small molecules

2026-09-14 | THE IMPACT OF ENDOGENOUS AND EXOGENOUS SEX HORMONES ON THE COURSE OF PORPHYRIA IN WOMEN: A NARRATIVE REVIEW

Porphyrias are a group of metabolic diseases caused by an impairment of the heme synthesis pathway, resulting in the accumulation of heme precursors. First symptoms usually occur during puberty and can be triggered by a range of factors such as drugs, alcohol, fasting, infection, and, most importantly for this study, hormonal changes. Women in the reproductive age are known to be the main group presenting with porphyria symptoms (1.5–2.5 times more frequent in women than in men) mainly due to higher concentrations of steroid hormones, particularly progesterone. Hormonal fluctuations associated with the menstrual cycle are the most commonly identified trigger causing an AIP attack in female patients. Pregnancy and exogenous hormone administration may also precipitate attacks in susceptible individuals, although there is considerable interindividual variability, and the underlying mechanisms remain incompletely understood. This review summarizes existing knowledge on hormonal changes induced by the menstrual cycle, pregnancy, hormonal contraception, and GnRH agonists in women diagnosed with porphyria. It compares it with the conclusions reached by the IPNET panelists in the newly published guidelines, released in May 2026. The available evidence, derived mainly from retrospective studies, small cohorts, and case reports, indicates that endogenous and exogenous hormones can have a major impact on susceptible women with porphyria. Most data confirmed that the use of oral contraceptives appears to carry the highest risk of precipitating attacks, whereas levonorgestrel-releasing IUDs seem to be better tolerated. GnRH agonist therapy proved highly effective and significantly safer than hormonal contraception in the treatment of recurrent cycle-related porphyria, although it requires add-back therapy, posing a threat itself. Despite recent advances and the publication of IPNET recommendations, high-quality evidence remains limited. Further prospective studies are required to establish evidence-based recommendations for hormonal management and contraception in women with acute hepatic porphyrias.

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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.

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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.

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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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2025-05-01 | Unexpected presentation of a first episode of acute hepatic porphyria (AHP) presenting with severe hyponatremia, seizure, severe rhabdomyolysis, arterial hypertension and posterior reversible encephalopathy syndrome (PRES) in a female adolescent

Background: Porphyrias are rare inherited diseases resulting from enzyme deficiencies/dysfunction or insufficient substrate processing in catalysing enzymes in the haem synthesis, predominantly affecting adult females of childbearing age. Accumulation of intermediary metabolites such as porphyrins, their precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) in various organs causing cytotoxic or tissue-damaging effects. Aggravating factors are fasting, alcohol, smoking, androgenic hormones, visible light/UV rays and use of porphyrinogenic medications. Acute porphyrias present with episodic, potentially life-threatening neurovisceral symptoms: abdominal pain, convulsion, autonomic hyperactivity, peripheral neuropathy and psychiatric symptoms. Case: A girl (17y) was transferred to our PICU with hyponatremia (114mg/dl) and signs of ileus, 5 days of abdominal pain, nausea and vomiting. She was afebrile, hypertensive, tachycardic and suffered from diffuse dysesthesia. She had a history of episodic abdominal pain with nausea and weight loss for two years. Family history revealed Crohn´s disease of the father but gastroscopy and colonoscopy a year ago were normal. On admission, she presented with a generalised tonic–clonic seizure (2min). Abdominal CT showed signs of at least four entero-enteric intussusceptions but contrast material showed no bowl obstruction. Laboratory investigations revealed severe rhabdomyolysis with a creatine kinase peak of 119.451 units/L, maximal serum creatinine was 1,4mg/dl. Abdominal MRI, gastroscopy and colonoscopy were normal. Intermittent neuropsychiatric symptoms with anxiety, depression, confusion, headache and visual disturbance occurred. MRI of the brain showed a PRES. Cerebrospinal fluid assessment, urine microscopy, drug screen, metabolic/endocrinology screening, serum/liquor autoimmune diagnostic were normal. Comprehensive search for infectious causes revealed positive mycoplasma pneumoniae PCR-test. Finally, the combination of non-specific abdominal pain and neuropsychiatric symptoms led to the diagnosis of AHP with abnormally elevated levels of porphyrins and PBG in urine. Intravenous dextrose was administered to inhibit aminolevulinic acid synthase (ALAS) and to stop catabolism. Intravenous hemin was started to upregulate the excretion of ALA and PBG. After 4 days of therapy, abdominal pain resolved and blood pressure as well as her behaviour normalised. Genetic testing is pending. Conclusion: The case illustrates the diagnostic challenges of AHP. Its overlapping symptoms with more common diseases and the extremely rare pediatric onset of AHPs lead to underdiagnosis. Treatment with porphyrinogenic medication increases the risk of potentially irreversible neurological sequelae. Therefore, pediatricians should be aware of AHPs and consider them as a differential diagnosis in children and adolescents with abdominal pain, autonomic nervous system dysfunction, and neuropsychiatric findings. Publication History Article published online: 19 May 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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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.

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2021-05-14 | 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.

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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.

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2017-11-29 | Perioperative Challenges in Liver Transplantation for a Patient With Acute Intermittent Porphyria

ACUTE INTERMITTENT PORPHYRIA (AIP) is a metabolic disease caused by an inherited deficiency of porphobilinogen deaminase in the heme biosynthetic pathway. Loss of this enzyme results in increased hepatic production of porphyrin precursors and manifests as episodic attacks of neurovisceral symptoms, including abdominal pain, nausea, vomiting, constipation, sweating, urinary retention, arrhythmias, peripheral neuropathy, and seizures. It is the most common type of acute porphyria worldwide and is more prevalent in women. 1 Pischik E. Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015; 8: 201-214 Crossref PubMed Scopus (118) Google Scholar Symptoms can be frequent in 5% to 10% of patients. Recurrent attacks result in diminished quality of life due to hospital admissions, multiple procedures and subsequent complications, and chronic pain. Liver transplantation corrects the genetic defect in the liver by replacing the missing enzyme, leading to normalization of porphobilinogen levels and resolution of symptoms. The first orthotopic liver transplant (OLT) for AIP was performed in 2004 on a 19-year-old patient with severe neurovisceral manifestations and complications related to therapy. 2 Soonawalla Z.F. Orug T. Badminton M.N. et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet. 2004; 363: 705-706 Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar She was cured of the disease. Fourteen other cases of OLT for AIP with severe manifestations have been reported in the literature, with clinical and biochemical remission. 3 Seth A.K. Badminton M.N. Mirza D. et al. Liver transplantation for porphyria: Who, when, and how?. Liver Transpl. 2007; 13: 1219-1227 Crossref PubMed Scopus (83) Google Scholar , 4 Wahlin S. Harper P. Sardh E. et al. Combined liver and kidney transplantation in acute intermittent porphyria. Transpl Int. 2010; 23: e18-e21 Crossref PubMed Scopus (62) Google Scholar , 5 Singal A.K. Parker C. Bowden C. et al. Liver transplantation in the management of porphyria. Hepatology. 2014; 60: 1082-1089 Crossref PubMed Scopus (90) Google Scholar , 6 Dowman J.K. Gunson B.K. Mirza D.F. et al. Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl. 2012; 18: 195-200 Crossref PubMed Scopus (83) Google Scholar

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2017-11-15 | Is liver transplantation for intractable attacks of porphyria a viable treatment in a developing country?

Potential conflict of interest: Nothing to report. To the editor: We read with great interest the guideline for the long‐term management of acute hepatic porphyrias by Balwani et al.1 The authors mentioned that orthotopic liver transplantation (OLT) has been used for intractable attacks that are refractory to heme therapy. The first successful OLT for this indication was reported in 2004,2 and then other cases were reported from European and American developed countries. However, there is no published evidence that this procedure has been successfully performed in a developing country. Therefore, we want to contribute by reporting the first experience in Latin America. A 30‐year‐old woman with asthma, allergic rhinitis, type 2 diabetes, and endometriosis was diagnosed with acute intermittent porphyria at age 27. Over 3 years, she was hospitalized 14.5 times per year on average, with a mean hospital stay of 11 days, due to recurrent and severe attacks which were mostly precipitated by the menstrual cycle. Gonadorelin analogues (Zoladex, AstraZeneca) and monthly prophylactic infusions of heme arginate (Normosang, Orphan Europe) were administered without bringing about any improvement. The patient received 193 heme doses (48.250 mg heme/4,381.1 mg iron) and developed secondary iron overload (ferritin 1,090 ng/mL), multiple venous thrombosis with loss of vascular access, catheter‐related bloodstream infections, and anaphylaxis. For the serious allergic reaction, she was pretreated with systemic corticosteroids during subsequent attacks to receive heme, which caused an exogenous Cushing syndrome. She was placed on the waiting list for an OLT as an exception and waited for 1 year (12 times the usual waiting average) because patients in worse conditions were always prioritized. As complications, she had postextubation respiratory insufficiency caused by anesthetic drug recirculation, early acute cell rejection, and cytomegalovirus syndrome, all of which were successfully managed. Postoperative anticoagulation was administered based on reports of a high rate of hepatic arterial thrombosis at acute hepatic porphyria receptors.3 Urinary levels of porphobilinogen and 5‐aminolevulinic acid normalized within 48 hours post‐OLT, and there have been no symptoms after 6 months. OLT is a viable treatment for intractable attacks in developing countries. One of the main expectable difficulties in these countries is very prolonged waiting times because most patients have structurally healthy livers and regular prioritization scores are not applicable. Hence, attempting to identify patients at high risk of becoming refractory to heme therapy is essential to avoid permanent neurological sequelae or death during the waiting period. Patients with multiple comorbidities might be more vulnerable to recurrent attacks, so it is essential to closely monitor and control their illnesses. This case supports the curative role of OLT in acute hepatic porphyrias.

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gene therapies

2026-08-31 | Acute Intermittent Porphyria Presenting as Refractory Hyponatremia, Seizures, and Paralytic Ileus Following Laparoscopic Appendectomy: A Case Report

describing AIP precipitated by laparoscopic appendectomy, presenting with refractory hyponatremia, paralytic ileus, and new-onset seizures. Case DesCription Patient History and Presenting ComplaintsA 27-year-old male, previously healthy with no known comorbidities or prior hospitalizations, underwent laparoscopic appendectomy introDuCtion Acute intermittent porphyria (AIP) is the most common of the acute hepatic porphyrias, with an estimated prevalence of 1-2 per 100,000 in the general population, though the true prevalence of latent gene carriers is considerably higher (estimated 1 in 1,000). 1 It is caused by a heterozygous pathogenic variant in the hydroxymethylbilane synthase (HMBS) gene encoding porphobilinogen deaminase (PBGD) (PBGD; EC 4.3.1.8),resulting in approximately 50% reduction in enzyme activity and consequent accumulation of neurotoxic heme precursors-δ-aminolevulinic acid (ALA) and PBG-during acute attacks. 2 Acute attacks present with neurological, autonomic, and visceral manifestations, including abdominal pain, neuropathy, psychiatric symptoms, hypertension, tachycardia, seizures, and hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).3 Recognized triggers include fasting, alcohol, hormonal fluctuations, infections, and-critically-certain anesthetic agents and medications commonly used in the perioperative setting.4 The overlap of AIP symptoms with common surgical and medical diagnoses frequently results in delayed recognition, sometimes over years, during which patients may receive potentially porphyrinogenic drugs that can worsen the condition.5 To our knowledge, only a limited number of cases have been reported in the Indian critical care literature 1-

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2026-08-11 | Autonomic and small fiber neuropathy in patients with acute hepatic porphyrias.

Neurovisceral pain and autonomic symptoms are the initial and most common symptoms of acute hepatic porphyrias (AHPs) attacks. These symptoms may also exist in between attacks. Autonomic dysfunction in AHPs has been evaluated previously, but systematic evaluation with modern methods has been lacking. In this study, we aimed to assess the prevalence of clinically diagnosed, electro-physiologically and pathologically confirmed autonomic/SFN in patients with AHPs. Eight genetically confirmed AHPs patients, who were enrolled in between attacks, underwent neurological examination quantified by the neuropathy impairment score; COMPASS-31 questionnaire to assess autonomic symptom severity; and skin biopsies to assess intra-epidermal nerve fiber density (IENFD) to test for SFN. To assess the autonomic functions, we tested the heart rate response to deep breathing, the Valsalva maneuver, head-up tilt test and performed the Quantitative Sudomotor Axon Reflex Test (QSART). The Composite Autonomic Severity Score (CASS) was calculated to quantify the impairment in different autonomic domains. We found evidence of SFN in the form of reduced IENFD or QSART responses and evidence of cardiovagal impairment in seven patients. Cardiovascular sympathetic impairment was present in three patients. COMPASS-31 and CASS scores ranged between 15 and 48/100 and 1-6/10, respectively, indicating a mild to moderate degree of autonomic impairment. A mild to moderate autonomic neuropathy involving different autonomic domains continues to exist in between AHPs attacks. Autonomic/small fiber neuropathy is invariably present in this patient population and offers a potential explanation for the chronic sensory neuropathic and autonomic manifestations.

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2025-06-09 | A Prospective, Blinded Study of Symptom Prevalence and Specificity of Porphyrin Precursors in Carriers of Acute Hepatic Porphyria.

This study aimed to characterise symptoms and assess the prevalence of elevated urine porphyrin precursors in first-degree relatives of acute hepatic porphyria (AHP) patients who have never experienced acute attacks and had no previous AHP genetic or biochemical testing. 149 first-degree relatives of confirmed AHP patients, previously unscreened for the family mutation, were recruited. All underwent genetic analysis, with 143 completing a study questionnaire and 118 undergoing urine analysis for delta aminolevulinic acid (ALA) and porphobilinogen (PBG). The questionnaire focused on symptoms, medical and family history, and quality of life. The study included 79 AHP mutation carriers and 70 non-carriers. Carriers had significantly higher ALA (6.98 vs. 2.21 mg/g creatinine) and PBG levels (9.17 vs. 1.31 mg/g creatinine) than non-carriers. Female carriers showed higher ALA (9.29 vs. 3.07 mg/g creatinine) and PBG levels (12.71 vs. 3.16 mg/g creatinine) than male carriers. Porphyria-related symptoms were reported by 27% (21/77) of carriers compared to 15% (10/66) of non-carriers, with carriers more likely to report dark urine and prolonged symptoms. Finally, 30.8% of carriers were asymptomatic high excreters (ASHE) with PBG levels exceeding four times the upper limit of normal (ULN). Significant differences in porphyrin precursor excretion and symptom profiles were found between AHP mutation carriers and controls, as well as between female and male carriers. Female carriers are more likely to excrete porphyrin metabolites above the normal range. A larger than expected number of undiagnosed carriers are ASHE with levels greater than four times the ULN.

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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.

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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.

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oligonucleotides

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.

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2025-06-01 | The new era of siRNA therapy: Advances in cancer treatment

Small interfering RNAs (siRNAs) have emerged as a groundbreaking tool in therapeutics, offering precise and efficient silencing of disease-related genes.Through the RNA interference (RNAi) mechanism, siRNAs operate through the RNAi pathway, selectively degrading target messenger RNAs (mRNAs) and thereby preventing the synthesis of aberrant or harmful proteins.1 This exquisite specificity allows siRNAs to target previously 'undruggable' proteins, offering significant potential for treating a wide spectrum of diseases, including genetic disorders, chronic diseases, and cancers. 2 Recent progress in siRNA technology has resulted in the clinical approval of groundbreaking therapies like Onpattro R , Amvuttra R , and Givlaari R , with over 130 siRNA candidates currently in clinical investigation.3,4 These therapies have already demonstrated remarkable efficacy in conditions such as transthyretin-mediated amyloidosis and acute hepatic porphyria, highlighting the broad therapeutic potential of this approach.Despite these achievements, the broader application of siRNA therapeutics faces significant hurdles.Key limitations include siRNA instability in biological fluids, inefficient intracellular delivery, immunogenicity, and off-target effects, all of which can compromise therapeutic efficacy.5 Overcoming these hurdles necessitates the development of innovative delivery systems that protect siRNA from degradation, promote efficient cellular uptake, and facilitate cytosolic release.6 Our study introduces a significant advance in siRNA-based therapeutics through the engineering of cholesterol-enriched exosomes (Chol/MEs).7 By enhancing the cholesterol content in the exosomal membrane, we created a delivery platform that enables siRNA to bypass endosomal entrapment and directly enter the cytosol via membrane fusion.This mechanism substantially improves intracellular delivery, leading to enhanced gene silencing and therapeutic efficacy.In pre-

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2024-09-11 | Canadian guidance for diagnosis and management of acute hepatic porphyrias.

Acute hepatic porphyrias (AHP) comprise four rare monogenic autosomal conditions. Each is linked to a deficiency of heme metabolizing enzymes. Common manifestations include severe abdominal pain, nausea, confusion, hyponatremia, hypertension, tachycardia, and neuropathy. Diagnosis is challenging due to a non-specific, variable presentation with symptoms mimicking other common conditions. Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, δ-aminolevulinic acid and porphyrins using a single random (spot) sample. However, many patients have complications due to delays in diagnosis and management. A novel small interfering RNA-based agent, givosiran, has demonstrated efficacy in reducing acute attacks in a recent Phase III trial, leading to its approval for the management of AHP. Early diagnosis is crucial for the timely introduction of disease-modifying treatments that reduce impairments, enhance quality of life, and extend survival. In this guidance, we aim to improve awareness and outcomes of AHP by making recommendations about diagnosis, monitoring, and treatment in Canada.

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2024-08-22 | Development of RNA interference-based therapy for rare genetic diseases

In December 2022, the Indonesian Ministry of Health projected that rare diseases might affect 8–10% of the population, equating to approximately 27 million people. These diseases, often congenital, are linked to genetic inheritance or mutations, leading to structural or functional defects. Despite advancements in diagnostic and treatment methods, many rare diseases remain challenging for healthcare practitioners. RNA interference (RNAi) presents a promising therapeutic approach by enabling the selective inhibition of genes responsible for genetic disorders. RNAi employs small RNA molecules, such as small interfering RNA (siRNA) and microRNA (miRNA), to bind specific mRNA molecules and prevent their translation into proteins. Current research showed that RNAi-based therapies have the potential to treat various genetic diseases, including acute hepatic porphyria (AHP) and primary hyperoxaluria type 1 (PH1). However, the mechanisms of RNAi in hereditary disorders like AHP and PH1 require further documentation. RNAi offers several advantages, including gene-specific targeting, versatility in treating diverse genetic disorders, and scalability for mass production. Nonetheless, challenges remain, such as side effects, difficulties in targeting specific cells, and high development cost. Despite these obstacles, RNAi-based therapy holds significant potential for revolutionize the treatment of genetic disorders.

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2024-05-26 | A randomized, placebo-controlled study of givosiran in patients with acute hepatic porphyrias (ENVISION): Final (36-month) analysis of the Taiwan Cohort.

Acute hepatic porphyrias (AHP) are rare genetic disorders associated with acute neurovisceral attacks and chronic symptoms. This analysis was conducted to examine the long-term efficacy and safety of givosiran in Taiwanese participants in the ENVISION study (NCT03338816). Patients (age ≥12 years) with AHP and recurrent attacks were randomized to receive givosiran 2.5 mg/kg or placebo for 6 months during the double-blind period. Patients then switched from placebo to givosiran (placebo crossover group) or continued taking givosiran (continuous givosiran group) during a 30-month open-label extension period. The total study duration was 36 months. An analysis was conducted that included patients enrolled in Taiwan (N = 7). During the double-blind period and open-label extension period, the median annualized attack rates were 0.0 and 0.0, respectively, in the continuous givosiran group (n = 5) and 15.1 and 4.6, respectively, in the placebo crossover group (n = 2; 70 % decrease). Median annualized days of hemin use in the double-blind period and open-label extension period were 0.0 and 0.0, respectively, in the continuous givosiran group, and 23.8 and 5.0, respectively, in the placebo crossover group (79 % decrease). EQ-5D VAS scores remained relatively stable in both groups, and PPEQ responses indicated improved functioning and satisfaction in both groups. Delta-aminolevulinic acid and porphobilinogen levels remained low with long-term givosiran treatment. Serious adverse events were reported by 3 patients (43 %). Long-term efficacy and safety results in the Taiwan cohort are consistent with those in the global cohort.

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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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2022-06-17 | Mechanistic modelling of enzyme-restoration effects of new recombinant liver-targeted proteins in acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a rare disease caused by a genetic mutation in the hepatic activity of the porphobilinogen-deaminase. We aimed to develop a mechanistic model of the enzymatic restoration effects of a novel therapy based on the administration of different formulations of recombinant human-PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circulates in blood, incorporating into HDL and penetrating hepatocytes. Single i.v. dose of different formulations of rhPBGD linked to ApoAI were administered to AIP mice in which a porphyric attack was triggered by i.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors, 5-aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non-linear mixed-effects analysis. The mechanistic model successfully characterized over time the amounts excreted in urine of the three heme precursors for different formulations of rhPBGD and unravelled several mechanisms in the heme pathway, such as the regulation in ALA synthesis by heme. Treatment with rhPBGD formulations restored PBGD activity, increasing up to 51 times the value of the rate of tPOR formation estimated from baseline. Model-based simulations showed that several formulation prototypes provided efficient protective effects when administered up to 1 week prior to the occurrence of the AIP attack. The model developed had excellent performance over a range of doses and formulation type. This mechanistic model warrants use beyond ApoAI-conjugates and represents a useful tool towards more efficient drug treatments of other enzymopenias as well as for acute intermittent porphyria.

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2022-04-06 | Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria.

Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.

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2003-09-01 | Biochemical Characterization of Porphobilinogen Deaminase-Deficient Mice During Phenobarbital Induction of Heme Synthesis and the Effect of Enzyme Replacement

Acute intermittent porphyria (AIP) is a genetic disorder caused by a deficiency of porphobilinogen deaminase (PBGD), the 3rd enzyme in heme synthesis. It is clinically characterized by acute attacks of neuropsychiatric symptoms and biochemically by increased urinary excretion of the porphyrin precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA). A mouse model that is partially deficient in PBGD and biochemically mimics AIP after induction of the hepatic ALA synthase by phenobarbital was used in this study to identify the site of formation of the presumably toxic porphyrin precursors and study the effect of enzyme-replacement therapy by using recombinant human PBGD (rhPBGD). After 4 d of phenobarbital administration, high levels of PBG and ALA were found in liver, kidney, plasma, and urine of the PBGD-deficient mice. The administration of rhPBGD intravenously or subcutaneously after a 4-d phenobarbital induction was shown to lower the PBG level in plasma in a dose-dependent manner with maximal effect seen after 30 min and 2 h, respectively. Injection of rhPBGD subcutaneously twice daily during a 4-d phenobarbital induction reduced urinary PBG excretion to 25% of the levels found in PBGD-deficient mice administered with only phenobarbital. This study points to the liver as the main producer of PBG and ALA in the phenobarbital-induced PBGD-deficient mice and demonstrates efficient removal of accumulated PBG in plasma and urine by enzyme-replacement therapy.

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1986-09-15 | Incorporation of haemoglobin haem into the rat hepatic haemoproteins tryptophan pyrrolase and cytochrome P-450.

After its administration to intact rats, haemoglobin haem was incorporated into hepatic tryptophan pyrrolase as shown by the marked increase in functional constitution of this enzyme. Incorporation of haemoglobin haem into cytochrome P-450 was demonstrated in intact rats and in the isolated rat liver perfused with haemoglobin-free medium. In both systems, haemoglobin haem restored cytochrome P-450 content and its dependent mixed-function-oxidase activity after substrate-induced destruction of the cytochrome P-450 haem moiety. Further confirmation that haemoglobin haem could be incorporated prosthetically into cytochrome P-450 was achieved by administration of [3H]haemoglobin to rats and subsequent isolation and characterization of radiolabelled substrate-alkylated products of cytochrome P-450 haem. Our findings indicate that, although hepatic uptake of parenteral haemoglobin is slower than that of haem, it appears to serve as an effective haem donor to the intrahepatic ‘free’ haem pool. Thus parenteral haemoglobin may warrant consideration as a therapeutic alternative to haem in the acute hepatic porphyrias.

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