Porphyrias

A group of inherited (rarely acquired) disorders caused by partial enzyme deficiencies in the haem biosynthetic pathway, resulting in accumulation of toxic pathway intermediates (porphyrins and their precursors) proximal to the deficient enzyme step. Classified by the predominant site of overproduction (hepatic versus erythropoietic) and by clinical presentation (acute neurovisceral attacks versus chronic cutaneous photosensitivity), with some overlap.

Acute hepatic porphyrias

• Acute intermittent porphyria (AIP): deficiency of porphobilinogen deaminase (hydroxymethylbilane synthase), the commonest and most severe acute porphyria, autosomal dominant with low penetrance (most carriers never have an attack).
• Variegate porphyria and hereditary coproporphyria: partial enzyme deficiencies further down the pathway, causing both acute neurovisceral attacks and cutaneous photosensitivity (the combination is a useful clue distinguishing these from AIP, which is purely neurovisceral).
• ALA dehydratase deficiency porphyria: extremely rare.

Cutaneous porphyrias

• Porphyria cutanea tarda: the commonest porphyria overall, due to acquired or inherited uroporphyrinogen decarboxylase deficiency, strongly associated with hepatitis C, alcohol excess, hepatic iron overload, oestrogen use, and HIV --- causing chronic blistering photosensitivity without acute attacks.
• Erythropoietic protoporphyria: painful acute photosensitivity (burning rather than blistering) from birth/early childhood.

Precipitants of acute attacks: drugs that induce hepatic cytochrome P450 (a large list including many anticonvulsants, sulfonamide antibiotics, certain anaesthetic agents, and importantly many commonly prescribed drugs --- always check a porphyria-safe drug list before prescribing in a known or suspected carrier), fasting/caloric restriction, alcohol, infection, stress, and the luteal phase of the menstrual cycle (oestrogen/progesterone fluctuation), explaining female predominance and cyclical attacks in some patients.

Acute attack (AIP, variegate porphyria, hereditary coproporphyria)

• Severe, diffuse, poorly localised abdominal pain, often the dominant and most striking symptom, frequently leading to unnecessary laparotomy if unrecognised.
• Nausea, vomiting, constipation, and sometimes diarrhoea.
• Autonomic instability: tachycardia and hypertension (very common and a useful clue), sweating, restlessness.
• Peripheral neuropathy, typically motor-predominant and can progress to severe weakness or even respiratory failure requiring ventilation if unrecognised and untreated --- this is the life-threatening dimension of an acute attack.
• Psychiatric symptoms: anxiety, agitation, confusion, hallucinations, seizures (which can also result from hyponatraemia, a common complication).
• Hyponatraemia, from SIADH or gastrointestinal losses, can itself worsen neurological symptoms and seizure risk.
• Dark urine that turns darker (port-wine coloured) on standing or exposure to light, due to porphobilinogen/porphyrin oxidation.
• Variegate porphyria and hereditary coproporphyria additionally cause cutaneous blistering photosensitivity, particularly during or after an acute attack.

Cutaneous disease (porphyria cutanea tarda)

• Fragile skin, blistering and erosions on sun-exposed areas (dorsum of hands, face), hyperpigmentation, hypertrichosis, and milia on healing.
• No acute neurovisceral symptoms.

• During an acute attack: urinary porphobilinogen (PBG) and delta-aminolevulinic acid (ALA), markedly elevated in all acute hepatic porphyrias --- this is the essential screening test and should be sent urgently (protected from light) in any patient with unexplained severe abdominal pain, neuropathy and psychiatric symptoms, particularly with a compatible drug or fasting trigger.
• Spot urine porphobilinogen is the fastest useful test; a normal result during symptoms essentially excludes an acute porphyric attack.
• Further characterisation (once an acute attack is biochemically confirmed) with 24-hour urinary and faecal porphyrin fractionation, and plasma porphyrin fluorescence scanning, distinguishes AIP from variegate porphyria and hereditary coproporphyria.
• Genetic testing for definitive enzyme/mutation characterisation and for family screening of asymptomatic relatives.
• Sodium and full blood count/renal function during an acute attack given risk of hyponatraemia and to assess severity.
• Porphyria cutanea tarda: elevated urinary and plasma uroporphyrin, with normal PBG/ALA (distinguishing it from an acute porphyria); investigate for hepatitis C, iron overload (ferritin, transferrin saturation), and HIV given strong associations.

Acute attack

• Stop and avoid all porphyrinogenic drugs immediately --- check every medication against a validated porphyria drug safety list.
• Intravenous haem arginate (or haematin), the specific and most effective treatment, which suppresses hepatic ALA synthase activity via negative feedback, reducing precursor accumulation; started as early as possible in a confirmed or strongly suspected attack.
• High carbohydrate intake (oral or intravenous glucose if unable to eat), which also suppresses ALA synthase, though less effectively than haem arginate; used for mild attacks or as an adjunct.
• Aggressive symptomatic management: opioids for pain (safe in porphyria), antiemetics (selecting porphyria-safe agents), and beta blockers for tachycardia/hypertension if needed (checking safety).
• Correct hyponatraemia carefully, avoiding overly rapid correction.
• Monitor closely for neurological deterioration (motor weakness, respiratory muscle involvement) with regular assessment of respiratory function (vital capacity) given the risk of rapid progression to respiratory failure requiring ventilatory support.
• Seizure management with porphyria-safe anticonvulsants (many standard agents, including phenytoin and sodium valproate, are porphyrinogenic).
• Address and remove any identifiable precipitant (treat infection, stop causative drugs, ensure adequate nutrition).

Recurrent attacks / prevention

• Givosiran, a small interfering RNA (siRNA) therapy targeting hepatic ALA synthase 1, given subcutaneously, is a major advance for patients with recurrent acute attacks, substantially reducing attack frequency.
• Prophylactic haem arginate infusions in selected patients with frequent attacks.
• Liver transplantation is curative and reserved for severe, refractory, disabling recurrent disease.
• Gonadotrophin-releasing hormone agonists for women with attacks clustering with the menstrual cycle.

General/lifelong measures

• Patient education, a medical alert bracelet/card, and a porphyria-safe drug reference for the patient and all treating clinicians.
• Avoid fasting and crash dieting; maintain regular carbohydrate intake, particularly during illness.
• Genetic counselling and screening of at-risk relatives, given low penetrance means many carriers are asymptomatic but still need to avoid precipitants.
• Regular monitoring for long-term complications in patients with recurrent attacks: chronic kidney disease, hypertension, and hepatocellular carcinoma (particularly in AIP).

Porphyria cutanea tarda specifically

• Treat underlying causes: hepatitis C antiviral therapy, alcohol cessation, stop oestrogen-containing medication, screen and treat iron overload.
• Therapeutic phlebotomy to reduce hepatic iron, which is highly effective and often first-line.
• Low-dose hydroxychloroquine as an alternative or adjunct, chelating porphyrins and enhancing their excretion.
• Sun protection (broad-spectrum, physical barrier since porphyrins absorb visible light which standard UV-only sunscreens do not block).