Porphyrias

• Porphyrias are rare disorders of haem (heme) synthesis. Each is caused by a partial deficiency of one enzyme in the eight-step pathway that makes haem, most of which is produced in bone marrow and liver.
• The enzyme block determines which intermediates accumulate. Early-block disorders such as acute intermittent porphyria (AIP) let neurotoxic precursors build up and cause acute neurovisceral attacks: severe abdominal pain, autonomic instability, and neuropathy.
• Late-block, cutaneous disorders such as porphyria cutanea tarda (PCT) let photoactive porphyrins accumulate in skin and liver, giving blistering photosensitivity on sun-exposed skin.
• AIP is the commonest acute hepatic porphyria; PCT is the commonest porphyria overall. Both are treatable: AIP with intravenous haemin and modern RNA therapy, PCT with phlebotomy or low-dose hydroxychloroquine plus treatment of its triggers.
• The key diagnostic step in AIP is a random urine test for porphobilinogen and delta-aminolaevulinic acid; in PCT it is plasma and urine porphyrin profiling. Genetic testing confirms the type. ^[4]

By the end of this page you should be able to:

1. Explain how an enzyme defect in haem synthesis produces different diseases depending on where the block sits and which intermediates accumulate.
2. Recognise an acute attack of AIP from its clinical picture and say which simple urine test establishes the diagnosis.
3. List the common triggers of an acute attack and the drugs and situations to avoid.
4. Describe the blistering photosensitivity of PCT, its susceptibility factors, and how it is distinguished from variegate and hereditary coproporphyria.
5. Plan first-line, second-line and prophylactic treatment for AIP, including doses of haemin and givosiran.
6. Plan treatment for PCT, including phlebotomy, hydroxychloroquine dosing and when to use direct-acting antivirals.
7. State the long-term complications of AIP and PCT and the surveillance they require.

Eight principal porphyrias are recognised, one for each enzyme of the pathway. They are grouped in two ways that both matter clinically: ^[2]

• By site of major accumulation: erythropoietic (marrow) or hepatic (liver).
• By presentation: acute hepatic porphyrias (AHPs), which cause sudden neurovisceral attacks, and cutaneous porphyrias, which cause photosensitivity.

The acute hepatic porphyrias are AIP, variegate porphyria (VP), hereditary coproporphyria (HCP) and ALA dehydratase deficiency porphyria (ADP). PCT is the commonest cutaneous porphyria. VP and HCP can present with both attacks and blistering skin lesions, which is the main diagnostic trap in this topic.

PCT is split into two forms. Type I is sporadic and accounts for roughly 80% of cases: an acquired inhibition of UROD in the liver. Type II is autosomal dominant, with a germline UROD mutation, but its enzyme reduction is only 50%, so clinical disease still needs environmental triggers.^[1] Hepatoerythropoietic porphyria is the rare, severe, autosomal recessive form with onset in early childhood and near-absent UROD activity.^[1][3]

AIP is the commonest acute hepatic porphyria. Symptomatic AIP affects roughly 1 in 100,000 people, and AHPs overall about 5 in 100,000.^[2][4] One Portuguese review gives AIP a prevalence of about 1 in 1,700 persons, with an incidence of 0.13 new cases per million person-years, reflecting the large pool of asymptomatic carriers.^[2] Pathogenic HMBS variants are carried by about 1 in 1,300 to 1 in 1,785 people, and phenotypic penetrance in unselected carriers is around 1%, rising to over 20% in families with symptomatic disease.^[4] Founder mutations raise prevalence in some populations, for example Sweden.^[1]

ADP is ultra-rare, with fewer than a dozen cases reported, and its attacks often begin in childhood.^[4]

PCT is the commonest porphyria overall, with a prevalence of roughly 1 in 10,000 in Norway and 1 in 25,000 in the USA.^[1] Sporadic PCT peaks in middle age; familial PCT may present earlier when triggers are present.

Women predominate among symptomatic AHP patients: about 90% are women, and attacks are rare before menses and after menopause. Acute episodes occur about four times more often in women than in men.^[2][4] Givosiran is approved for adults (USA) or persons 12 years and older (European Union).^[4]

AIP, VP, HCP and ADP are mostly inherited. AIP is autosomal dominant with low penetrance, with more than 400 HMBS (porphobilinogen deaminase, also called hydroxymethylbilane synthase) mutations documented.^[1] Enzyme activity is reduced by at least half in carriers, yet most never have an attack.^[4]

PCT type I is acquired: no germline mutation. It arises when hepatic UROD is inhibited by a combination of factors, most of which produce liver iron overload. The recognised susceptibility factors are smoking, alcohol use, oestrogen use, HIV infection, hepatitis C infection, haemochromatosis and iron overload.^[1][3] Clinical disease in PCT usually appears only when at least two such factors, including a UROD mutation in familial cases, are present.^[1] HIV is detected in about 13% of PCT patients.^[3]

Sporadic mutations occur, and triggers or family history are not always present. Family history should never be required before considering the diagnosis.^[2]

Haem is synthesised in eight steps; most of the body's haem (75 to 80%) is made in bone marrow and 15 to 20% in hepatocytes.^[2] The pathway begins in mitochondria, where glycine and succinyl-CoA condense to form delta-aminolaevulinic acid (ALA), catalysed by ALA synthase (ALAS). Two ALAS isoforms exist. ALAS1 is the rate-limiting enzyme in hepatocytes and is under negative feedback from haem. ALAS2 is the erythroid isoform. Precipitating factors up-regulate ALAS1, which is the final common mechanism of every acute attack.^[2][4]

ALA becomes porphobilinogen (PBG), then hydroxymethylbilane, and finally haem after five more reactions. A partial enzyme block raises the substrates upstream of it. Where the block falls determines the phenotype:

• Early blocks (ALAD, porphobilinogen deaminase, coproporphyrinogen oxidase, protoporphyrinogen oxidase) raise ALA and/or PBG. These precursors are water-soluble, neurotoxic, and excreted in urine. They act on the autonomic, peripheral and central nervous systems. ALA is the principal neurotoxin, which is why pain, neuropathy and autonomic instability dominate.
• Late blocks (UROD, and uroporphyrinogen III synthase for CEP) raise photoactive porphyrins such as uroporphyrins and heptacarboxyl porphyrins. These are lipid-soluble, deposit in skin and liver, and generate reactive oxygen species when exposed to visible light, producing blistering, fragility and scarring.

AIP in particular produces no skin lesions: ALA and PBG are not photoactive. An absence of photosensitivity therefore does not exclude an acute porphyria.^[1]

PCT specifically arises from UROD activity reduced to about 25% in the liver. The inhibitor is a uroporphomethene generated by iron-dependent partial oxidation of uroporphyrinogen, catalysed in part by cytochrome P450 1A2. Hence the central role of iron in both sporadic and familial PCT. UROD flux in a heterozygous type II patient is reduced by 50%, but 20% residual activity suffices for normal haem synthesis, so the block becomes clinical only with triggers.^[1][3]

VP and HCP accumulate both porphyrin precursors and porphyrins, so they can cause both neurovisceral attacks and blistering photosensitivity. This explains the diagnostic confusion with PCT.

An AIP attack is a neurovisceral syndrome, not a pain syndrome of one organ. Severe abdominal pain is the hallmark, present in 74 to 100% of cases and lasting from hours to several days.^[2] The pain is diffuse and colicky, often with nausea, vomiting, constipation and dark urine. Despite its severity, the abdomen is not rigid and there are no focal signs.^[2]

Autonomic findings include tachycardia, hypertension and, importantly, hyponatraemia, which worsens the risk of seizures and mental state change.^[2] Neurological features follow or accompany the attack: limb pain, proximal muscle weakness, paresthesia in a stocking-glove distribution, neuropathic pain, and, in severe cases, paralysis and respiratory failure. Central features include anxiety, agitation, confusion, hallucinations, depression and seizures. Constipation is common. Neuropsychiatric symptoms occur in roughly 20 to 58% of patients.^[2]

Women aged 15 to 50 years with recurrent unexplained severe abdominal pain are the classic presentation; attacks are rare before menarche and after menopause. Many attacks cluster in the luteal phase, driven by progesterone.^[2][4] Over 90% of symptomatic patients have only one or a few attacks in their lives, but a small group, about 3 to 5%, have recurrent attacks (4 or more per year).^[4]

Clinical clues that distinguish an acute porphyric attack from surgical abdomen:

• pain disproportionate to physical findings;
• unexplained hyponatraemia;
• dark urine (reddish-brown);
• neuropathy or neuropsychiatric features;
• tachycardia and hypertension without fever;
• a history of similar episodes precipitated by fasting, infection, or a porphyrinogenic drug.

Between attacks, most patients recover fully. Those with recurrent attacks report chronic pain, nausea, fatigue, neuropathy, anxiety and sleep disturbance, and have markedly impaired quality of life. Roughly 60% of symptomatic AIP patients have porphyria-associated kidney disease with concomitant hypertension, losing about 1 mL/min/1.73 m2 of glomerular filtration per year in affected cases.^[1][4] AIP and the other AHPs also carry an increased risk of hepatocellular carcinoma and cholangiocarcinoma.^[4]

PCT presents in adults with painless blistering and fragile skin on light-exposed areas: dorsal hands, fingers, forearms and face. Bullae rupture into slow-healing erosions and scars, with milia, pigment change and hypertrichosis (excess facial or forearm hair).^[3] Lesions are most often on the backs of the hands and around the mouth.^[3] Photosensitivity is chronic rather than acute. Unlike AIP, PCT has no neurovisceral attack. Long-term risks include liver cirrhosis and hepatocellular carcinoma.^[1]

PCT should not be confused with pseudoporphyria, a clinically and histologically similar bullous photodermatosis with normal porphyrin levels, associated with NSAIDs, retinoids, antibiotics, diuretics and chronic kidney disease.^[1]

Variegate and hereditary coproporphyria produce neurovisceral attacks like AIP plus blistering lesions like PCT. Given that their cutaneous features are clinically identical to PCT, a patient presenting with blisters must be investigated for all three before a diagnosis of PCT is settled.^[1][2]

For the patient with severe recurrent abdominal pain the differential includes acute abdomen, functional bowel disease, irritable bowel syndrome, diabetic gastroparesis, lead poisoning and tabes dorsalis. For the patient with photosensitivity it includes PCT's mimics, VP and HCP, pseudoporphyria, cutaneous lupus, epidermolysis bullosa, and porphyria cutanea tarda overlap with liver disease shown in the table below.

The first-line test in every AHP is a random urine sample for PBG, ALA and creatinine, collected during or shortly after an attack. A 24-hour collection is unnecessary and impractical. Results should be normalised to creatinine.^[4][2]

• During attacks, both ALA and PBG are raised at least 5-fold above the upper limit of normal in all AHPs except ADP, where only ALA is raised.^[4]
• Urinary PBG and/or ALA above 10 mg/g creatinine are highly specific for an AHP; values are usually below 2 to 4 mg/g creatinine in health.^[2]
• Urine porphyrins alone must not be used to screen for AHP: mild secondary porphyrinuria is common in liver and biliary disease, alcohol use and drug exposure, and leads to overdiagnosis.^[1][4]

Testing is most useful during an attack. In sporadic AIP, 15 to 44% of patients have normal urine ALA and PBG between attacks; the proportion is at least as high in VP and HCP.^[4] ALA and PBG can fall quickly after VP or HCP attacks, whereas they may persist for months to years in AIP. If suspicion remains, repeat testing during symptoms. Rapid qualitative PBG tests (Hoesch, Watson-Schwartz) exist and give a red colour when positive, but have limited sensitivity and miss ADP because they do not measure ALA.^[2]

Second-line tests to define the subtype include plasma and stool porphyrins and plasma fluorescence (VP shows a peak at about 626 nm). Raised urine coproporphyrin relative to protoporphyrin, with coproporphyrin III at 60 to 95% of total, suggests HCP.^[2]

Definitive diagnosis is genetic: sequencing of HMBS, CPOX, PPOX and ALAD.^[2][4] Once a pathogenic variant is known, first-degree relatives are offered testing and counselling.^[4]

Diagnosis rests on biochemical testing: raised plasma and urine porphyrins, with a predominance of uroporphyrin and heptacarboxyl porphyrin.^[1] A skin biopsy supports the diagnosis by showing subepidermal blistering and vessel wall thickening, but these findings are not specific; pseudoporphyria looks identical histologically. The distinction rests on porphyrin studies and on searching for susceptibility factors and, where relevant, UROD mutation testing.^[1]

• Serum ferritin and iron studies, to quantify iron load (PCT, and secondary iron overload from prophylactic haemin).
• Creatinine and estimated glomerular filtration rate, because of porphyria-associated kidney disease.^[4]
• Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin and albumin, to assess the liver.
• Alpha-fetoprotein and liver ultrasound from age 50 for HCC surveillance.^[4]

There are no universal staging scores, but several thresholds guide management:

• In AHP, during an attack, urinary ALA and PBG are raised at least 5-fold the upper limit of normal, and values above 10 mg/g creatinine are highly specific.^[2][4]
• Recurrent attacks are defined as 4 or more acute attacks in the past year after 1 to 2 years of standard treatment.^[2]
• In PCT, serum ferritin guides treatment choice: hydroxychloroquine or chloroquine can be preferred when ferritin is under 500 ng/mL, whereas phlebotomy is used when iron overload is more marked.^[3]
• In AIP on prophylactic haemin, ferritin above 1000 ng/mL indicates secondary iron overload and should prompt therapeutic phlebotomy.^[4]
• HCC surveillance begins at age 50 with liver ultrasound every 6 months, in AIP and the other AHPs.^[4]

In PCT, two susceptibility factors (including a UROD mutation) are generally required before clinical disease appears.^[1]

Start treatment on clinical grounds as soon as the diagnosis is likely; do not wait for confirmation, because acute attacks can progress to paralysis, respiratory failure and death. The goals are to reduce hepatic ALAS1 expression and to treat symptoms.

1. Remove triggers immediately: stop porphyrinogenic drugs, treat infections, provide calories.
2. Carbohydrate loading: an oral high-carbohydrate diet supplying 55 to 60% of calories if tolerated. If not, intravenous 5% dextrose in saline, to a maximum of 2 litres per day, or 10 to 20% glucose if haemin is unavailable.^{[2] [4]}
3. Intravenous haemin for any attack severe enough to require hospital admission: 3 to 4 mg/kg once daily, usually for 4 days (the AGA update frames this as 3 to 5 days), to a maximum of about 250 mg per day. Collect a random urine for ALA, PBG and creatinine before starting. Give it into a high-flow central vein through a PICC line or port; a peripheral vein risks thrombophlebitis. Hemin stabilised with human serum albumin is preferred (a 350 mg vial diluted in 147 mL of 25% albumin).^[2][4]
4. Symptom control: acetaminophen (paracetamol) and NSAIDs such as ibuprofen or naproxen are first-line for mild pain; morphine for severe pain. Nausea and vomiting need early treatment with ondansetron, chlorpromazine or promethazine. Constipation usually responds to lactulose.^[2]
5. Electrolytes: monitor sodium and magnesium; correct hyponatraemia slowly. For seizures, benzodiazepines, magnesium sulfate and levetiracetam appear safe; avoid phenobarbitone, phenytoin, carbamazepine and valproate, which are unsafe.^{[4] [2]}
6. Analgesia and antiemetics should be given early and adequately; attacks are very painful.

Haemin acts quickly: symptoms improve as ALA and PBG are cleared, typically over 48 to 72 hours, although neurological recovery varies. ^[4]

Treatment works by removing the trigger and depleting hepatic iron, which restores UROD activity.

• Treat the cause first: correct alcohol use, stop smoking, stop oestrogen where possible, treat or refer hepatitis C. Eradication of hepatitis C with direct-acting antivirals usually resolves PCT and normalises urinary porphyrins; interferon-based regimens are avoided because they may worsen PCT initially.^[3]
• Phlebotomy is the mainstay: repeated removal of blood depletes iron and restores UROD activity, leading to biochemical and clinical remission. It is contraindicated with severe cirrhotic anaemia or iron-loading myelodysplastic syndromes.^[1][3]
• Hydroxychloroquine (or chloroquine) is preferred to phlebotomy when ferritin is not exceedingly high, that is under 500 ng/mL. Low-dose regimens are used to avoid drug-induced hepatitis: hydroxychloroquine 100 mg or 200 mg twice weekly, or chloroquine 125 mg or 250 mg twice weekly. It is contraindicated in pregnancy and in liver, retinal and hepatotoxic-drug exposure.^[3]
• Iron chelation (desferrioxamine or deferasirox) has been used when phlebotomy is contraindicated.^[3]
• Photoprotection and sun avoidance are essential supportive measures, with broad-spectrum sunscreen and protective clothing.
• Monitor serum ferritin for relapse after phlebotomy, and urine and plasma porphyrins for recurrence.^[1]

HIV is found in about 13% of PCT patients, so test for it, along with HCV and haemochromatosis, when PCT is diagnosed.^[3]

Recurrent attacks (4 or more per year) are challenging. After 1 to 2 years of standard prophylaxis:

• Prophylactic intravenous haemin, 3 mg/kg once weekly, can be tried off-label, but its preventive effect is less certain than its effect on an acute attack, and chronic use carries thrombophlebitis, coagulation abnormality and secondary iron overload. Patients on it need ferritin checked every 3 to 6 months.^[2][4]
• Givosiran, a small interfering RNA targeting hepatic ALAS1, given subcutaneously at 2.5 mg/kg once a month. It is approved for adults with AHP (USA) and persons 12 years and older (EU), with both biochemical and genetic confirmation, and it lowers ALA and PBG and reduces attack frequency. It should not be used in pregnancy or when pregnancy is planned. Monitor liver enzymes, creatinine, homocysteine, amylase and lipase; transaminase elevations above 3 times the upper limit of normal have been seen in the first 3 to 6 months.^[2][4]
• GnRH analogues help menstrual-cycle-related attacks by suppressing the progesterone peak, at the cost of oestrogen deficiency. Annual bone density scanning and gynaecological review are advised.^[2][4]
• Liver transplantation is curative, normalising ALA and PBG and resolving attacks, and is reserved for intractable, treatment-refractory disease. One-year and five-year survival are about 92% and 82%.^[4]

• Sporadic attacks: review every 6 months; recurrent attacks every 3 months.^[2]
• Urine ALA and PBG, full blood count and metabolic panel with liver enzymes, electrolytes, urea and creatinine at each visit.^[2][4]
• Annual alpha-fetoprotein and 6-monthly liver ultrasound from age 50 for HCC.^[2][4]
• Colon and renal screening: annual creatinine and estimated glomerular filtration rate; abdominal and renal ultrasound and cardiac evaluation at least annually for symptomatic patients.^[4]
• For givosiran: monthly liver and renal tests and homocysteine for the first 3 months, then every 3 to 6 months.^[2][4]
• For asymptomatic carriers: annual review with urine ALA/PBG, full blood count, liver and renal panel, and HCC surveillance from age 50.^[2][4]

• Neurological: during and after attacks, motor neuropathy, paralysis and respiratory failure; seizures from hyponatraemia.
• Renal: porphyria-associated kidney disease and hypertension in 29% (CKD) to 59% (PAKD) of symptomatic AIP patients.^[4]
• Hepatic: chronic enzyme elevation; hepatocellular carcinoma in 1.5 to 1.8% of AHP patients, often without cirrhosis, predominantly AIP.^[4]
• Iron overload from chronic haemin, with ferritin above 1000 ng/mL.^[4]
• PCT: liver cirrhosis and hepatocellular carcinoma; scarring and milia from chronic photosensitivity.^[1]
• Givosiran-related: raised homocysteine, transaminase elevation, renal function decline, injection-site reactions, pancreatitis, retinal vein thrombosis.^[2][4]

Mortality from an untreated acute attack used to be high; with current care it is near zero, although residual neurological damage or chronic pain can persist. Most patients are symptom-free between attacks. Chronic recurrent disease carries a high burden of pain, fatigue and reduced quality of life. With surveillance, HCC and CKD are detected and managed.^[2][4]

Primary prevention is trigger avoidance: fasting and crash dieting, certain drugs, excess alcohol, smoking, infection and stress. Patients should be counselled with a recognised drug-safety database for the acute porphyrias.^[2][4] HCV should be treated when present. HCC, CKD and iron overload are screened as above. First-degree relatives of an AIP patient are offered genetic testing and counselling.^[4]

• Pregnancy: attacks may worsen; givosiran is contraindicated in pregnancy and when pregnancy is planned. Haemin is used for acute attacks when needed. Iron overload aside, oestrogen use can trigger PCT, so review hormonal contraception in PCT.^[3][4]
• Children: AIP and ADP can present in childhood; ADP is autosomal recessive and severe. Paediatric management requires specialist care. Givosiran is approved from age 12 in the EU.^[4]
• Older adults: HCC surveillance begins at 50; monitoring should be individualised when life expectancy is short.
• Immunocompromised/HIV: HIV is a recognised PCT Trigger and should be sought and treated.^[1]

• A random urine test for PBG and ALA, or even a rapid bedside Hoesch test that turns red when PBG is present, is the single most useful step when an acute abdomen might be an attack, but send a sample for quantitative testing as soon as possible.^[2][4]
• If haemin is unavailable, use intravenous glucose and aggressive carbohydrate feeding, plus trigger removal, analgesia and antiemetics.^[2]
• In PCT, phlebotomy and removal of triggers are low-cost and effective; where phlebotomy is not feasible, consider low-dose chloroquine, with attention to pregnancy, liver disease and retinal safety.^[3]
• Any blistering photosensitivity with an adult onset needs plasma and urine porphyrin profiling, not just a skin biopsy.^[1]
• Where specialist care is distant, use telemedicine or referral pathways early; involve regional porphyria centres when available.

• Porphyrias are disorders of haem synthesis: each enzyme defect accumulates its own substrate, producing either neurotoxicity (AIP) or photosensitivity (PCT).
• AIP presents with severe recurrent abdominal pain plus autonomic and neurological features, dark urine and hyponatraemia, often in women aged 15 to 50 years.
• PCT is the commonest porphyria, with adult blistering photosensitivity on sun-exposed skin, and is driven by hepatic UROD inhibition and iron.
• VP and HCP combine attack and skin features; confirm the type with porphyrins and genetics before settling on a diagnosis.
• In AIP, diagnose with random urine PBG and ALA normalised to creatinine; do not use urine porphyrins alone.
• Treat severe attacks with intravenous haemin 3 to 4 mg/kg daily for 4, or 3 to 5, days, plus carbohydrate loading, analgesia, antiemetics and electrolyte care.
• Recurrent attacks (4 or more per year) warrant prophylactic haemin or monthly givosiran 2.5 mg/kg; givosiran is contraindicated in pregnancy.
• PCT needs treatment of triggers, then phlebotomy or low-dose hydroxychloroquine, guided by ferritin (under 500 ng/mL for the oral agent).
• Cessation of porphyrinogenic triggers, HCV treatment and first-degree relative testing are central to prevention.
• Long-term surveillance covers HCC from age 50 with 6-monthly ultrasound, renal function, iron status and, in PCT, liver biochemistry and imaging. ^[3]

Acute abdominal pain; biochemical tests and reference ranges; hepatitis C and direct-acting antivirals; haemochromatosis and iron overload; cytochrome P450 enzyme induction; drug safety in porphyria; chronic kidney disease and hypertension; liver cancer surveillance; pregnancy and drug safety; photodermatoses.