Porphyria Dr S Spijkerman

Porphyria A heterogenic group of inborn errors in the haem biosynthesis pathway. An enzyme deficiency at any point in the pathway can cause accumulation of haem precursors. These precursors cause the neuropathy which is responsible for the symptoms of the acute attacks of the disease. Different enzyme defects cause the different kinds of porphyria

Haem at the end of pathway → negative feedback to the rate-limiting enzyme in the pathway, called ALA synthase. This prevents the formation of excessive precursors Some events may trigger an acute attack in a genetically enzyme deficient (porphyric) patient in one of the following ways: Induction of ALA synthase activity → ↑ formation of precursors → accumulation due to genetically deficient enzyme (can’t cope with ↑ load). Increase in haem demand, thus decreasing the haem pool and reducing the negative feedback on ALA synthase.

Haem pathway

Triggers Table 1. Triggers of acute porphyric attacks Stress Infection Alcohol Starvation Dehydration Menstruation Drugs – see table 2

Table 2: Drugs Indication UWC UWEC Avoid Anaesthesia Thiopentone Etomidate Analgesics Tramadol Mefenamic acid Diclofenac Ketorolac Pentazocine Tilidine Sedatives/ anticonvulsives Diazepam Phenobarbitone Antibiotics Clindamycin Metronidazole Sulphonamides Erythromycin Co-trimoxazole Chloramphenicol Local anaesthetics - Asthma Aminophylline Antiemetics Metoclopramide

Clinical presentation Chronic types cause skin reactions (bullae, rash etc) → not life threatening

Clinical presentation – acute attack Possible symptoms of an acute porphyric attack (remember: accumulation of precursors cause neuropathy) Sensory neuropathy Motor neuropathy: Respiratory muscles, quadriparesis Autonomic neuropathy: Abdominal pain, nausea and vomiting (causing dehydration), tachycardia, hypertension, postural hypotension, cardiovascular collapse and death Central nervous system/psychiatric: anxiety, depression, psychosis, convulsions Bulbar: Decreased ability to swallow, can lead to aspiration

Diagnosis Type of patient Samples to send to laboratory Sample Suspected acute attack Urine (30 ml) Define the type of porphyria EDTA blood sample (2 tubes) Urine (30ml) Stool sample Skin disease Sample Tests done Urine* Enzyme quantitation Blood* Erythrocyte fluorescence screen, plasma porphyrin scan, DNA testing (R59W mutation for Porphyria Variegata) Stool* NB: All samples to be protected against light Porphyrin and protoporphyrin quantitation (to determine type of porphyria)

Treatment of acute attack Symptom to treat Treatment Definitive treatment of acute attack with neuropathy Haematin arginate (NormosangTM ) 3-4mg/kg/d IV x 4 days (This works by increasing the haem pool to enhance negative feedback to ALA to reduce formation of precursors) Might be useful in acute attack Carbohydrates: 10% Dextrose saline Oral carbohydrate loading – 2000 kcal/d General treatment of acute attack Withdraw trigger Hydrate well Monitor electrolytes Abdominal pain Codeine, morphine, pethidine

Treatment (cont) Nausea and vomiting Prochlorperazine Hypertension and tachycardia β-blockers Psychosis Chlorpromazine, promazine, trifluoperazine Convulsions Clonazepam, Lorasepam Bulbar involvement/respiratory failure Intubate and ventilate

A “safe” anaesthetic technique Pre-operatively Limit NPO time (prevent starvation) Start Dextrose saline drip early if patient not first on list Anxiolysis (midazolam, temazepam) Intra-operatively Sufentanil, alfentanil, fentanyl Propofol Suxamethonium, pancuronium (atracurium has been used) Halothane (sevoflurane has been used) Neostigmine, glycopyrrolate Post-operatively Morphine, pethidine, codeine, paracetamol, Ibuprofen