Acute Porphyrias & Lead Poisoning (Clinical)
Two heme-pathway poisons that masquerade as a surgical abdomen
The heme pathway connection
Rate-limiting step. ALA synthase joins glycine and succinyl-CoA to start heme synthesis. The hepatic isoform (ALAS1) is rate-limiting and repressed by heme, so anything that consumes hepatic heme — especially cytochrome P450 induction — ramps it up. ALA dehydratase then forms porphobilinogen (PBG), PBG deaminase (HMBS) builds the porphyrin ring, and ferrochelatase finally inserts iron into protoporphyrin.
Two blocks. In acute intermittent porphyria (AIP), PBG deaminase activity is about half normal, so a trigger that induces ALAS1 floods the body with neurotoxic ALA and PBG. Lead inhibits ALA dehydratase and ferrochelatase: ALA rises but PBG does not, and zinc is inserted into protoporphyrin instead of iron. Both cause abdominal pain and neuropathy, which is why they are confused.
Acute intermittent porphyria
Presentation. AIP is autosomal dominant with low penetrance; attacks begin after puberty and mainly affect women in their 20s to 40s. The hallmark is severe, poorly localized abdominal pain with a soft, nonperitoneal abdomen, plus vomiting, constipation, tachycardia, and hypertension. Urine is dark reddish or darkens on standing in light as PBG oxidizes to porphobilin. There is no photosensitivity, because ALA and PBG are not light-activated porphyrins — unlike porphyria cutanea tarda, which blisters sun-exposed skin without attacks.
Neuropsychiatric features. Hyponatremia from SIADH (which can provoke seizures); anxiety, agitation, hallucinations, or psychosis; and an acute motor neuropathy that starts proximally, often in the arms, and can progress to respiratory failure, mimicking Guillain–Barré syndrome. Patients are often labeled drug-seeking or undergo negative laparotomies.
Triggers. CYP-inducing drugs (barbiturates, phenytoin, carbamazepine, rifampin) and sulfonamides, alcohol, fasting or crash dieting, progesterone (luteal phase, OCPs), infection, surgery, and stress.
Diagnosis. Send a spot urine PBG while symptoms are present. A marked rise, often more than 10 times normal, confirms an acute porphyria and justifies immediate treatment; ALA, urine, stool, and plasma porphyrins, and HMBS genetic testing then define the type. Urine porphyrins alone rise in many conditions and mislead.
- Stop triggersporphyrinogenic drugs, alcohol, fasting; treat infection
- Supportopioids for pain, propranolol for tachycardia and hypertension, careful sodium correction
- Carbohydrate loadingIV dextrose for mild attacks or until hemin arrives; watch for worsening hyponatremia
- IV hemindaily for about 4 days; represses ALAS1 and ends the attack
- Prevent recurrencegivosiran, prophylactic hemin, GnRH agonists for cyclic premenstrual attacks, liver transplant if refractory
Seizures: correct sodium, stop an acute seizure with a benzodiazepine, and maintain with gabapentin or levetiracetam. Phenytoin, carbamazepine, barbiturates, and valproate worsen attacks.
Long-term care. Givosiran is a monthly subcutaneous, liver-targeted siRNA against ALAS1 mRNA; monitor creatinine and liver enzymes. Carriers face higher risks of hepatocellular carcinoma, chronic kidney disease, and hypertension, and genetic testing of relatives lets carriers avoid triggers.
Lead poisoning in adults
Exposure. Adults mainly inhale dust or fumes: battery manufacturing and recycling, smelting, indoor firing ranges, renovation that sands or burns pre-1978 paint, and radiator repair. Retained bullet fragments, especially in joints where synovial fluid dissolves them, leach lead for years. Workers carry dust home on clothes and shoes, so test their children.
Clinical picture. Colicky abdominal pain with constipation, fatigue, headache, irritability, memory and cognitive decline, and an extensor motor neuropathy (wrist drop, foot drop). Chronic exposure causes hypertension, chronic interstitial nephropathy, and "saturnine" gout from impaired urate excretion; gingival lead lines may appear. Very high levels cause encephalopathy with confusion, seizures, and coma.
Laboratory findings. Zinc protoporphyrin rises (reflecting about 3 months of exposure, but also elevated in iron deficiency). Inhibited pyrimidine 5′-nucleotidase leaves RNA aggregates seen as coarse basophilic stippling, and the anemia is microcytic or normocytic, sometimes sideroblastic. A venous blood lead level is diagnostic; capillary samples can be contaminated by lead on the skin.
| Feature | Acute intermittent porphyria | Lead poisoning |
|---|---|---|
| Enzyme | Inherited PBG deaminase deficiency | ALA dehydratase and ferrochelatase inhibited |
| Typical patient | Young woman with a drug, fasting, or hormonal trigger | Worker exposed to dust or fumes; retained bullet |
| Neurologic | Psychosis, seizures, proximal motor neuropathy | Cognitive change, wrist and foot drop, encephalopathy |
| Blood | No anemia; hyponatremia | Microcytic anemia, basophilic stippling, ↑ zinc protoporphyrin |
| Urine | PBG and ALA high | ALA high, PBG normal |
| Treatment | IV hemin; givosiran if recurrent | Remove exposure; succimer, or BAL then CaNa2EDTA |
Management. Removing the source comes first: workplace controls or reassignment, and surgical excision of leaching bullet fragments. Chelate symptomatic patients or very high levels. Oral succimer (DMSA) treats most; encephalopathy requires IM dimercaprol (BAL) first, then IV calcium disodium EDTA, because EDTA alone can mobilize lead into the brain.
Give calcium disodium EDTA, never disodium EDTA (fatal hypocalcemia). Dimercaprol is formulated in peanut oil and can hemolyze G6PD-deficient red cells.