Drug-Induced Pathology
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Direct answer
No organ escapes adverse drug reactions, and pathology sorts them into two families: type A — dose-dependent augmentation of the drug's known pharmacology, predictable and common — and type B, idiosyncratic reactions that are dose-independent, unpredictable and often immune-mediated, allergy being the paradigm. The liver bears the heaviest burden: paracetamol produces dose-related centrilobular necrosis through NAPQI glutathione depletion, reversible within a window by N-acetylcysteine, while anti-tubercular therapy causes idiosyncratic hepatotoxicity — isoniazid, rifampicin and pyrazinamide together — a daily clinical event in India, where national programme guidance hinges on monitoring and timely drug withdrawal. The skin contributes Stevens-Johnson syndrome and toxic epidermal necrolysis, the marrow aplasia, and the kidneys interstitial nephritis and crystal injury — each with named culprit drugs the exam expects verbatim.
What you must remember
- Paracetamol mechanism to recite: metabolised to the toxic NAPQI, which is detoxified by glutathione; overdose floods the pathway, NAPQI covalently binds centrilobular hepatocytes, and N-acetylcysteine (within roughly 8-24 hours, best early) repletes glutathione — the antidote logic examiners reward.
- ATT hepatotoxicity, the Indian standard: baseline and periodic liver function testing under the national programme; the usual working rule is withdrawal when transaminases exceed three times the upper limit with symptoms, or a substantially higher asymptomatic threshold per current guidance — learn it as "jaundice or symptoms plus enzymes", and rechallenge cautiously.
- SJS/TEN continuum: epidermal necrosis with mucosal involvement — under 10 per cent body-surface detachment is SJS, over 30 per cent is TEN, between lies the overlap; culprit drugs are sulphonamides, aromatic anticonvulsants (carbamazepine, phenytoin), allopurinol, nevirapine and NSAIDs; keratinocyte apoptosis via Fas-Fas ligand and granulysin; mortality is scored by SCORTEN.
- DRESS syndrome: drug reaction with eosinophilia and systemic symptoms — rash, fever, eosinophilia, hepatitis, onset two to eight weeks after the culprit (which distinguishes it from SJS timing), with HHV-6 reactivation implicated; treated by drug withdrawal and systemic steroids.
- HLA-pharmacogenomics pairs to quote: abacavir with HLA-B57:01 (hypersensitivity) and carbamazepine with HLA-B15:02 (SJS) — the clearest proof that idiosyncrasy has genetic structure.
- Marrow and blood: chloramphenicol aplasia, methotrexate mucositis and myelosuppression, heparin-induced thrombocytopenia (paradoxical thrombosis), clopidogrel-associated TTP — and linezolid's lactic acidosis with prolonged use.
- Renal patterns: acute interstitial nephritis (NSAIDs, beta-lactams — with the classic trial of fever, rash and eosinophilia), aminoglycoside proximal tubular injury, tenofovir Fanconi syndrome, and crystal nephropathy from aciclovir or indinavir.
- Timing is diagnosis: type A follows dose and time-on-drug predictably; immune reactions cluster at one to eight weeks; idiosyncratic DILI has no safe window — a drug started years ago can still be the culprit.
Rash and fever three weeks into a new drug
A 34-year-old started on carbamazepine for focal seizures three weeks ago presents with fever, a spreading maculopapular rash on the trunk, facial oedema, tender cervical lymphadenopathy and eosinophilia on the smear; transaminases are three times normal. The differential now runs SJS/TEN versus DRESS versus a simple exanthem, and three questions decide it. Are mucosae involved — conjunctivitis, oral erosions, genital ulceration? SJS/TEN yes, DRESS minimal. Is the skin blistering or detaching with lateral pressure (Nikolsky sign)? That settles TEN. How far does the rash go — DRESS is a spreading infiltrated eruption with systemic organ involvement, at times desquamating late? The patient has mucosal sparing, no blisters, marked eosinophilia and hepatitis: DRESS. Management: stop carbamazepine immediately, never rechallenge, switch to a structurally unrelated anticonvulsant (levetiracetam is the usual choice), supportive care with steroid judgement, and observe hepatic function over weeks. Had the answer been TEN, the patient would go to a burns-style unit, fluids and wound care; the two pathways diverge completely from one bedside examination.
Where students slip
Type A versus type B is a guaranteed one-mark question answered wrongly by assuming all drug toxicity is allergic — paracetamol is type A, penicillin anaphylaxis type B. Do not call every DILI pattern "hepatitis": cholestatic (amoxicillin-clavulanate, anabolic steroids) and mixed patterns exist, and the R-ratio (ALT/ALP multiples of normal) sorts them. Students forget that N-acetylcysteine works beyond the classic eight-hour window — late is still better than never. And the nevirapine SJS signal matters in Indian HIV practice: escalating dose, women with higher CD4 counts, and the first six weeks carry the risk.
Frequently asked questions
How does paracetamol kill hepatocytes?
Its reactive metabolite NAPQI, normally detoxified by glutathione, accumulates in overdose and covalently binds centrilobular hepatocyte proteins, causing necrosis.
Which drugs are the commonest causes of SJS/TEN?
Sulphonamides, aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbitone), allopurinol, nevirapine and oxicam NSAIDs, typically one to three weeks after starting.
What distinguishes DRESS from SJS?
DRESS shows eosinophilia, systemic organ involvement and onset two to eight weeks after the drug, with minimal mucosal involvement; SJS/TEN is mucosa-eroding epidermal necrosis.
When should anti-tubercular drugs be stopped for liver injury?
Per national programme practice, when jaundice appears or transaminases exceed three times the upper limit with symptoms — with rechallenge and alternative regimens thereafter.
Which HLA allele predicts abacavir hypersensitivity?
HLA-B*57:01 — screening before prescription has essentially eliminated the hypersensitivity reaction in carriers.