is complex in the post-transplant population.

9.3.8 Prognosis

• Variable Mortality:
  • Mortality rates vary widely (from 3% to 67%) depending on severity, patient population, and treatment regimens.
• Predictors of Poor Outcome:
  • High bilirubin levels, severe weight gain, and presence of pleural effusions are among the factors linked to worse outcomes.

9.4 Congestive Hepatopathy (Cardiac Cirrhosis)

9.4.1 Epidemiology and Causes

• Prevalence:
  • While mild hepatic dysfunction is common in patients with congestive heart failure, progression to true cardiac cirrhosis is relatively rare.
• Underlying Cardiac Conditions:
  • Ischaemic heart disease, cardiomyopathy, valvular heart disease, restrictive lung disease, and pericardial disease.

9.4.2 Aetiology

• Primary Cause:
  • Chronic right-sided heart failure leading to persistent venous congestion.
• Contributing Factors:
  • Elevated central venous pressures transmitted to the liver, causing passive congestion.

9.4.3 Pathophysiology

• Hepatic Congestion:
  • Increased venous pressure causes sinusoidal dilation and congestion.
• Nutmeg Liver Appearance:
  • Alternating red (congested) and yellow (normal or fatty) areas develop, giving a “nutmeg” appearance.
• Fibrosis:
  • Chronic congestion leads to perivenular fibrosis and eventually bridging fibrosis between central veins, which differs from typical portal-based cirrhosis.

9.4.4 Clinical Features

• Symptoms:
  • Often asymptomatic or with mild RUQ discomfort.
  • In more severe cases: mild jaundice, ascites, and right upper quadrant pain due to capsule stretching.
• Examination Findings:
  • Hepatomegaly (may be tender and occasionally pulsatile, especially with tricuspid regurgitation).
  • Signs of right heart failure (jugular venous distension, hepatojugular reflux).
  • Splenomegaly is less common unless portal hypertension is significant.

9.4.5 Complications

• Portal Hypertension:
  • Can lead to the development of oesophageal varices and variceal bleeding.
• Progressive Liver Fibrosis:
  • Although the synthetic function is often preserved, long-term congestion may result in fibrosis.
• Cardiac-Related Mortality:
  • Ultimately, the prognosis is primarily determined by the severity of the underlying cardiac disease rather than the liver pathology itself.

9.4.6 Immediate Management

• Cardiac Optimisation:
  • Treatment of the underlying heart failure (e.g. diuretics, ACE inhibitors, beta-blockers) is paramount.
• Ascites Management:
  • Fluid and sodium restriction, use of diuretics, and therapeutic paracentesis if necessary.
• Monitoring:
  • Regular assessment of liver function tests; improvement with heart failure treatment supports the diagnosis.

9.4.7 Long-Term Management

• Long-Term Cardiac Therapy:
  • Continual optimisation of heart failure management remains the mainstay.
• Surveillance:
  • Monitor for development of complications such as variceal bleeding; endoscopic screening may be warranted in patients with significant portal hypertension.
• Patient Education:
  • Emphasise lifestyle modifications and adherence to cardiac medications to reduce the progression of hepatic congestion.

9.4.8 Prognosis

• Determined by Cardiac Disease:
  • The liver dysfunction is usually mild, and morbidity/mortality is primarily driven by the underlying cardiac condition.
• Reversibility:
  • Early changes in congestive hepatopathy may be reversible if cardiac function is improved, whereas advanced fibrosis is less likely to regress.

9.5 Ischaemic/Hypoxic Hepatitis

9.5.1 Epidemiology and Causes

• Incidence:
  • Occurs in approximately 1% of critically ill patients and accounts for more than 50% of marked aminotransferase elevations in hospital settings.
• Causes:
  • Primarily due to suboptimal oxygen delivery as a result of:
    • Reduced hepatic arterial flow
    • Passive venous congestion (e.g. due to heart failure)
    • Systemic hypotension or shock
    • Respiratory failure

9.5.2 Pathophysiology

• Hepatocellular Injury:
  • Insufficient oxygen leads to mitochondrial dysfunction and endoplasmic reticulum stress, particularly in the centrilobular regions (zone 3).
• Biochemical Cascade:
  • Rapid, profound transient elevation in serum aminotransferases occurs, reflecting acute hepatocellular damage.
• Histology:
  • Centrilobular necrosis, congestion, and fragmentation of hepatic architecture.

9.5.3 Clinical Features

• Symptoms:
  • Frequently subclinical or with non‐specific symptoms such as nausea and vomiting.
  • RUQ tenderness or pain may be present.
• Laboratory Findings:
  • Marked transient elevation in ALT and AST (often 10–100 times the normal values).
  • Associated with disturbances in coagulation and renal function.

9.5.4 Complications

• Acute Liver Failure:
  • In severe cases, the extensive hepatocellular necrosis may lead to acute liver failure.
• High Mortality:
  • Mortality rates can vary widely (25–73%), largely reflecting the severity of the underlying condition.

9.5.5 Immediate Management

• Supportive Care:
  • Rapid correction of hypotension, optimisation of oxygen delivery, and treatment of underlying cardiac or respiratory failure.
  • Intensive monitoring of vital signs, liver function tests, and coagulation parameters.
• Avoid Further Hepatotoxins:
  • Withhold or adjust any medications that may further impair hepatic function.

9.5.6 Long-Term Management

• Depends on Underlying Cause:
  • Management of heart failure, sepsis, or respiratory failure is critical.
  • There is typically no direct liver-specific therapy; improvement depends on the resolution of the systemic insult.

9.5.7 Prognosis

• Prognostic Determinants:
  • Largely dependent on the resolution of the underlying condition rather than the liver injury itself.
  • The presence of hypoxic hepatitis is an indicator of severe systemic illness and is associated with increased overall mortality.

9.6 Portal Vein Thrombosis (PVT)

9.6.1 Epidemiology and Aetiology

• Incidence:
  • Exact incidence is uncertain; however, PVT is most commonly seen as a complication of cirrhosis and is found in up to 35% of cirrhotic patients with hepatocellular carcinoma.
• Causes:
  • Systemic Thrombophilic Factors: Inherited prothrombotic disorders, myeloproliferative diseases, sepsis (e.g. Bacteroides fragilis infection).
  • Local Factors: Inflammation, tumour invasion (e.g. HCC, cholangiocarcinoma), or post-surgical changes.
  • The development of a portal cavernoma (cavernous transformation) may occur when the body recanalises an occluded portal vein.

9.6.2 Pathophysiology

• Thrombosis and Collateral Formation:
  • Thrombus formation in the portal vein leads to the development of collateral channels (cavernous transformation) to bypass the occlusion.
• Portal Hypertension:
  • Chronic PVT results in portal hypertension with subsequent development of varices, splenomegaly, and, occasionally, ascites.

9.6.3 Clinical Features

• Acute PVT:
  • May be asymptomatic or present without established signs of portal hypertension if occurring within the past 60 days.
• Chronic PVT:
  • Presentations include signs of portal hypertension: gastrointestinal bleeding (from varices), splenomegaly, and sometimes hypersplenism.
• Biliary Complications:
  • Extrahepatic bile duct obstruction may occur due to compression by varices or collateral vessels.

9.6.4 Complications

• Variceal Bleeding:
  • A major complication, presenting in approximately 30% of cases.
• Bowel Infarction:
  • Especially if the thrombus extends into the superior mesenteric vein.
• Extrahepatic Biliary Obstruction:
  • Leading to cholangitis or jaundice.

9.6.5 Immediate Management

• Diagnostic Imaging:
  • Colour Doppler ultrasound is the initial investigation, with contrast-enhanced CT used for further evaluation.
• Anticoagulation:
  • Consider thrombolysis in acute PVT and initiate anticoagulation therapy (duration tailored to whether the cause is reversible or not).
• Management of Bleeding:
  • Variceal bleeding is managed with standard protocols (endoscopic therapy, non-selective beta-blockers).

9.6.6 Long-Term Management

• Anticoagulation:
  • Long-term therapy may be necessary in patients with irreversible prothrombotic conditions.
• Surveillance:
  • Regular monitoring for variceal development and complications of portal hypertension.
• Management of Biliary Complications:
  • Endoscopic treatment for biliary strictures or cholangitis.

9.6.7 Prognosis

• Variable Outcomes:
  • Mortality rates vary widely (0–76%) and are closely related to the extent of thrombosis, presence of complications (such as bowel infarction), and the underlying liver disease.

9.7 Consolidated Clinical Implications

• Diagnostic Vigilance:
  • A high index of suspicion is required for vascular liver diseases in patients presenting with ascites, hepatomegaly, RUQ pain, or abnormal liver function tests—especially in those with known cardiac or haematological disorders.
• Multidisciplinary Approach:
  • Collaboration between hepatologists, radiologists, cardiologists, and interventional specialists is crucial for accurate diagnosis, timely management, and optimisation of outcomes.
• Individualised Management:
  • Treatment strategies are tailored according to the underlying cause and severity of the vascular disorder.
  • Prompt intervention (e.g. anticoagulation, interventional radiology procedures) can prevent progression to liver failure, whereas long-term management focuses on treating the underlying systemic condition (e.g. heart failure in congestive hepatopathy).
• Prognosis and Follow-Up:
  • Prognosis depends largely on the extent of vascular obstruction and the success of both immediate and long-term management strategies.
  • Regular follow-up with imaging and liver function testing is essential to monitor disease progression and guide further treatment.

10. Hereditary and Congenital Liver Diseases

Inherited liver disorders encompass a diverse group of conditions caused by genetic abnormalities that affect liver metabolism and structure. In many cases, early genetic testing allows diagnosis even before clinical disease becomes overt. The following sections cover the most common conditions: Hereditary Haemochromatosis, Alpha‐1‐Antitrypsin Deficiency, Wilson’s Disease, and Alagille’s Syndrome.

10.1 Hereditary Haemochromatosis (HH)

10.1.1 Epidemiology

• Prevalence:
  • Affects approximately 1 in 300–400 Caucasians.
  • Carrier frequency may be as high as 1 in 9 in some populations, though not all homozygotes develop clinical disease.

10.1.2 Aetiology and Genetics

• Genetic Basis:
  • An autosomal recessive disorder primarily caused by mutations in the HFE gene.
  • The most common mutation is the C282Y (a G-to-A transition causing a cysteine-to-tyrosine substitution at position 282) – present in 80–90% of clinically diagnosed patients.
  • A second mutation, H63D, is less common; while homozygotes for H63D rarely develop significant iron overload, compound heterozygotes (C282Y/H63D) may have modestly increased iron stores.
• Modifier Factors:
  • Female gender (menstrual blood loss) may be protective, leading to later or milder presentation.
  • Nutritional status, alcohol use, and other co-existing liver conditions may modify disease expression.

10.1.3 Pathophysiology

• Iron Overload Mechanism:
  • Mutations in HFE disrupt normal iron regulation by affecting the interaction with the transferrin receptor, leading to increased intestinal absorption of iron.
  • Excess iron accumulates in multiple organs (liver, pancreas, heart, joints, pituitary).
• Tissue Injury:
  • High levels of iron catalyse the formation of free radicals, causing oxidative damage to hepatocytes and leading to fibrosis and eventual cirrhosis.

10.1.4 Clinical Features

• General:
  • Fatigue and lethargy.
  • Episodic abdominal pain (possibly severe).
• Hepatic:
  • Hepatomegaly with often preserved synthetic function in early stages.
  • May progress to chronic liver disease with cirrhosis in advanced cases.
• Extrahepatic Manifestations:
  • Pancreas: Diabetes mellitus (“bronze diabetes”) due to islet cell damage.
  • Cardiac: Dilated cardiomyopathy, arrhythmias, and congestive heart failure.
  • Musculoskeletal: Arthropathy (especially affecting the second and third metacarpophalangeal joints); joint pain may persist despite treatment.
  • Endocrine: Hypogonadotropic hypogonadism (leading to reduced libido and sexual dysfunction).
  • Dermatologic: Bronze or slate-grey skin pigmentation.
  • Infectious: Increased susceptibility to Yersinia enterocolitica due to excess circulating iron.

10.1.5 Complications

• Development of cirrhosis and subsequent portal hypertension.
• Increased risk of hepatocellular carcinoma (HCC), especially in cirrhotic patients.
• Cardiac complications (heart failure, arrhythmias) may be life‐threatening.
• Progressive arthropathy that may be refractory to treatment.

10.1.6 Investigations

• Biochemical Tests:
  • Elevated serum iron and ferritin levels.
  • Increased transferrin saturation (often >45%).
• Genetic Testing:
  • HFE gene mutation analysis for C282Y and H63D mutations.
• Liver Biopsy (if indicated):
  • Quantification of hepatic iron concentration and assessment of fibrosis.
  • Calculation of the hepatic iron index (hepatic iron concentration divided by the patient’s age; values >1.9 suggest HH).

10.1.7 Management and Treatment

• Venesection (Phlebotomy):
  • Mainstay of treatment.
  • Initially performed weekly until serum ferritin falls to low-normal (target approximately 50–100 µg/L) and haemoglobin is maintained (avoid dropping below 10.5 g/dL).
  • Maintenance therapy is lifelong (approximately quarterly sessions) tailored to maintain transferrin saturation <40% and ferritin within the low-normal range.
• Adjunctive Therapies:
  • Iron-chelating agents (e.g. desferrioxamine) may be considered in patients who are intolerant of venesection, though they remove iron less efficiently.
• Lifestyle and Monitoring:
  • Avoid alcohol and high-iron foods if indicated.
  • Monitor liver function, screen for diabetes, and evaluate for complications such as cardiac dysfunction.
  • Regular surveillance for HCC in patients with established cirrhosis.

10.1.8 Prognosis

• With regular venesection and early treatment, life expectancy can be normal in patients without advanced liver disease or diabetes.
• Prognosis worsens in the presence of cirrhosis, diabetes, or cardiac complications.

10.2 Alpha‐1‐Antitrypsin (A1AT) Deficiency

10.2.1 Epidemiology

• Prevalence:
  • Occurs in approximately 1 in 1,500 to 3,500 individuals of European descent.
• Inheritance:
  • Autosomal co-dominant; the most common high-risk genotype is PiZZ, while heterozygotes (PiMZ, PiSZ) carry a lower risk.

10.2.2 Aetiology and Genetics

• Genetic Defect:
  • Caused by mutations in the SERPINA1 gene on chromosome 14, which encodes alpha‐1‐antitrypsin, a key serine protease inhibitor.
  • Variants are classified based on electrophoretic mobility (M, S, Z); the Z allele (PiZZ) is associated with severe deficiency.
• Pathogenesis of Deficiency:
  • Misfolded protein accumulates in hepatocytes’ endoplasmic reticulum, forming PAS-positive, diastase-resistant globules.
  • The deficiency leads to reduced protection of lung tissue from neutrophil elastase, predisposing to emphysema, especially in smokers.

10.2.3 Pathophysiology

• Liver Disease:
  • Hepatic accumulation of abnormal A1AT causes hepatocellular injury, leading to inflammation, fibrosis, and eventual cirrhosis.
• Lung Disease:
  • Lack of A1AT in the lung results in unopposed proteolytic activity, resulting in progressive emphysema.
• Extrahepatic Manifestations:
  • Association with small-vessel vasculitis and, rarely, other inflammatory conditions.

10.2.4 Clinical Features

• Childhood Presentation:
  • Neonatal hepatitis syndrome with cholestasis, hepatomegaly, and conjugated hyperbilirubinaemia.
  • In some, the liver disease resolves, while others progress to cirrhosis.
• Adult Presentation:
  • Many adults develop pulmonary emphysema (often in the context of smoking) and may have minimal liver symptoms initially.
  • When liver involvement becomes clinically significant, features include hepatomegaly, signs of chronic liver disease, and, rarely, HCC.

10.2.5 Complications

• Progression to cirrhosis and risk of hepatocellular carcinoma.
• Severe pulmonary disease (emphysema) leading to respiratory failure.
• Extrahepatic manifestations such as vasculitis.

10.2.6 Investigations

• Serum A1AT Levels:
  • Typically low (<0.9 g/L), but may be falsely normal during acute-phase reactions.
• Phenotyping:
  • Isoelectric focusing (IEF) to identify Pi variants (e.g. PiZZ, PiMZ, PiSZ).
• Liver Biopsy:
  • Shows PAS-positive, diastase-resistant globules within hepatocytes.
• Pulmonary Function Tests:
  • To assess for emphysema, especially in symptomatic individuals.

10.2.7 Management and Treatment

• Lifestyle Modification:
  • Smoking cessation is critical.
  • Avoid passive smoking and other pulmonary irritants.
• Pulmonary Support:
  • Regular monitoring with pulmonary function tests.
  • Inhaled therapies and bronchodilators may be used as needed.
• Augmentation Therapy:
  • Intravenous A1AT replacement therapy may be considered for progressive emphysema, although evidence is variable.
• Liver Transplantation:
  • Indicated for decompensated cirrhosis or hepatocellular carcinoma due to A1AT deficiency.
• Screening and Monitoring:
  • Regular liver function tests, ultrasound screening for HCC in patients with cirrhosis, and monitoring of pulmonary status.

10.2.8 Prognosis

• Prognosis varies considerably:
  • Many individuals with the PiZZ genotype remain asymptomatic until adulthood.
  • Mortality is largely related to pulmonary complications; liver disease accounts for a smaller proportion of deaths.
  • Smoking dramatically worsens outcomes.

10.3 Wilson’s Disease

10.3.1 Epidemiology

• Prevalence:
  • Approximately 1 in 30,000 individuals, with a carrier frequency of about 1 in 90.
• Age of Onset:
  • Typically presents between 6 and 45 years of age, with a variable clinical course.

10.3.2 Aetiology and Genetics

• Genetic Defect:
  • Autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13.
  • This gene encodes a copper-transporting ATPase essential for incorporating copper into caeruloplasmin and excreting copper into bile.
• Pathogenesis:
  • Impaired copper excretion leads to accumulation of copper in the liver, which eventually spills into the circulation and deposits in other organs such as the brain, kidneys, and cornea.

10.3.3 Pathophysiology

• Liver Damage:
  • Excess copper generates free radicals, resulting in oxidative stress, hepatocellular injury, and eventual fibrosis or cirrhosis.
• Extrahepatic Manifestations:
  • Copper deposition in the brain leads to neurological and psychiatric disturbances.
  • Characteristic Kayser–Fleischer rings develop due to copper deposition in the cornea.

10.3.4 Clinical Features

• Hepatic Presentation:
  • Can range from asymptomatic elevation of liver enzymes to acute hepatitis, chronic liver disease, or fulminant liver failure.
  • In children, presents more commonly with liver disease; in young adults, neurological manifestations may predominate.
• Neurological and Psychiatric:
  • Movement disorders (tremor, dystonia, chorea, ataxia, Parkinsonian features).
  • Cognitive impairment, mood disturbances, personality changes, and psychosis.
• Other Manifestations:
  • Haemolysis, renal dysfunction, endocrine abnormalities (e.g. hypogonadism, amenorrhoea), and musculoskeletal complaints.

10.3.5 Complications

• Progression to cirrhosis and end-stage liver disease.
• Neurological deterioration, which may be partially reversible with treatment.
• Increased risk of acute liver failure, particularly in untreated cases.

10.3.6 Investigations

• Blood Tests:
  • Low serum caeruloplasmin (typically <50 mg/L); note potential false negatives in inflammatory states or pregnancy.
  • Elevated 24-hour urinary copper excretion (>100 μg/24 h).
• Ophthalmologic Examination:
  • Slit-lamp examination for Kayser–Fleischer rings.
• Liver Biopsy:
  • Quantification of hepatic copper concentration (>250 μg/g dry weight is diagnostic).
• Genetic Testing:
  • Identification of mutations in ATP7B, particularly in ambiguous cases.
• Imaging:
  • MRI may show basal ganglia changes due to copper deposition.

10.3.7 Management and Treatment

• Chelation Therapy:
  • First-line treatment is with D-penicillamine, which increases urinary copper excretion.
  • Pyridoxine (vitamin B6) supplementation (approximately 25 mg/day) is given concurrently to reduce side effects.
• Alternative Chelators:
  • Trientine is used in patients intolerant of penicillamine, with fewer neurological side effects.
  • Zinc is employed as maintenance therapy; it works by inducing metallothionein in enterocytes, reducing copper absorption.
• Dietary Management:
  • Avoid foods high in copper (e.g. shellfish, liver, nuts, chocolate).
• Liver Transplantation:
  • Considered in patients with fulminant liver failure or decompensated cirrhosis not responsive to medical therapy.
• Monitoring:
  • Regular assessment of liver function, neurological status, and copper studies.
• Family Screening:
  • First-degree relatives should undergo genetic testing and biochemical screening.

10.3.8 Prognosis

• Early treatment significantly improves outcomes.
• Hepatic disease is largely reversible if caught before advanced fibrosis or cirrhosis develops, although neurological damage may be less reversible.
• Lifelong treatment and close monitoring are essential.

10.4 Alagille’s Syndrome

10.4.1 Epidemiology

• Incidence:
  • Occurs in approximately 1 in 100,000 live births.
• Inheritance:
  • Autosomal dominant, with up to 15% of cases due to de novo mutations.

10.4.2 Aetiology and Genetics

• Genetic Basis:
  • Caused by mutations in the JAG1 gene on chromosome 20 (some literature may reference chromosome 12; verify with local guidelines), which encodes a Notch ligand involved in cellular differentiation and organogenesis.
• Mechanism:
  • The mutation leads to a marked paucity of interlobular bile ducts (bile duct paucity), resulting in cholestasis.

10.4.3 Pathophysiology

• Cholestasis:
  • Inadequate bile duct development leads to impaired bile flow, causing cholestasis and subsequent accumulation of bile acids in the liver.
• Systemic Effects:
  • The developmental defect affects multiple organ systems due to the role of Notch signalling in embryogenesis.

10.4.4 Clinical Features

• Hepatic Manifestations:
  • Neonatal cholestasis with jaundice, pale stools, and dark urine.
  • In older children, features of chronic liver disease such as pruritus and xanthomas may be present.
• Extrahepatic Manifestations:
  • Facial Features: Triangular face with a broad forehead, saddle‐shaped nose, deep-set eyes, and a pointed chin.
  • Cardiovascular: Congenital heart defects (commonly peripheral pulmonary stenosis, tetralogy of Fallot, or septal defects).
  • Skeletal: Vertebral anomalies such as butterfly vertebrae and spina bifida occulta.
  • Ocular: Posterior embryotoxon (a prominent, anteriorly displaced Schwalbe’s line).
  • Renal: Various renal abnormalities may be present.
  • Neurodevelopmental: Delays in cognitive and motor development.
• Additional Findings:
  • Failure to thrive and malnutrition due to chronic cholestasis.

10.4.5 Complications

• Progressive cholestasis leading to cirrhosis.
• Severe cardiovascular anomalies can be life-threatening in early life.
• Potential development of hepatocellular carcinoma (HCC) in the setting of cirrhosis.
• Complications of malabsorption (fat-soluble vitamin deficiencies).

10.4.6 Investigations

• Clinical Assessment:
  • Detailed history and physical examination focusing on liver dysfunction and associated systemic features.
• Laboratory Testing:
  • Liver biochemistry showing cholestatic pattern (elevated bilirubin, alkaline phosphatase, and gamma-GT).
  • Serum bile acids, cholesterol, and triglycerides may be abnormal.
• Imaging:
  • Abdominal ultrasound to evaluate liver structure and biliary anatomy.
  • MRI may be used for detailed assessment.
• Liver Biopsy:
  • Demonstrates a paucity of interlobular bile ducts.
• Genetic Testing:
  • Molecular analysis for mutations in the JAG1 gene, along with family pedigree analysis.
• Additional Evaluations:
  • Cardiac evaluation (echocardiogram), spinal X-rays, and slit-lamp eye examination to document extrahepatic manifestations.

10.4.7 Management and Treatment

• Supportive Nutritional Management:
  • Ensure adequate caloric intake and supplementation with fat‐soluble vitamins (A, D, E, and K).
  • Monitor for and treat any mineral deficiencies.
• Management of Cholestasis:
  • Bile acid sequestrants (e.g., cholestyramine) and ursodeoxycholic acid (UDCA) may be used to improve bile flow and reduce pruritus.
• Cardiovascular and Other Anomalies:
  • Manage congenital heart defects as per standard protocols.
  • Orthopaedic and ophthalmological interventions as indicated.
• Advanced Liver Disease:
  • Liver transplantation may be required in cases of decompensated cirrhosis or intractable cholestasis.
• Multidisciplinary Care:
  • Requires coordinated care with hepatologists, cardiologists, ophthalmologists, and genetic counsellors.

10.4.8 Prognosis

• Variable Course:
  • Ten-year survival is approximately 74%, with cardiovascular anomalies being the major cause of early mortality.
  • Hepatic complications determine long-term morbidity and mortality.
  • Early diagnosis and comprehensive multidisciplinary management improve outcomes.

10.5 Consolidated Clinical Implications

• Integrated Diagnosis:
  • Early genetic testing and comprehensive evaluation (including family history, biochemical markers, imaging, and liver biopsy when needed) are key to diagnosing inherited liver diseases.
• Individualised Treatment:
  • Management strategies (e.g. venesection in HH, chelation in Wilson’s disease, immunosuppression in AIH, supportive care in Alagille’s syndrome) must be tailored to the specific disease and patient characteristics.
• Long-Term Monitoring:
  • Lifelong surveillance is critical to monitor treatment efficacy, assess for complications (e.g. cirrhosis, HCC, emphysema), and adjust therapy as necessary.
• Prevention and Family Screening:
  • Screening of first-degree relatives (especially in HH and A1AT deficiency) can facilitate early diagnosis and treatment.
• Multidisciplinary Approach:
  • Optimal outcomes require collaboration among hepatologists, geneticists, transplant teams, and supportive services (e.g. nutritional and pulmonary care).