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Current Opinion in Gastroenterology May 2021Acute hepatic porphyrias (AHP) are a group of rare diseases that are characterized by episodic acute neurovisceral pain episodes caused by abnormal accumulation of the... (Review)
Review
PURPOSE OF REVIEW
Acute hepatic porphyrias (AHP) are a group of rare diseases that are characterized by episodic acute neurovisceral pain episodes caused by abnormal accumulation of the neurotoxic porphyrin precursor delta-aminolevulinic acid (ALA). Patient with frequent recurrent acute attacks have been difficult to treat and these patients sometimes require liver transplantation. Recent developments in small interfering RNA (siRNA)-based therapy led to the development of an effective prophylactic treatment for patients with frequent recurrent attacks. This review will describe treatment options for AHP and highlight management in light of new treatment option.
RECENT FINDINGS
Givosiran is a novel siRNA-based therapy targeted specifically to hepatocytes to inhibit ALA synthase 1, the first and rate-limiting step in heme biosynthesis. Patients with frequent recurrent attacks treated with givosiran had durable normalization of ALA and significantly reduced numbers of acute attacks and need for hemin treatment. The overall safety profile for givosiran was comparable with placebo and the drug was recently approved by the Food and Drug Administration for treatment of AHP patients.
SUMMARY
Givosiran is an effective treatment for prevention of acute porphyria attacks in AHP patients with frequent recurrent attacks.
Topics: Humans; Pain; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Treatment Outcome
PubMed: 33769375
DOI: 10.1097/MOG.0000000000000734 -
Journal of Medical Case Reports Dec 2022Prompt diagnosis of metabolic disorders in a resource-limited country like Nepal is daunting. Acute intermittent porphyria is a rare but common hepatic porphyria mostly...
BACKGROUND
Prompt diagnosis of metabolic disorders in a resource-limited country like Nepal is daunting. Acute intermittent porphyria is a rare but common hepatic porphyria mostly seen in females of the reproductive age group. As its incidence is quite uncommon, conjectures about porphyria diagnosis are often duped into a diagnostic conundrum.
CASE PRESENTATION
Here we unravel a case of a 15-year-old Hindu Nepalese girl distraught by the myriad of symptoms in the setting of severe abdominal pain accompanied by constipation and limb pain as the chief complaints. She presented with acute severe hypertension with marked persistent hyponatremia (up to 109 mEq/L). Despite conservative management of hypertension and electrolytes, unresolved electrolyte imbalance led us to the speculation of disturbance in the renin-angiotensin-aldosterone system. Due to her exacerbating neurovisceral status, she also required intensive care during the disease course. After thorough investigations and exemption of presumed provisional diagnoses, based on sustained symptomatic presentation, the clinical suspicion was driven towards a diagnosis of porphyria-related disorders. Positive Watson-Schwartz test substantiated the diagnosis of acute intermittent porphyria. Her symptoms gradually abated after the consumption of high carbohydrate diets.
CONCLUSION
This case highlights the baffling amalgamation of symptoms that simulate common diseases of concern yet are buried in the realm of porphyric disorders. Porphyria can be diagnosed using simple screening tools and timely treatment can diminish serious consequences.
Topics: Female; Humans; Adolescent; Porphyria, Acute Intermittent; Porphyrias; Abdominal Pain; Constipation; Hypertension
PubMed: 36575494
DOI: 10.1186/s13256-022-03708-w -
Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study.Orphanet Journal of Rare Diseases Aug 2022Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks.
RESULTS
Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0-46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo.
CONCLUSIONS
Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.
Topics: Cost of Illness; Hemin; Humans; Pain; Porphobilinogen; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Quality of Life
PubMed: 36028858
DOI: 10.1186/s13023-022-02463-x -
Clinics in Dermatology 1996
Review
Topics: Female; Heme; Humans; Male; Porphyria, Erythropoietic; Porphyria, Hepatoerythropoietic; Porphyrias; Porphyrias, Hepatic
PubMed: 8862915
DOI: 10.1016/0738-081x(96)00067-3 -
Molecular Genetics and Metabolism Nov 2019Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic... (Review)
Review
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2-5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation. Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.
Topics: 5-Aminolevulinate Synthetase; Anemia; Clinical Trials as Topic; Dermatitis, Phototoxic; Disease Management; Genes, X-Linked; Heme; Humans; Liver Diseases; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30704898
DOI: 10.1016/j.ymgme.2019.01.020 -
Liver Transplantation : Official... Sep 2007Porphyrias are a heterogenous group of diseases that may result in disabling or life threatening neurovisceral symptoms and/or cutaneous photosensitivity. In acute... (Review)
Review
Porphyrias are a heterogenous group of diseases that may result in disabling or life threatening neurovisceral symptoms and/or cutaneous photosensitivity. In acute intermittent porphyria, the clinical features, particularly neurological symptoms, may be life-threatening and disabling. Conventional treatment with human hemin, though effective in reducing symptoms, does not reverse neuropathy when structural nerve damage has occurred and may cause intense phlebitis. Liver transplantation (LT) may be considered as treatment for those with repeated life-threatening acute attacks resulting in poor quality of life, requirement of ventilatory support, and progressive loss of venous access due to hemin infusion. Patients with variegate porphyria (VP) present after puberty with neurovisceral symptoms and skin manifestations. LT resolved VP in the 1 patient reported in the literature. Aminolaevulinic acid dehydratase deficient porphyria is a rare autosomal recessive disorder and a child who presented with failure to thrive and required transfusions and parenteral nutrition did not improve with LT. In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin in the bone marrow. Protoporphyrin is hepatotoxic and pigment loading of hepatocytes and bile canalicular sludging may result in progressive cholestasis and cirrhosis. LT is beneficial for such patients with end-stage liver disease. Perioperative management includes use of filters on operative lights to prevent skin burns and intestinal perforation. Other concerns include development of neuropathy, biliary complications, and recurrent liver disease. This review addresses the rationale, patient selection, evaluation, management issues, and technique of performing LT in various types of porphyria.
Topics: Carcinoma, Hepatocellular; Graft Survival; Hemin; Humans; Liver Neoplasms; Liver Transplantation; Porphyrias, Hepatic; Retrospective Studies; Safety; Survival Analysis
PubMed: 17763398
DOI: 10.1002/lt.21261 -
Hepatology (Baltimore, Md.) Oct 2017The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic... (Review)
Review
The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic pathway. These disorders present clinically with acute neurovisceral symptoms which may be sporadic or recurrent and, when severe, can be life-threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions. There are four major subgroups: symptomatic patients with sporadic attacks (<4 attacks/year) or recurrent acute attacks (≥4 attacks/year), asymptomatic high porphyrin precursor excretors, and asymptomatic latent patients without symptoms or porphyrin precursor elevations. Given their clinical heterogeneity and potential for significant morbidity with suboptimal management, comprehensive clinical guidelines for initial evaluation, follow-up, and long-term management are needed, particularly because no guidelines exist for monitoring disease progression or response to treatment. The Porphyrias Consortium of the National Institutes of Health's Rare Diseases Clinical Research Network, which consists of expert centers in the clinical management of these disorders, has formulated these recommendations. These recommendations are based on the literature, ongoing natural history studies, and extensive clinical experience. Initial assessments should include diagnostic confirmation by biochemical testing, subsequent genetic testing to determine the specific acute hepatic porphyria, and a complete medical history and physical examination. Newly diagnosed patients should be counseled about avoiding known precipitating factors. The frequency of follow-up depends on the clinical subgroup, with close monitoring of patients with recurrent attacks who may require treatment modifications as well as those with clinical complications. Comprehensive care should include subspecialist referrals when needed. Annual assessments include biochemical testing and monitoring for long-term complications. These guidelines provide a framework for monitoring patients with acute hepatic porphyrias to ensure optimal outcomes. (Hepatology 2017;66:1314-1322).
Topics: Disease Management; Humans; Porphyrias, Hepatic
PubMed: 28605040
DOI: 10.1002/hep.29313 -
Blood Nov 2012The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous,"... (Review)
Review
The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.
Topics: Biosynthetic Pathways; Genetic Predisposition to Disease; Heme; Humans; Mutation; Porphyrias
PubMed: 22791288
DOI: 10.1182/blood-2012-05-423186 -
BMJ (Clinical Research Ed.) Jun 2000
Review
Topics: Acute Disease; Genetic Testing; Humans; Porphyria Cutanea Tarda; Porphyrias
PubMed: 10856069
DOI: 10.1136/bmj.320.7250.1647 -
Pharmacotherapy 1984Acute intermittent porphyria is caused by an inherent error of porphyrin metabolism characterized by a deficiency of porphobilinogen deaminase and increased activity of... (Review)
Review
Acute intermittent porphyria is caused by an inherent error of porphyrin metabolism characterized by a deficiency of porphobilinogen deaminase and increased activity of delta-aminolevulinic acid synthase, key enzymes necessary for the biosynthesis of heme. During an attack patients may have abdominal pain, vomiting, muscle weakness, constipation and neuropsychiatric symptoms. In the majority of individuals the disease remains clinically latent throughout life. Various drugs and chemicals, hormones and nutritional factors predispose to clinical attacks, probably by inducing hepatic delta-aminolevulinic acid synthase. Avoidance of these substances is important in preventing attacks. Screening of family members to detect genetic carriers permits precautionary measures. Management of attacks includes symptomatic therapy, high carbohydrate intake and intravenous administration of hematin.
Topics: Acute Disease; Carbohydrates; Hemin; Humans; Porphyrias
PubMed: 6377248
DOI: 10.1002/j.1875-9114.1984.tb03340.x