RARE DISEASE
Acute intermittent porphyria
Acute intermittent porphyria
Acute intermittent porphyria
Drug discovery
2
drugs
With orphan designations
Overview
Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by hydroxymethylbilane synthase (HMBS) deficiency, leading to accumulation of neurotoxic porphyrin precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). It manifests as acute neurovisceral attacks characterized by severe abdominal pain, autonomic instability, psychiatric symptoms, and potentially life-threatening paralysis. Attacks are triggered by factors like certain medications, hormonal changes, fasting, and alcohol. Diagnosis requires elevated urinary PBG during acute episodes. First-line treatment involves intravenous heme preparations (e.g., Panhematin®) to suppress hepatic ALAS1 activity. [3][6][9][11]
Population
Symptomatic prevalence: ~5.9/million in Europe, with regional variations (up to 192/million in Northern Sweden) [7][9][12]
80-90% of HMBS mutation carriers remain asymptomatic; 80% of symptomatic cases occur in women of reproductive age [2][9][17]
Estimated HMBS mutation prevalence 1:1,300 with clinical penetrance <1% in general populations [7][12][17]
Burden
Recurrent cases (3-5% of symptomatic patients) account for >95% of hospitalization costs (median 82 days/patient) [4][12][16]
Chronic complications: 60-90% develop hypertension, 40-60% chronic kidney disease, 5-8% hepatocellular carcinoma [4][9][12]
Median direct healthcare costs: €292,000 vs €2,200 for recurrent vs single-attack patients [4][12]
Therapies
Acute attacks: IV hemin (Panhematin®) + high-dose carbohydrates; symptom control with porphyria-safe analgesics (morphine, fentanyl) and antiemetics [3][6][16][18]
Prevention: Trigger avoidance, prophylactic heme infusions, and siRNA therapy (givosiran) for recurrent attacks (>4/year) [5][18][6]
Emerging options: mRNA therapy and liver transplantation for refractory cases [5][8][18]
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
438 drug discovery papers about Acute intermittent porphyria, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
438 drug discovery papers about Acute intermittent porphyria, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-12 | Tolerability of hormonal treatments in acute hepatic porphyria patients.
Acute hepatic porphyria (AHP) flares have been associated with female hormones and the use of hormonal treatments. Women with AHP are traditionally advised to avoid exogenous oestrogen and progesterone, limiting options for contraception and management of menorrhagia, dysmenorrhoea and menopausal symptoms. Evidence on specific hormonal therapies is limited; a 2003 study found that 25% of women with acute intermittent porphyria (AIP) experienced attacks with contraceptives containing progesterone, oestrogen or both. To update the current understanding of the tolerability of hormonal treatments in women with AHP. An anonymous questionnaire was distributed to women with AHP (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) via hospital records and a national patient support group, capturing prior hormonal therapy use and associated flares. Thirty responses were analysed; 23 participants had used hormonal therapies. Flares were most frequent in hereditary coproporphyria (66%) and less common in variegate porphyria and acute intermittent porphyria (~20%). No flares were reported with hormone replacement therapy, the progesterone-only pill or progesterone implants. Flares occurred with combined oral contraceptives (46.6%) and progesterone-containing intrauterine devices (28.5%), particularly drospirenone-containing pills. Levonorgestrel-based therapies, including the Mirena IUD, were better tolerated and often improved symptoms. Although limited by sample size and retrospective design, this study provides clinically useful data on the tolerability of specific hormonal therapies in women with AHP, supporting personalised prescribing and patient counselling for contraception and symptom management.
2026-07-01 | Diagnosis and management of acute intermittent porphyria in teenage fraternal twins
Background Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder caused by pathogenic variants in hydroxymethylbilane synthase ( HMBS ). Different factors including hormonal fluctuations trigger neurovisceral attacks. Pediatric data on prophylactic therapies, particularly the small interfering RNA therapeutic givosiran, remain limited. Case presentation We report dizygotic/fraternal twin teenage girls, both 15 years old, who presented separately with acute abdominal and hip pain, hypertension, and tachycardia. In both patients, symptoms were temporally associated with menses and reduced oral intake. Biochemical evaluation revealed markedly elevated urinary δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Genetic testing confirmed a heterozygous pathogenic HMBS variant (c.730_731del; p.Leu244Alafs⁎6) in both patients. Acute attacks were treated with intravenous hemin (4 mg/kg/day for four days with significant symptom resolution). Recurrent attacks in Patient A initially prompted prophylactic monthly hemin infusion, followed by transition to subcutaneous givosiran (2.5 mg/kg monthly). Patient B had a milder clinical course but was also started on prophylactic therapy after shared decision-making because of her confirmed genotype, biochemical activity, strong family history, and her fraternal twin sister’s recurrent course. Both patients demonstrated sustained reductions in urinary PBG and absence of recurrent attacks on givosiran. Despite sharing the same familial pathogenic HMBS variant, the twins exhibited variable disease severity, with Patient B ultimately requesting a supervised trial discontinuation of givosiran after a prolonged attack-free period. Conclusion This case series highlights the diagnostic approach to AIP in adolescents and adds to the limited pediatric experience with givosiran. Phenotypic variability despite identical HMBS variants underscores incomplete penetrance, potential genetic or epigenetic modifiers, environmental triggers, and the need for individualized management.
2026-06-19 | [Acute intermittent porphyria: When diagnostic errance jeopardizes patient health].
Acute intermittent porphyria is a rare genetic disorder characterized by an enzyme deficiency in heme synthesis, causing an accumulation of neurotoxic precursors. Its clinical symptoms include abdominal and/or lumbar pain, reddish-brown urine, and neuropsychiatric signs. We report the case of a young female patient who presented with several episodes of intense low back pain followed by confusion, visual hallucinations, epileptic seizures, and severe dysautonomia with hypotension and impaired alertness. The diagnosis was established after several weeks of investigation, one year after the onset of symptoms. The course of the disease was marked by an early relapse without any triggering factor, which led to treatment with givosiran, which was spectacularly successful. Treatment-induced hyperhomocysteinemia was successfully corrected with pyridoxine. It is essential to be aware of the epidemiology, risk factors, and suggestive symptoms of this potentially serious treatable disease to reduce diagnostic uncertainty, limit long-term complications, and improve prognosis.
2026-05-18 | A Delayed Progression of Porphyria-Associated Kidney Disease After Hemin Therapy in a Patient with Acute Intermittent Porphyria: A Case Report.
Acute intermittent porphyria (AIP) is a condition characterized by the neurotoxic accumulation of δ-aminolevulinic acid and porphobilinogen. However, chronic kidney disease is an under-recognized complication. A 50-year-old woman experienced recurrent abdominal pain with repeated acute kidney injury and hyponatremia, resulting in a rapid decline in renal function. Marked elevations of both metabolites, as well as her genetic mutation, confirmed AIP. The administration of hemin markedly decreased the frequency of porphyria attacks and significantly attenuated the annual estimated glomerular filtration rate decline. Although the patient eventually developed end-stage kidney disease, hemin treatment slowed the progression of renal failure.
2026-05-02 | Severe peripheral neuropathy secondary to acute intermittent porphyria caused by a rare HMBS gene mutation: a case report.
Peripheral neuropathy is caused by numerous etiologies, such as immune, infectious, neoplastic, metabolic, toxic, traumatic, vasculitic, hereditary factors, etc. Each etiological type has no special manifestation, and the misdiagnosis rate is relatively high. Acute intermittent porphyria (AIP) is a rare disease, often complicated by peripheral nerve injury, and can develop sequelae after delayed diagnosis or treatment. A 26-year-old female patient presented with recurrent abdominal pain, limb numbness and weakness, and autonomic neuropathy. Symptoms aggravated and respiratory and circulatory failure develop gradually, following the recurrence of the disease. She was initially diagnosed with neurosis, intestinal obstruction, and Guillain-Barré syndrome. She underwent treatment for inflammatory peripheral neuropathy, including intravenous immunoglobulin (IVIG) and plasmapheresis; however, no improvement in symptoms was observed. Clinical assessment revealed brown urine that turned reddish-brown after sunlight exposure. Whole exome sequencing (WES) identified a mutation in the HMBS gene (exon 10, c.651G > C, p.Gln217His), which was confirmed through Sanger sequencing and diagnosed as rare AIP with severe peripheral nerve damage. Numbness and weakness gradually improved after the initiation of hemin therapy and high-carbohydrate therapy. The AIP is an easily missed or misdiagnosed disease. In the absence of timely and effective intervention, patients are at risk of developing irreversible and permanent neurological damage. It is essential for clinicians to enhance their awareness of the disease to ensure prompt diagnosis, appropriate treatment, and avoidance of triggering factors.
2026-07-12 | Tolerability of hormonal treatments in acute hepatic porphyria patients.
Acute hepatic porphyria (AHP) flares have been associated with female hormones and the use of hormonal treatments. Women with AHP are traditionally advised to avoid exogenous oestrogen and progesterone, limiting options for contraception and management of menorrhagia, dysmenorrhoea and menopausal symptoms. Evidence on specific hormonal therapies is limited; a 2003 study found that 25% of women with acute intermittent porphyria (AIP) experienced attacks with contraceptives containing progesterone, oestrogen or both. To update the current understanding of the tolerability of hormonal treatments in women with AHP. An anonymous questionnaire was distributed to women with AHP (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) via hospital records and a national patient support group, capturing prior hormonal therapy use and associated flares. Thirty responses were analysed; 23 participants had used hormonal therapies. Flares were most frequent in hereditary coproporphyria (66%) and less common in variegate porphyria and acute intermittent porphyria (~20%). No flares were reported with hormone replacement therapy, the progesterone-only pill or progesterone implants. Flares occurred with combined oral contraceptives (46.6%) and progesterone-containing intrauterine devices (28.5%), particularly drospirenone-containing pills. Levonorgestrel-based therapies, including the Mirena IUD, were better tolerated and often improved symptoms. Although limited by sample size and retrospective design, this study provides clinically useful data on the tolerability of specific hormonal therapies in women with AHP, supporting personalised prescribing and patient counselling for contraception and symptom management.
2026-07-01 | Diagnosis and management of acute intermittent porphyria in teenage fraternal twins
Background Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder caused by pathogenic variants in hydroxymethylbilane synthase ( HMBS ). Different factors including hormonal fluctuations trigger neurovisceral attacks. Pediatric data on prophylactic therapies, particularly the small interfering RNA therapeutic givosiran, remain limited. Case presentation We report dizygotic/fraternal twin teenage girls, both 15 years old, who presented separately with acute abdominal and hip pain, hypertension, and tachycardia. In both patients, symptoms were temporally associated with menses and reduced oral intake. Biochemical evaluation revealed markedly elevated urinary δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Genetic testing confirmed a heterozygous pathogenic HMBS variant (c.730_731del; p.Leu244Alafs⁎6) in both patients. Acute attacks were treated with intravenous hemin (4 mg/kg/day for four days with significant symptom resolution). Recurrent attacks in Patient A initially prompted prophylactic monthly hemin infusion, followed by transition to subcutaneous givosiran (2.5 mg/kg monthly). Patient B had a milder clinical course but was also started on prophylactic therapy after shared decision-making because of her confirmed genotype, biochemical activity, strong family history, and her fraternal twin sister’s recurrent course. Both patients demonstrated sustained reductions in urinary PBG and absence of recurrent attacks on givosiran. Despite sharing the same familial pathogenic HMBS variant, the twins exhibited variable disease severity, with Patient B ultimately requesting a supervised trial discontinuation of givosiran after a prolonged attack-free period. Conclusion This case series highlights the diagnostic approach to AIP in adolescents and adds to the limited pediatric experience with givosiran. Phenotypic variability despite identical HMBS variants underscores incomplete penetrance, potential genetic or epigenetic modifiers, environmental triggers, and the need for individualized management.
2026-06-19 | [Acute intermittent porphyria: When diagnostic errance jeopardizes patient health].
Acute intermittent porphyria is a rare genetic disorder characterized by an enzyme deficiency in heme synthesis, causing an accumulation of neurotoxic precursors. Its clinical symptoms include abdominal and/or lumbar pain, reddish-brown urine, and neuropsychiatric signs. We report the case of a young female patient who presented with several episodes of intense low back pain followed by confusion, visual hallucinations, epileptic seizures, and severe dysautonomia with hypotension and impaired alertness. The diagnosis was established after several weeks of investigation, one year after the onset of symptoms. The course of the disease was marked by an early relapse without any triggering factor, which led to treatment with givosiran, which was spectacularly successful. Treatment-induced hyperhomocysteinemia was successfully corrected with pyridoxine. It is essential to be aware of the epidemiology, risk factors, and suggestive symptoms of this potentially serious treatable disease to reduce diagnostic uncertainty, limit long-term complications, and improve prognosis.
2026-05-18 | A Delayed Progression of Porphyria-Associated Kidney Disease After Hemin Therapy in a Patient with Acute Intermittent Porphyria: A Case Report.
Acute intermittent porphyria (AIP) is a condition characterized by the neurotoxic accumulation of δ-aminolevulinic acid and porphobilinogen. However, chronic kidney disease is an under-recognized complication. A 50-year-old woman experienced recurrent abdominal pain with repeated acute kidney injury and hyponatremia, resulting in a rapid decline in renal function. Marked elevations of both metabolites, as well as her genetic mutation, confirmed AIP. The administration of hemin markedly decreased the frequency of porphyria attacks and significantly attenuated the annual estimated glomerular filtration rate decline. Although the patient eventually developed end-stage kidney disease, hemin treatment slowed the progression of renal failure.
2026-05-02 | Severe peripheral neuropathy secondary to acute intermittent porphyria caused by a rare HMBS gene mutation: a case report.
Peripheral neuropathy is caused by numerous etiologies, such as immune, infectious, neoplastic, metabolic, toxic, traumatic, vasculitic, hereditary factors, etc. Each etiological type has no special manifestation, and the misdiagnosis rate is relatively high. Acute intermittent porphyria (AIP) is a rare disease, often complicated by peripheral nerve injury, and can develop sequelae after delayed diagnosis or treatment. A 26-year-old female patient presented with recurrent abdominal pain, limb numbness and weakness, and autonomic neuropathy. Symptoms aggravated and respiratory and circulatory failure develop gradually, following the recurrence of the disease. She was initially diagnosed with neurosis, intestinal obstruction, and Guillain-Barré syndrome. She underwent treatment for inflammatory peripheral neuropathy, including intravenous immunoglobulin (IVIG) and plasmapheresis; however, no improvement in symptoms was observed. Clinical assessment revealed brown urine that turned reddish-brown after sunlight exposure. Whole exome sequencing (WES) identified a mutation in the HMBS gene (exon 10, c.651G > C, p.Gln217His), which was confirmed through Sanger sequencing and diagnosed as rare AIP with severe peripheral nerve damage. Numbness and weakness gradually improved after the initiation of hemin therapy and high-carbohydrate therapy. The AIP is an easily missed or misdiagnosed disease. In the absence of timely and effective intervention, patients are at risk of developing irreversible and permanent neurological damage. It is essential for clinicians to enhance their awareness of the disease to ensure prompt diagnosis, appropriate treatment, and avoidance of triggering factors.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Acute intermittent porphyria.
2 orphan drug designations for Acute intermittent porphyria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant human porphobilinogen deaminase | proteins | FDA | 2002-09-09 | — | Chiesi USA, Inc. |
recombinant human porphobilinogen deaminase, erythropoetic form | proteins | FDA | 2002-07-11 | — | Chiesi USA, Inc. |
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