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
444 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:
444 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:
categories:
Small molecules
small molecules
2026-08-20 | Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
2026-08-01 | Navigating tuberculosis therapy in acute intermittent porphyria: A case report and narrative review
Tuberculosis (TB) treatment in patients with acute intermittent porphyria (AIP) is challenging because several first-line antituberculous drugs can precipitate porphyric crises, and evidence to guide management is limited. We describe a 26-year-old woman with peritoneal TB who developed acute abdominal pain, hyponatraemia, seizures, and neuropsychiatric manifestations within 24 hours of standard isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) therapy. AIP was confirmed by elevated urinary porphobilinogen levels, and the patient required hemin for the acute crises. Antituberculous therapy was modified to a rifampicin-free regimen including moxifloxacin, linezolid, and ethambutol; isoniazid was cautiously reintroduced once the patient had stabilised. Recurrent porphyric crises and treatment-related toxicity ultimately led to therapy discontinuation after 167 doses. The patient achieved substantial neurological recovery without TB relapse after one year of follow-up. This case illustrates the need to balance TB control with porphyria safety, and to consider acute hepatic porphyria when patients develop unexplained abdominal pain, hyponatraemia, or neurological symptoms after starting antituberculous therapy. Rifampicin and isoniazid carry the highest porphyrinogenic risk, whereas moxifloxacin, ethambutol, and linezolid appear to be safer alternatives. Given limited evidence and the absence of standardised protocols for this rare coexistence, we offer a pragmatic framework to support shared decision-making in tuberculosis and porphyria.
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.
2026-05-18 | 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.
gene therapies
2025-12-18 | The Case of a 37-Year-Old Woman Presenting With Subacute Weakness and Paresthesias.
Acute intermittent porphyria (AIP) is a rare metabolic disorder that may present with subacute neuropathy and systemic symptoms, often leading to diagnostic delay. We report a 37-year-old woman with eight weeks of progressive bilateral upper extremity weakness and paresthesias, followed by lower extremity involvement and falls, in the setting of chronic abdominal pain, presyncope, weight loss, and neuropsychiatric symptoms. Examination revealed profound proximal arm weakness, sensory deficits, bulbar involvement, and autonomic features. MRI of the brain and spine and cerebrospinal fluid analysis were normal. Electrodiagnostic studies demonstrated a severe diffuse motor neurogenic process. Markedly elevated urinary porphobilinogen and aminolevulinic acid levels confirmed the diagnosis of acute intermittent porphyric neuropathy, supported by identification of a variant of uncertain significance in the HMBS gene. This case underscores the importance of considering AIP in patients with subacute motor-predominant neuropathy accompanied by abdominal pain and autonomic dysfunction, as early diagnosis enables timely treatment and improved outcomes.
2025-10-01 | S5432 Hepatic and Gastrointestinal Complications in Acute Intermittent Porphyria: Investigating the Role of Iron Metabolism and Disease Progression Factors
Introduction: Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder characterized by a deficiency of porphobilinogen deaminase (PBGD), leading to the accumulation of neurotoxic porphyrin precursors. While AIP is primarily considered a neurovisceral disease, emerging evidence suggests an association with hepatic dysfunction, including cirrhosis and hepatocellular carcinoma (HCC). Case Description/Methods: We present a 63-year-old man with a history of AIP, cryptogenic liver cirrhosis, and H63D mutation carrier status, who was admitted for recurrent gastrointestinal (GI) bleeding. Serial esophagogastroduodenoscopies (EGDs) demonstrated a progressive worsening of vascular lesions, including gastric antral vascular ectasia (GAVE) and duodenal angioectasias, despite stable cirrhosis. The patient underwent endoscopic interventions, including argon plasma coagulation (APC) and clip placement, with successful hemostasis. The progressive nature of the patient's GI vascular abnormalities raises questions regarding the interplay between AIP, chronic oxidative stress, hepatic dysfunction, and vascular fragility. Discussion: While portal hypertension remains a primary contributor to GI bleeding in cirrhosis, additional mechanisms such as endothelial dysfunction and porphyrin-related oxidative damage may play a role in vascular ectasia development. Furthermore, the patient’s H63D mutation status, though typically a low-penetrance variant, could contribute to hepatic dysfunction in the presence of other risk factors. This case underscores the need for heightened surveillance in patients with AIP and cirrhosis, particularly regarding progressive vascular pathology and GI bleeding. Future research should investigate the pathophysiologic mechanisms linking AIP to hepatic and vascular complications to optimize long-term management strategies.
2024-11-23 | Genetic and clinical approach in acute intermittent porphyria and porphyria cutanea tarda.
This article examines the genetic and clinical features of two main types of porphyrias: acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT). AIP, a common hereditary disorder in young women, is characterized by severe neurovisceral crises, with abdominal pain, neuromuscular dysfunction and psychiatric disturbances, which are caused by mutations in the HMBS gene, affecting heme synthesis, causing intense symptoms in the nervous and gastrointestinal systems. PCT manifests mainly in adults, associated with photosensitivity, skin lesions and risk of hepatocellular carcinoma, resulting from deficiency of the enzyme uroporphyrinogen decarboxylase (UROD), which causes an accumulation of photosensitive compounds in the skin and liver. The importance of genetic sequencing tests to identify possible alterations in the specific HMBS and UROD genes, essential to confirm the diagnosis and facilitate appropriate treatment, is emphasized. The need for early diagnosis and management of triggering factors to reduce morbidity and improve patients' quality of life is highlighted. The findings emphasize the importance of increasing the investigation of these pathologies, given that the initial symptoms may confuse the diagnosis, delaying detection and increasing the risk of complications.
2024-07-12 | Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs.
Hepatic porphyrias are a group of metabolic disorders that are characterized by overproduction and accumulation of porphyrin precursors in the liver. These porphyrins cause neurologic symptoms as well as cutaneous photosensitivity, and in some cases patients can experience life-threatening acute neurovisceral attacks. This review describes the acute hepatic porphyrias in detail, including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, as well as the hepatic porphyrias with cutaneous manifestations such as porphyria cutanea tarda and hepatoerythropoietic porphyria. Each section will cover disease prevalence, clinical manifestations, and current therapies, including strategies to manage symptoms. Finally, we review new and emerging treatment modalities, including gene therapy through use of adeno-associated vectors and chaperone therapies such as lipid nanoparticle and small interfering RNA-based therapeutics.
2023-03-13 | Acute Intermittent Porphyria’s Symptoms and Management: A Narrative Review
Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis in the liver that is caused by the accumulation of toxic heme metabolites aminolevulinic acid (ALA) and porphobilinogen (PBG) due to a deficiency in the enzyme hydroxymethylbilane synthase (HMBS).The prevalence of AIP is found to commonly affect females of reproductive age (ages 15-50) and people of Northern European descent.The clinical manifestations of AIP include acute and chronic symptoms that can be outlined into three phases: the prodromal phase, the visceral symptom phase, and the neurological phase.Major clinical symptoms involve severe abdominal pain, peripheral neuropathy, autonomic neuropathies, and psychiatric manifestations.Symptoms are often heterogeneous and vague, which can lead to life-threatening signs if not treated and managed appropriately.Whether treating AIP in its acute or chronic form, the cornerstone of treatment consists of the suppression of the production of ALA and PBG.The mainstay of managing acute attacks continues to comprise discontinuing porphyrogenic agents, adequate caloric support, heme treatment, and the treatment of symptoms.In recurrent attacks and chronic management, prevention is key with the consideration of liver transplantation and/or renal transplantation.In recent years, there has been great interest in emerging treatments that focus on a molecular level such as enzyme replacement therapy, ALAS1 gene inhibition, and even liver gene therapy (GT), which has changed the way of traditionally managing this disease and will pave the way for innovative therapies to come.
cell therapies
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.
2023-08-09 | The Management of Motor Neuropathy With Plasmapheresis in a Patient With Acute Porphyria: A Case Report
Acute porphyria results from a deficiency of enzymes crucial for the heme synthesis process. This deficiency leads to elevated levels of intermediates, resulting in the characteristic symptoms of porphyrias such as abdominal and limb pain, neuropsychiatric issues, and sensitivity to light. In this report, we present the case of a 15-year-old male who experienced deteriorating motor neuropathy and recurrent bouts of abdominal pain. Numerous investigations were conducted, eventually leading to a diagnosis of acute porphyria. Despite attempts with hemin and glucose therapy, his motor neuropathy did not improve. However, significant progress was observed following plasmapheresis sessions. This case emphasizes the importance of considering acute porphyrias as a potential cause when managing patients with acute abdominal problems. By fostering a collaborative approach involving hematologists, physicians, neurologists, and surgeons, timely diagnosis and effective management of this condition can be achieved.
2021-01-29 | Liver Transplantation for Acute Intermittent Porphyria
Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18‐58), and 34 (89%) of the patients were women. A total of 9 patients died during follow‐up, and 2 patients were retransplanted. The 1‐year and 5‐year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5‐year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy ( P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
2020-10-05 | Combined Liver and Kidney Transplant in Acute Intermittent Porphyria: A Case Report
BACKGROUND:Acute intermittent porphyria is an inherited disease caused by a defect in heme biosynthesis, with accumulation of neurotoxic metabolites leading to acute neurovisceral symptoms. Some patients develop long-term neurological and renal damage after the acute episodes, many of them requiring hemodialysis. Since heme production in the human body occurs predominantly in the bone marrow and liver, liver transplantation has been shown to significantly reduce the production of neurotoxic metabolites, effectively controlling the disease. Patients with severe acute intermittent porphyria who have chronic kidney failure may benefit from combined kidney and liver transplant. Only 2 uses of this approach have been previously reported in the literature. CASE REPORT:We report here the case of a 19-year-old male patient who received a combined liver and kidney transplant for the treatment of acute intermittent porphyria. He presented the first symptoms of the disease 4 years before the procedure, with abdominal pain and significant neurological impairment, with weakness requiring prolonged mechanical ventilation. He also had chronic kidney failure secondary to the porphyria. A combined liver and kidney transplant was performed, with no intraoperative complications. The explanted liver showed light siderosis, as well as portal and perisinusoidal fibrosis at microscopy. At 3.5 years of follow-up, he remains clinically well, with normal hepatic and renal function, had had no further acute porphyria episodes, and shows progressive neurological recovery. CONCLUSIONS:This case demonstrates that combined liver and kidney transplant can be a curative treatment for patients with severe acute intermittent porphyria associated with end-stage renal failure. The patient shows satisfactory long-term function of both grafts, with no clinical or biochemical signs of porphyria recurrence.
2020-09-01 | Kidney transplantation improves the clinical outcomes of Acute Intermittent Porphyria
Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known. We examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry. AIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 μmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients. Kidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity.
oligonucleotides
2026-09-28 | Single-center real-world experience with givosiran for management of acute intermittent porphyria.
Givosiran, an ALAS1 targeted siRNA therapy, decreases the frequency of acute attacks in acute hepatic porphyrias by lowering the neurotoxic heme precursors, aminolevulinic acid and porphobilinogen. Here, we present real-world data on clinical, biochemical, efficacy and safety for fifteen patients with acute intermittent porphyria evaluated at our center. Our experience shows that givosiran reduces the frequency of acute attacks, with eleven out of thirteen patients being attack-free after approximately one year of treatment. Dose reduction was attempted in eight patients due to adverse events, including elevated creatinine, acute pancreatitis, and severe injection site reactions. The most common side effects reported from our cohort were nausea, fatigue, and headaches. In this real-world cohort, fewer hemin-treated events were observed during givosiran treatment. Our experience suggests that personalized dosing can be implemented in selected patients, particularly in those who experience adverse events.
2026-09-23 | Single-Dose Hemin Treatment, δ-Aminolevulinic Acid overflow and PEPT2-mediated nephrotoxicity in Acute Intermittent Porphyria (PAKD)
In acute intermittent porphyria (AIP), the empirical use of single-dose hemin does not ensure metabolic quiescence. Rapid HO-1 induction degrades exogenous heme before the excess porphobilinogen (PBG) upstream of the HMBS deficit can be cleared, forcing a continuous retrograde overflow of δ-aminolevulinic acid (δ-ALA). This patient-led longitudinal N-of-1 study, conducted in accordance with CARE guidelines and the CENT extension, correlates principles of physical chemistry, enzyme kinetics, and mass balance with clinical and laboratory data from seven years of follow-up (2016–2023). Analysis of 18 documented single-infusion cycles reveals a transient 24-hour reduction in δ-ALA (-53.8%) but a failure to clear PBG (post-dose: 17.45 µmol/mmol creatinine), followed by a rebound at 4 days and chronic drift (up to 34.80 µmol/mmol creatinine). Proximal tubular uptake of δ-ALA via PEPT2/SLC15A2 triggers mitochondrial peroxidation and activates the TGF-β1/SMAD axis, providing the biophysical basis for a severe decline in eGFR from 115 to 51 mL/min/1.73 m² (-55.7% over 31.1 months; nadir: CKD stage 3a). Silencing ALAS1 mRNA with givosiran (February 2021) halts synthesis at the source, arresting the decline in renal function and restoring function at 60–70 mL/min/1.73 m². This study suggests the risk of kinetic fallacy of single-dose administration and advocates for the mandatory use of cystatin C.
2026-09-08 | Acute intermittent porphyria presenting with rhabdomyolysis and polyneuropathy with severe quadriparesis and respiratory failure: A case report.
Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Very rarely, an acute AIP attack can be complicated by rhabdomyolysis as illustrated in this case report. A 28-year-old female presented with severe abdominal pain and muscle weakness, which progressed to severe rhabdomyolysis and acute kidney injury requiring dialysis. The disease course was further complicated by an acute severe axonal peripheral motor neuropathy with quadriparesis and respiratory muscle weakness requiring prolonged invasive mechanical ventilation. An important clue for diagnosis was red urine without hematuria. The diagnosis was established by the finding of elevated δ-aminolevulinic acid and porphobilinogen in a random urine sample and later confirmed by genetic testing. The patient was initially treated with hemin and parenteral glucose. However, since she needed prolonged treatment, givosiran was commenced and continued after discharge. When the period between givosiran administrations was extended to two months, this led to a new (milder) attack. After 40 months of givosiran treatment and continued physical rehabilitation, the patient is ambulatory and without acute attacks. Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed for neurological recovery after an AIP attack with severe motor polyneuropathy and multisystem involvement.
2026-08-21 | Unmasking clinical heterogeneity and diagnostic conundrums of acute intermittent porphyria: a case series from the middle east
Abstract Background Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder caused by an alteration in the heme synthesis pathway leading to the accumulation of porphyrins and their precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Although most patients are asymptomatic, AIP is typically characterized by a triad of abdominal pain, neurologic impairment, and psychiatric abnormalities; experienced by only a small percentage of symptomatic patients. The disease onset is usually reported to occur between the ages of 20 and 40. Due to its heterogeneity, the diagnosis of AIP is challenging and ruling out other diseases solely based on clinical assessment is difficult. Results This case series presents three cases of AIP with diverse clinical presentations encountered in Emirati patients at Burjeel Hospital in Abu Dhabi. Conclusions This case series highlights the diagnostic difficulties and the impact of novel therapeutic strategies such as givosiran in improving patient outcomes.
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.
other
2023-12-06 | Use of Optical Coherence Tomography and Optical Coherence Tomography Angiography in the Diagnosis and Follow-Up of Endogenous Candida Endophthalmitis: a Case Report.
Background: Endogenous Candida endophthalmitis (ECE) is a rare but sight-threatening disease. Patients with ECE present with various clinical signs and symptoms, which can complicate the diagnosis. The aim of this report was to describe the characteristic features of ECE on optical co-herence tomography (OCT) and OCT angiography (OCTA). Another objective was to demon-strate the outcomes of treatment and to diagnose macular complications caused by intraocular inflammation. Case presentation: A 41-year-old woman with a history of acute intermittent por-phyria presented with a progressive vision loss in her left eye. Left-eye OCT revealed findings consistent with a fungal etiology, which was confirmed by the culture of swabs collected from a central vein catheter. The outcomes of intravenous fluconazole treatment were not satisfactory, and the patient developed recurrent attacks of porphyria, suggesting a porphyrogenic effect of systemic antifungal therapy. Repeated intravitreal injections with amphotericin B led to a gradu-al regression of inflammatory lesions. However, follow-up examinations revealed active macular neovascularization on both OCT and OCTA. The patient was administered intravitreal bevaci-zumab. Conclusions: This case highlights the importance of OCT and OCTA as valuable noninva-sive imaging techniques for the identification of ECE, the monitoring of its clinical course, and the diagnosis of macular complications.
2023-01-11 | Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria.
Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.
small molecules
2026-08-20 | Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
2026-08-01 | Navigating tuberculosis therapy in acute intermittent porphyria: A case report and narrative review
Tuberculosis (TB) treatment in patients with acute intermittent porphyria (AIP) is challenging because several first-line antituberculous drugs can precipitate porphyric crises, and evidence to guide management is limited. We describe a 26-year-old woman with peritoneal TB who developed acute abdominal pain, hyponatraemia, seizures, and neuropsychiatric manifestations within 24 hours of standard isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) therapy. AIP was confirmed by elevated urinary porphobilinogen levels, and the patient required hemin for the acute crises. Antituberculous therapy was modified to a rifampicin-free regimen including moxifloxacin, linezolid, and ethambutol; isoniazid was cautiously reintroduced once the patient had stabilised. Recurrent porphyric crises and treatment-related toxicity ultimately led to therapy discontinuation after 167 doses. The patient achieved substantial neurological recovery without TB relapse after one year of follow-up. This case illustrates the need to balance TB control with porphyria safety, and to consider acute hepatic porphyria when patients develop unexplained abdominal pain, hyponatraemia, or neurological symptoms after starting antituberculous therapy. Rifampicin and isoniazid carry the highest porphyrinogenic risk, whereas moxifloxacin, ethambutol, and linezolid appear to be safer alternatives. Given limited evidence and the absence of standardised protocols for this rare coexistence, we offer a pragmatic framework to support shared decision-making in tuberculosis and porphyria.
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.
2026-05-18 | 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.
gene therapies
2025-12-18 | The Case of a 37-Year-Old Woman Presenting With Subacute Weakness and Paresthesias.
Acute intermittent porphyria (AIP) is a rare metabolic disorder that may present with subacute neuropathy and systemic symptoms, often leading to diagnostic delay. We report a 37-year-old woman with eight weeks of progressive bilateral upper extremity weakness and paresthesias, followed by lower extremity involvement and falls, in the setting of chronic abdominal pain, presyncope, weight loss, and neuropsychiatric symptoms. Examination revealed profound proximal arm weakness, sensory deficits, bulbar involvement, and autonomic features. MRI of the brain and spine and cerebrospinal fluid analysis were normal. Electrodiagnostic studies demonstrated a severe diffuse motor neurogenic process. Markedly elevated urinary porphobilinogen and aminolevulinic acid levels confirmed the diagnosis of acute intermittent porphyric neuropathy, supported by identification of a variant of uncertain significance in the HMBS gene. This case underscores the importance of considering AIP in patients with subacute motor-predominant neuropathy accompanied by abdominal pain and autonomic dysfunction, as early diagnosis enables timely treatment and improved outcomes.
2025-10-01 | S5432 Hepatic and Gastrointestinal Complications in Acute Intermittent Porphyria: Investigating the Role of Iron Metabolism and Disease Progression Factors
Introduction: Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder characterized by a deficiency of porphobilinogen deaminase (PBGD), leading to the accumulation of neurotoxic porphyrin precursors. While AIP is primarily considered a neurovisceral disease, emerging evidence suggests an association with hepatic dysfunction, including cirrhosis and hepatocellular carcinoma (HCC). Case Description/Methods: We present a 63-year-old man with a history of AIP, cryptogenic liver cirrhosis, and H63D mutation carrier status, who was admitted for recurrent gastrointestinal (GI) bleeding. Serial esophagogastroduodenoscopies (EGDs) demonstrated a progressive worsening of vascular lesions, including gastric antral vascular ectasia (GAVE) and duodenal angioectasias, despite stable cirrhosis. The patient underwent endoscopic interventions, including argon plasma coagulation (APC) and clip placement, with successful hemostasis. The progressive nature of the patient's GI vascular abnormalities raises questions regarding the interplay between AIP, chronic oxidative stress, hepatic dysfunction, and vascular fragility. Discussion: While portal hypertension remains a primary contributor to GI bleeding in cirrhosis, additional mechanisms such as endothelial dysfunction and porphyrin-related oxidative damage may play a role in vascular ectasia development. Furthermore, the patient’s H63D mutation status, though typically a low-penetrance variant, could contribute to hepatic dysfunction in the presence of other risk factors. This case underscores the need for heightened surveillance in patients with AIP and cirrhosis, particularly regarding progressive vascular pathology and GI bleeding. Future research should investigate the pathophysiologic mechanisms linking AIP to hepatic and vascular complications to optimize long-term management strategies.
2024-11-23 | Genetic and clinical approach in acute intermittent porphyria and porphyria cutanea tarda.
This article examines the genetic and clinical features of two main types of porphyrias: acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT). AIP, a common hereditary disorder in young women, is characterized by severe neurovisceral crises, with abdominal pain, neuromuscular dysfunction and psychiatric disturbances, which are caused by mutations in the HMBS gene, affecting heme synthesis, causing intense symptoms in the nervous and gastrointestinal systems. PCT manifests mainly in adults, associated with photosensitivity, skin lesions and risk of hepatocellular carcinoma, resulting from deficiency of the enzyme uroporphyrinogen decarboxylase (UROD), which causes an accumulation of photosensitive compounds in the skin and liver. The importance of genetic sequencing tests to identify possible alterations in the specific HMBS and UROD genes, essential to confirm the diagnosis and facilitate appropriate treatment, is emphasized. The need for early diagnosis and management of triggering factors to reduce morbidity and improve patients' quality of life is highlighted. The findings emphasize the importance of increasing the investigation of these pathologies, given that the initial symptoms may confuse the diagnosis, delaying detection and increasing the risk of complications.
2024-07-12 | Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs.
Hepatic porphyrias are a group of metabolic disorders that are characterized by overproduction and accumulation of porphyrin precursors in the liver. These porphyrins cause neurologic symptoms as well as cutaneous photosensitivity, and in some cases patients can experience life-threatening acute neurovisceral attacks. This review describes the acute hepatic porphyrias in detail, including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, as well as the hepatic porphyrias with cutaneous manifestations such as porphyria cutanea tarda and hepatoerythropoietic porphyria. Each section will cover disease prevalence, clinical manifestations, and current therapies, including strategies to manage symptoms. Finally, we review new and emerging treatment modalities, including gene therapy through use of adeno-associated vectors and chaperone therapies such as lipid nanoparticle and small interfering RNA-based therapeutics.
2023-03-13 | Acute Intermittent Porphyria’s Symptoms and Management: A Narrative Review
Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis in the liver that is caused by the accumulation of toxic heme metabolites aminolevulinic acid (ALA) and porphobilinogen (PBG) due to a deficiency in the enzyme hydroxymethylbilane synthase (HMBS).The prevalence of AIP is found to commonly affect females of reproductive age (ages 15-50) and people of Northern European descent.The clinical manifestations of AIP include acute and chronic symptoms that can be outlined into three phases: the prodromal phase, the visceral symptom phase, and the neurological phase.Major clinical symptoms involve severe abdominal pain, peripheral neuropathy, autonomic neuropathies, and psychiatric manifestations.Symptoms are often heterogeneous and vague, which can lead to life-threatening signs if not treated and managed appropriately.Whether treating AIP in its acute or chronic form, the cornerstone of treatment consists of the suppression of the production of ALA and PBG.The mainstay of managing acute attacks continues to comprise discontinuing porphyrogenic agents, adequate caloric support, heme treatment, and the treatment of symptoms.In recurrent attacks and chronic management, prevention is key with the consideration of liver transplantation and/or renal transplantation.In recent years, there has been great interest in emerging treatments that focus on a molecular level such as enzyme replacement therapy, ALAS1 gene inhibition, and even liver gene therapy (GT), which has changed the way of traditionally managing this disease and will pave the way for innovative therapies to come.
cell therapies
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.
2023-08-09 | The Management of Motor Neuropathy With Plasmapheresis in a Patient With Acute Porphyria: A Case Report
Acute porphyria results from a deficiency of enzymes crucial for the heme synthesis process. This deficiency leads to elevated levels of intermediates, resulting in the characteristic symptoms of porphyrias such as abdominal and limb pain, neuropsychiatric issues, and sensitivity to light. In this report, we present the case of a 15-year-old male who experienced deteriorating motor neuropathy and recurrent bouts of abdominal pain. Numerous investigations were conducted, eventually leading to a diagnosis of acute porphyria. Despite attempts with hemin and glucose therapy, his motor neuropathy did not improve. However, significant progress was observed following plasmapheresis sessions. This case emphasizes the importance of considering acute porphyrias as a potential cause when managing patients with acute abdominal problems. By fostering a collaborative approach involving hematologists, physicians, neurologists, and surgeons, timely diagnosis and effective management of this condition can be achieved.
2021-01-29 | Liver Transplantation for Acute Intermittent Porphyria
Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18‐58), and 34 (89%) of the patients were women. A total of 9 patients died during follow‐up, and 2 patients were retransplanted. The 1‐year and 5‐year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5‐year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy ( P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
2020-10-05 | Combined Liver and Kidney Transplant in Acute Intermittent Porphyria: A Case Report
BACKGROUND:Acute intermittent porphyria is an inherited disease caused by a defect in heme biosynthesis, with accumulation of neurotoxic metabolites leading to acute neurovisceral symptoms. Some patients develop long-term neurological and renal damage after the acute episodes, many of them requiring hemodialysis. Since heme production in the human body occurs predominantly in the bone marrow and liver, liver transplantation has been shown to significantly reduce the production of neurotoxic metabolites, effectively controlling the disease. Patients with severe acute intermittent porphyria who have chronic kidney failure may benefit from combined kidney and liver transplant. Only 2 uses of this approach have been previously reported in the literature. CASE REPORT:We report here the case of a 19-year-old male patient who received a combined liver and kidney transplant for the treatment of acute intermittent porphyria. He presented the first symptoms of the disease 4 years before the procedure, with abdominal pain and significant neurological impairment, with weakness requiring prolonged mechanical ventilation. He also had chronic kidney failure secondary to the porphyria. A combined liver and kidney transplant was performed, with no intraoperative complications. The explanted liver showed light siderosis, as well as portal and perisinusoidal fibrosis at microscopy. At 3.5 years of follow-up, he remains clinically well, with normal hepatic and renal function, had had no further acute porphyria episodes, and shows progressive neurological recovery. CONCLUSIONS:This case demonstrates that combined liver and kidney transplant can be a curative treatment for patients with severe acute intermittent porphyria associated with end-stage renal failure. The patient shows satisfactory long-term function of both grafts, with no clinical or biochemical signs of porphyria recurrence.
2020-09-01 | Kidney transplantation improves the clinical outcomes of Acute Intermittent Porphyria
Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known. We examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry. AIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 μmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients. Kidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity.
oligonucleotides
2026-09-28 | Single-center real-world experience with givosiran for management of acute intermittent porphyria.
Givosiran, an ALAS1 targeted siRNA therapy, decreases the frequency of acute attacks in acute hepatic porphyrias by lowering the neurotoxic heme precursors, aminolevulinic acid and porphobilinogen. Here, we present real-world data on clinical, biochemical, efficacy and safety for fifteen patients with acute intermittent porphyria evaluated at our center. Our experience shows that givosiran reduces the frequency of acute attacks, with eleven out of thirteen patients being attack-free after approximately one year of treatment. Dose reduction was attempted in eight patients due to adverse events, including elevated creatinine, acute pancreatitis, and severe injection site reactions. The most common side effects reported from our cohort were nausea, fatigue, and headaches. In this real-world cohort, fewer hemin-treated events were observed during givosiran treatment. Our experience suggests that personalized dosing can be implemented in selected patients, particularly in those who experience adverse events.
2026-09-23 | Single-Dose Hemin Treatment, δ-Aminolevulinic Acid overflow and PEPT2-mediated nephrotoxicity in Acute Intermittent Porphyria (PAKD)
In acute intermittent porphyria (AIP), the empirical use of single-dose hemin does not ensure metabolic quiescence. Rapid HO-1 induction degrades exogenous heme before the excess porphobilinogen (PBG) upstream of the HMBS deficit can be cleared, forcing a continuous retrograde overflow of δ-aminolevulinic acid (δ-ALA). This patient-led longitudinal N-of-1 study, conducted in accordance with CARE guidelines and the CENT extension, correlates principles of physical chemistry, enzyme kinetics, and mass balance with clinical and laboratory data from seven years of follow-up (2016–2023). Analysis of 18 documented single-infusion cycles reveals a transient 24-hour reduction in δ-ALA (-53.8%) but a failure to clear PBG (post-dose: 17.45 µmol/mmol creatinine), followed by a rebound at 4 days and chronic drift (up to 34.80 µmol/mmol creatinine). Proximal tubular uptake of δ-ALA via PEPT2/SLC15A2 triggers mitochondrial peroxidation and activates the TGF-β1/SMAD axis, providing the biophysical basis for a severe decline in eGFR from 115 to 51 mL/min/1.73 m² (-55.7% over 31.1 months; nadir: CKD stage 3a). Silencing ALAS1 mRNA with givosiran (February 2021) halts synthesis at the source, arresting the decline in renal function and restoring function at 60–70 mL/min/1.73 m². This study suggests the risk of kinetic fallacy of single-dose administration and advocates for the mandatory use of cystatin C.
2026-09-08 | Acute intermittent porphyria presenting with rhabdomyolysis and polyneuropathy with severe quadriparesis and respiratory failure: A case report.
Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Very rarely, an acute AIP attack can be complicated by rhabdomyolysis as illustrated in this case report. A 28-year-old female presented with severe abdominal pain and muscle weakness, which progressed to severe rhabdomyolysis and acute kidney injury requiring dialysis. The disease course was further complicated by an acute severe axonal peripheral motor neuropathy with quadriparesis and respiratory muscle weakness requiring prolonged invasive mechanical ventilation. An important clue for diagnosis was red urine without hematuria. The diagnosis was established by the finding of elevated δ-aminolevulinic acid and porphobilinogen in a random urine sample and later confirmed by genetic testing. The patient was initially treated with hemin and parenteral glucose. However, since she needed prolonged treatment, givosiran was commenced and continued after discharge. When the period between givosiran administrations was extended to two months, this led to a new (milder) attack. After 40 months of givosiran treatment and continued physical rehabilitation, the patient is ambulatory and without acute attacks. Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed for neurological recovery after an AIP attack with severe motor polyneuropathy and multisystem involvement.
2026-08-21 | Unmasking clinical heterogeneity and diagnostic conundrums of acute intermittent porphyria: a case series from the middle east
Abstract Background Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder caused by an alteration in the heme synthesis pathway leading to the accumulation of porphyrins and their precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Although most patients are asymptomatic, AIP is typically characterized by a triad of abdominal pain, neurologic impairment, and psychiatric abnormalities; experienced by only a small percentage of symptomatic patients. The disease onset is usually reported to occur between the ages of 20 and 40. Due to its heterogeneity, the diagnosis of AIP is challenging and ruling out other diseases solely based on clinical assessment is difficult. Results This case series presents three cases of AIP with diverse clinical presentations encountered in Emirati patients at Burjeel Hospital in Abu Dhabi. Conclusions This case series highlights the diagnostic difficulties and the impact of novel therapeutic strategies such as givosiran in improving patient outcomes.
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.
other
2023-12-06 | Use of Optical Coherence Tomography and Optical Coherence Tomography Angiography in the Diagnosis and Follow-Up of Endogenous Candida Endophthalmitis: a Case Report.
Background: Endogenous Candida endophthalmitis (ECE) is a rare but sight-threatening disease. Patients with ECE present with various clinical signs and symptoms, which can complicate the diagnosis. The aim of this report was to describe the characteristic features of ECE on optical co-herence tomography (OCT) and OCT angiography (OCTA). Another objective was to demon-strate the outcomes of treatment and to diagnose macular complications caused by intraocular inflammation. Case presentation: A 41-year-old woman with a history of acute intermittent por-phyria presented with a progressive vision loss in her left eye. Left-eye OCT revealed findings consistent with a fungal etiology, which was confirmed by the culture of swabs collected from a central vein catheter. The outcomes of intravenous fluconazole treatment were not satisfactory, and the patient developed recurrent attacks of porphyria, suggesting a porphyrogenic effect of systemic antifungal therapy. Repeated intravitreal injections with amphotericin B led to a gradu-al regression of inflammatory lesions. However, follow-up examinations revealed active macular neovascularization on both OCT and OCTA. The patient was administered intravitreal bevaci-zumab. Conclusions: This case highlights the importance of OCT and OCTA as valuable noninva-sive imaging techniques for the identification of ECE, the monitoring of its clinical course, and the diagnosis of macular complications.
2023-01-11 | Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria.
Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.
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Drug Discovery Landscape
2 orphan drug designations for Acute intermittent porphyria.
2 orphan drug designations for Acute intermittent porphyria.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
recombinant human porphobilinogen deaminase | proteins | FDA | Chiesi USA, Inc. | |
recombinant human porphobilinogen deaminase, erythropoetic form | proteins | FDA | — | Chiesi USA, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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