RARE DISEASE
Acute hepatic porphyria
Acute hepatic porphyria
Acute hepatic porphyria
Drug discovery
3
drugs
With orphan designations
Overview
Acute hepatic porphyria (AHP) encompasses four rare genetic disorders of heme biosynthesis (AIP, VP, HCP, and ADP), characterized by neurotoxic accumulation of δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients present with acute neurovisceral attacks featuring severe abdominal pain, autonomic instability, neuropathy, and psychiatric symptoms, often triggered by medications, hormonal changes, or fasting [2][12]. Diagnosis relies on elevated urinary PBG and ALA during attacks [12]. Treatment includes intravenous hemin, carbohydrate loading, and prophylactic givosiran to suppress ALAS1 [8][13]. Trigger avoidance and genetic counseling are essential components of management [1].
Burden
47% of patients report unemployment; 85% experience daily activity limitations due to chronic pain/fatigue [4].
Annualized attack rates: median 4.5 (IQR 2–12); 58.7% have moderate-to-severe depression [4][5].
Long-term risks: Chronic kidney disease (59% in symptomatic cases), hepatocellular carcinoma (monitor annually from age 50) [1][10][12].
Therapies
Acute attacks: IV hemin (3–4 mg/kg/day) ± high-dose glucose; pain management with opioids [8][13].
Prophylaxis: Monthly subcutaneous givosiran (siRNA) reduces recurrent attacks; routine hemin infusions or gonadotropin analogs for select cases [5][13].
Refractory cases: Liver transplantation (last-line) [10][13].
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
335 drug discovery papers about Acute hepatic porphyria, with 5 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
335 drug discovery papers about Acute hepatic porphyria, with 5 first-in-class and 4 next-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.
2026-02-27 | RNA as Medicine: The Pharmacological Revolution of Therapeutic Oligonucleotides- A Review article
Therapeutic oligonucleotides have matured into clinically validated medicines across neurology, hepatic/metabolic disease, cardiometabolic risk, and infectious disease. Antisense oligonucleotides (ASOs) act via RNase H–mediated degradation or splice modulation, with intrathecal splice-switching improving motor outcomes in spinal muscular atrophy and exhibiting month-scale CNS tissue half-lives. Gapmer ASOs that suppress transthyretin (TTR) synthesis deliver meaningful neuropathy improvements but require platelet and renal monitoring consistent with phosphorothioate backbones. Small interfering RNAs (siRNA) achieve potent, durable hepatic gene silencing through two delivery paradigms: subcutaneous N-acetylgalactosamine (GalNAc) conjugates with short plasma but long hepatic residence enabling quarterly to twice-yearly maintenance, and intravenous lipid nanoparticles (LNPs) that provide efficient hepatic uptake with manageable infusion reactions. Clinically, this translates to large attack reductions in acute hepatic porphyria, sustained ~50% LDL-C lowering with twice-yearly dosing in hypercholesterolemia, and ~90% TTR reduction with functional benefit in amyloidosis. mRNA vaccines using N1-methylpseudouridine and LNPs demonstrated rapid design-to-clinic timelines and high efficacy at population scale, establishing a manufacturable platform now extending toward therapeutic mRNA applications. Safety profiles largely reflect chemistry and delivery and are mitigable by sequence design, dosing strategies, premedication (for IV LNPs) - and routine laboratory monitoring. Extrahepatic targeting, stereo-controlled chemistries that enhance the potency without class toxicity and model based interval selection can expand organ reach and therapeutic breadth.
2025-10-01 | Rare Report of Simultaneous Liver and Kidney Transplant for Acute Intermittent Porphyria
Introduction: AIP is a rare autosomal dominant disorder of heme biosynthesis characterized by acute porphyric episodes caused by a deficiency of the hydroxymethylbilane synthase (HMBS) enzyme. These episodes present as abdominal pain, autonomic instability, and neurologic dysfunction resulting in AKI. Most patients experience infrequent episodes, while a subset develop relapsing porphyria leading to chronic kidney disease. Liver transplantation has been shown to reduce attacks by decreasing hepatic overproduction of porphyrin metabolites by replacing with HMBS producing hepatocytes. However, in patients with end-stage kidney disease (ESKD) and refractory symptoms, options are limited. Simultaneous liver-kidney transplant (SLKT) offers a comprehensive solution for these patients but has been rarely reported as a cure for AIP. Case Description: A 47-year-old woman with confirmed AIP via HMBS gene mutation experienced recurrent porphyric attacks since adolescence, which progressively worsened despite regular hemin infusions and plasmapheresis. Her urine porphyrins were quantified at 99 uM at age 33 which increased to 665 uM at age 37. She was later started on Givosiran, siRNA against ALA synthetase, reducing the frequency of her attacks but not preventing them. Over time, she developed ESKD from porphyrin-associated nephropathy, worsened by hypertensive crises during attacks, requiring peritoneal dialysis. Due to refractory symptoms and kidney failure, she was listed for SLKT. At the time of transplant, she received simulect induction and was discharged on tacrolimus, cellcept, and prednisone. Her Model for End-Stage Liver Disease (MELD) 3.0 score was elevated to 21 mainly due to her high creatinine (Cr). One month later, she underwent uncomplicated SLKT. Both allografts functioned immediately. She was discharged on tacrolimus, mycophenolate mofetil, and prednisone. 3 month follow up shows excellent liver allograft function with normal synthetic function, and kidney allograft function with Cr 0.9-1.1mg/dl. She has been able to stop givosiran and has had no porphyric attacks since SLKT. Discussion: This case details a rare, successful SLKT for AIP, leading to complete remission of porphyric symptoms and full recovery of kidney function. AIP is among a group of select disorders where combined transplant should be considered for optimal outcomes.
2025-09-25 | Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches
Porphyria refers to a group of rare inherited metabolic disorders caused by enzymatic deficiencies in the heme biosynthesis pathway. These deficiencies lead to the pathological accumulation of neurotoxic porphyrin precursors, resulting in multisystem damage. Currently, there are no curative therapeutic interventions, and patients frequently experience severe morbidity or life-threatening complications. Among the most critical manifestations is protoporphyric liver disease, in which hepatotoxic porphyrins and their precursors drive progressive hepatic injury and cholestasis. Persistent elevation of these metabolites can lead to irreversible parenchymal damage, significantly affecting both quality of life and long-term prognosis. The clinical presentation of porphyria-associated liver injury is highly variable and often has an insidious onset. However, a subset of patients may experience rapid progression to acute liver failure or fulminant hepatic dysfunction. Diagnosis is based on clinical evaluation and is confirmed by genetic testing. Current treatment strategies are focused on symptom management while underlying disease mechanisms remain unaddressed, posing significant therapeutic challenges. This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.
2025-06-11 | Managing Psychosis in Acute Intermittent Porphyria: A Case Report on Olanzapine Use
Acute intermittent porphyria (AIP) is the most common type of acute porphyria, caused by reduced porphobilinogen deaminase activity, leading to accumulations of neurotoxic compounds. Symptoms usually include abdominal pain, autonomic dysfunction, neurological involvement, and psychiatric symptoms. Neuropsychiatric symptoms such as psychosis are common and may contribute to diagnostic delays. We report a case of a middle-aged woman presenting with psychiatric and neurovisceral symptoms of AIP. This report discusses the case of a 41-year-old woman with no prior psychiatric history presenting with an acute onset of psychotic symptoms, including persecutory, erotomanic, and Capgras delusions, disorganized behavior, and agitation, along with physical symptoms of acute abdominal pain and autonomic disturbances. An extensive organic workup revealed elevated urinary porphobilinogen, which confirmed the diagnosis of AIP. The patient was treated medically, and her psychiatric symptoms completely resolved with olanzapine within eight days, without adverse effects. This case reveals the importance of considering AIP in patients presenting with acute psychosis, particularly when accompanied by autonomic and abdominal symptoms. Olanzapine appears to be a safe and effective treatment for AIP-related psychosis, though careful monitoring is essential due to the variable drug responses and potential hepatic risks. Further studies are needed to establish standardized treatment guidelines for neuropsychiatric symptoms in AIP.
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.
2026-02-27 | RNA as Medicine: The Pharmacological Revolution of Therapeutic Oligonucleotides- A Review article
Therapeutic oligonucleotides have matured into clinically validated medicines across neurology, hepatic/metabolic disease, cardiometabolic risk, and infectious disease. Antisense oligonucleotides (ASOs) act via RNase H–mediated degradation or splice modulation, with intrathecal splice-switching improving motor outcomes in spinal muscular atrophy and exhibiting month-scale CNS tissue half-lives. Gapmer ASOs that suppress transthyretin (TTR) synthesis deliver meaningful neuropathy improvements but require platelet and renal monitoring consistent with phosphorothioate backbones. Small interfering RNAs (siRNA) achieve potent, durable hepatic gene silencing through two delivery paradigms: subcutaneous N-acetylgalactosamine (GalNAc) conjugates with short plasma but long hepatic residence enabling quarterly to twice-yearly maintenance, and intravenous lipid nanoparticles (LNPs) that provide efficient hepatic uptake with manageable infusion reactions. Clinically, this translates to large attack reductions in acute hepatic porphyria, sustained ~50% LDL-C lowering with twice-yearly dosing in hypercholesterolemia, and ~90% TTR reduction with functional benefit in amyloidosis. mRNA vaccines using N1-methylpseudouridine and LNPs demonstrated rapid design-to-clinic timelines and high efficacy at population scale, establishing a manufacturable platform now extending toward therapeutic mRNA applications. Safety profiles largely reflect chemistry and delivery and are mitigable by sequence design, dosing strategies, premedication (for IV LNPs) - and routine laboratory monitoring. Extrahepatic targeting, stereo-controlled chemistries that enhance the potency without class toxicity and model based interval selection can expand organ reach and therapeutic breadth.
2025-10-01 | Rare Report of Simultaneous Liver and Kidney Transplant for Acute Intermittent Porphyria
Introduction: AIP is a rare autosomal dominant disorder of heme biosynthesis characterized by acute porphyric episodes caused by a deficiency of the hydroxymethylbilane synthase (HMBS) enzyme. These episodes present as abdominal pain, autonomic instability, and neurologic dysfunction resulting in AKI. Most patients experience infrequent episodes, while a subset develop relapsing porphyria leading to chronic kidney disease. Liver transplantation has been shown to reduce attacks by decreasing hepatic overproduction of porphyrin metabolites by replacing with HMBS producing hepatocytes. However, in patients with end-stage kidney disease (ESKD) and refractory symptoms, options are limited. Simultaneous liver-kidney transplant (SLKT) offers a comprehensive solution for these patients but has been rarely reported as a cure for AIP. Case Description: A 47-year-old woman with confirmed AIP via HMBS gene mutation experienced recurrent porphyric attacks since adolescence, which progressively worsened despite regular hemin infusions and plasmapheresis. Her urine porphyrins were quantified at 99 uM at age 33 which increased to 665 uM at age 37. She was later started on Givosiran, siRNA against ALA synthetase, reducing the frequency of her attacks but not preventing them. Over time, she developed ESKD from porphyrin-associated nephropathy, worsened by hypertensive crises during attacks, requiring peritoneal dialysis. Due to refractory symptoms and kidney failure, she was listed for SLKT. At the time of transplant, she received simulect induction and was discharged on tacrolimus, cellcept, and prednisone. Her Model for End-Stage Liver Disease (MELD) 3.0 score was elevated to 21 mainly due to her high creatinine (Cr). One month later, she underwent uncomplicated SLKT. Both allografts functioned immediately. She was discharged on tacrolimus, mycophenolate mofetil, and prednisone. 3 month follow up shows excellent liver allograft function with normal synthetic function, and kidney allograft function with Cr 0.9-1.1mg/dl. She has been able to stop givosiran and has had no porphyric attacks since SLKT. Discussion: This case details a rare, successful SLKT for AIP, leading to complete remission of porphyric symptoms and full recovery of kidney function. AIP is among a group of select disorders where combined transplant should be considered for optimal outcomes.
2025-09-25 | Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches
Porphyria refers to a group of rare inherited metabolic disorders caused by enzymatic deficiencies in the heme biosynthesis pathway. These deficiencies lead to the pathological accumulation of neurotoxic porphyrin precursors, resulting in multisystem damage. Currently, there are no curative therapeutic interventions, and patients frequently experience severe morbidity or life-threatening complications. Among the most critical manifestations is protoporphyric liver disease, in which hepatotoxic porphyrins and their precursors drive progressive hepatic injury and cholestasis. Persistent elevation of these metabolites can lead to irreversible parenchymal damage, significantly affecting both quality of life and long-term prognosis. The clinical presentation of porphyria-associated liver injury is highly variable and often has an insidious onset. However, a subset of patients may experience rapid progression to acute liver failure or fulminant hepatic dysfunction. Diagnosis is based on clinical evaluation and is confirmed by genetic testing. Current treatment strategies are focused on symptom management while underlying disease mechanisms remain unaddressed, posing significant therapeutic challenges. This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.
2025-06-11 | Managing Psychosis in Acute Intermittent Porphyria: A Case Report on Olanzapine Use
Acute intermittent porphyria (AIP) is the most common type of acute porphyria, caused by reduced porphobilinogen deaminase activity, leading to accumulations of neurotoxic compounds. Symptoms usually include abdominal pain, autonomic dysfunction, neurological involvement, and psychiatric symptoms. Neuropsychiatric symptoms such as psychosis are common and may contribute to diagnostic delays. We report a case of a middle-aged woman presenting with psychiatric and neurovisceral symptoms of AIP. This report discusses the case of a 41-year-old woman with no prior psychiatric history presenting with an acute onset of psychotic symptoms, including persecutory, erotomanic, and Capgras delusions, disorganized behavior, and agitation, along with physical symptoms of acute abdominal pain and autonomic disturbances. An extensive organic workup revealed elevated urinary porphobilinogen, which confirmed the diagnosis of AIP. The patient was treated medically, and her psychiatric symptoms completely resolved with olanzapine within eight days, without adverse effects. This case reveals the importance of considering AIP in patients presenting with acute psychosis, particularly when accompanied by autonomic and abdominal symptoms. Olanzapine appears to be a safe and effective treatment for AIP-related psychosis, though careful monitoring is essential due to the variable drug responses and potential hepatic risks. Further studies are needed to establish standardized treatment guidelines for neuropsychiatric symptoms in AIP.
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Drug Discovery Landscape
3 orphan drug designations for Acute hepatic porphyria, including 2 approved therapies.
3 orphan drug designations for Acute hepatic porphyria, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Synthetic double-stranded siRNA oligonucleotide directed against delta-aminolevulinic acid synthase 1 mRNA covalently linked to a ligand containing three N-acetylgalactosamine residues [Givlaari] | RNAs | EMA | 2016-08-29 | 2020-03-04 | Alnylam Netherlands B.V. |
givosiran [GIVLAARI] | RNAs | FDA | 2016-08-29 | 2019-11-20 | Alnylam Pharmaceuticals, Inc. |
Heme arginate | small molecules | FDA | 1988-03-10 | — | Orphan Europe SARL |
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