Drug, toxic and autoimmune hepatitis

Overview

The liver metabolises most drugs, so it is often injured by them. Drug-induced liver injury (DILI) should be considered in every patient with abnormal liver tests, especially when viral and other causes are negative. Toxins such as alcohol, poisonous mushrooms and industrial solvents damage the liver in similar ways.

Autoimmune hepatitis (AIH) is a chronic immune attack on liver cells. It matters because it responds well to steroids but leads to cirrhosis if missed.

Drug-induced liver injury

Types

Factors that increase risk: chronic alcohol use (enzyme induction), fasting or malnutrition (low glutathione), older age, pre-existing liver disease, and genetics (e.g. slow acetylators with isoniazid).

Patterns of damage

Important individual drugs

• Anti-tuberculosis drugs (very common cause in Pakistan):
  • Isoniazid raises transaminases in about 10–20%; true hepatitis is less common and linked to its metabolites (acetylator status).
  • Rifampicin causes hepatitis, usually in the first weeks, and can raise unconjugated bilirubin early by competing for uptake without real liver damage.
  • Pyrazinamide is hepatotoxic and also raises uric acid.
  • Kumar advises stopping the drugs only if bilirubin rises or transaminases exceed three times normal. Then stop all hepatotoxic drugs, let the liver tests settle and reintroduce the drugs one at a time while monitoring. Follow the current national TB programme guideline.
• Halothane: hepatitis after repeated exposure within a short time; immune reaction to altered liver proteins; fever, eosinophilia, high mortality.
• Chlorpromazine: cholestatic hypersensitivity, usually within 4 weeks, with fever and eosinophilia; recovers on stopping.
• Sodium valproate: mitochondrial injury, microvesicular steatosis, can be fulminant in young children; IV carnitine is the antidote.
• Amiodarone: steatohepatitis that can progress if the drug is continued.
• Methotrexate: dose-related fibrosis and cirrhosis.
• Propylthiouracil: severe hepatotoxicity, so it is mainly kept for the first trimester of pregnancy.
• Combined pill: cholestasis (rare), gallstones, hepatic adenoma, Budd-Chiari syndrome.

Paracetamol overdose

Mechanism

• In normal use, most paracetamol is made safe in the liver by joining it to glucuronide or sulphate. A small amount is oxidised by cytochrome P450 to NAPQI, which is at once made safe by glutathione.
• In overdose the conjugation pathways saturate, more NAPQI is made, glutathione runs out, and NAPQI binds to liver cell proteins → centrilobular (zone 3) necrosis. Kidney injury (acute tubular necrosis) can also occur.
• Higher risk: chronic alcohol use, enzyme-inducing drugs, and starvation or eating disorders (low glutathione).

Clinical course

• First 24 hours: often no symptoms, or just nausea and vomiting.
• Liver tests start to rise after about 18 hours; damage peaks at 72–96 hours (highest ALT and INR).
• Then right upper quadrant pain, jaundice, encephalopathy, hypoglycaemia and bleeding in severe cases.

Management

1. Note the time, dose and formulation; weigh the patient and calculate mg/kg.
2. Take a paracetamol level at 4 hours (or on arrival if later), plus INR, creatinine, bicarbonate, glucose and liver tests.
3. Plot on the treatment nomogram. The UK line starts at 100 mg/L at 4 hours; many other countries use a line starting at 150 mg/L (older line 200 mg/L). Follow your hospital's protocol.
4. Give IV acetylcysteine if the level is above the line, if the overdose is staggered or the timing is unknown, or if the patient presents late with abnormal tests.
5. If results will not be ready until after 8 hours and the dose is over 150 mg/kg, start acetylcysteine straight away.

Acetylcysteine works by replenishing glutathione. It is most effective within 8–10 hours of ingestion but is still given to late presenters. Standard regimen in Kumar: 150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (total 300 mg/kg over 21 hours). Up to 15% get a histamine-type reaction (rash, wheeze, low BP) related to the first bag; pause the infusion and give an antihistamine, then continue.

Referral for liver transplant (King's College criteria, paracetamol)

• Arterial pH below 7.3 after fluid resuscitation, or all three of:
• Prothrombin time above 100 seconds, creatinine above 300 µmol/L, and grade III–IV encephalopathy.

Toxic hepatitis

Alcohol

• Alcohol causes a spectrum: fatty liver (reversible) → alcoholic hepatitis → cirrhosis.
• Alcoholic hepatitis: heavy drinker with jaundice, fever, tender enlarged liver, raised white cell count; AST usually higher than ALT; may have ascites and encephalopathy.
• Biopsy: ballooned cells, neutrophils, Mallory-Denk bodies (damaged keratin filaments), fat.
• Severity: Maddrey discriminant function = 4.6 × (prothrombin time above control, seconds) + bilirubin (mg/dL). Above 32 = severe. The Glasgow alcoholic hepatitis score (above 9 = poor outlook) is also used.
• Management: stop alcohol, IV thiamine (prevent Wernicke), nutrition, treat infection and withdrawal. Prednisolone may improve short-term survival in severe disease once infection and GI bleeding are excluded; the Lille score at day 7 shows whether to continue.

Mushrooms and chemicals

• Amanita phalloides (death cap): amatoxins block RNA polymerase II → liver cells cannot make proteins → zone 3 necrosis. Classically, severe gut symptoms after a delay, an apparent recovery, then liver failure.
• Carbon tetrachloride (industrial solvent): zone 3 necrosis with fatty change.
• Iron overdose: periportal (zone 1) necrosis.
• Aflatoxin (mould on stored groundnuts and maize): linked to liver cancer.
• Pyrrolizidine alkaloids (herbal teas): veno-occlusive disease.

Autoimmune hepatitis

Who gets it

• Women much more than men (about 75% female).
• Two peaks: teens and early twenties (often type 2, may present as acute hepatitis) and peri- or post-menopausal women (often vague tiredness or found on blood tests).
• About 40% have a family history of autoimmunity, and others have thyroiditis, coeliac disease, pernicious anaemia, type 1 diabetes, vitiligo or ulcerative colitis.

Clinical features

• Fatigue, jaundice, amenorrhoea, acne, arthralgia; may be found with established cirrhosis (about one-third at presentation).
• Young patients may have fever, polyarthritis, pleurisy or glomerulonephritis.
• Can present as acute severe hepatitis with very high transaminases that do not settle.

Investigations

• Transaminases high, ALP and bilirubin less so.
• Raised IgG (hypergammaglobulinaemia, often about twice normal).
• Autoantibodies:

• Liver biopsy is needed: interface hepatitis with a plasma cell-rich infiltrate, fibrosis or cirrhosis.
• Exclude viral hepatitis (especially HBV, HCV), drugs, Wilson disease and alcohol.

Treatment

• Prednisolone 30 mg daily, tapered slowly to a maintenance dose, plus azathioprine 1–2 mg/kg a day, which lets the steroid dose come down (check TPMT first; monitor blood count and liver tests).
• Budesonide is an option in non-cirrhotic patients; mycophenolate, ciclosporin or tacrolimus in resistant cases.
• Remission in over 80%; the response itself supports the diagnosis.
• Treatment is usually long term; relapse is common after stopping.
• Liver transplant if treatment fails or liver failure develops; AIH can recur in the graft.

Quick revision

• DILI: stop the drug; most reactions occur within 3 months.
• Zone 3 necrosis: paracetamol, Amanita, carbon tetrachloride.
• Paracetamol: NAPQI + glutathione depletion; acetylcysteine refills glutathione; best within 8–10 h.
• Acetylcysteine 150, 50, 100 mg/kg (300 mg/kg over 21 h).
• King's criteria (paracetamol): pH below 7.3, or PT above 100 s + creatinine above 300 µmol/L + grade III–IV encephalopathy.
• Anti-TB hepatitis: stop if bilirubin rises or transaminases over 3 times normal; reintroduce singly.
• Alcoholic hepatitis: DF above 32 = severe; consider prednisolone.
• AIH type 1: ANA + anti-smooth muscle; type 2: anti-LKM1; raised IgG; interface hepatitis.
• AIH treatment: prednisolone + azathioprine; over 80% remit.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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