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Journal of Inherited Metabolic Disease Jul 2021
Topics: Acetylgalactosamine; Homocysteine; Humans; Porphyria, Acute Intermittent; Pyrrolidines
PubMed: 34145602
DOI: 10.1002/jimd.12411 -
Therapeutics and Clinical Risk... 2019Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder characterized by a deficiency in heme biosynthesis. Heme biosynthesis occurs throughout... (Review)
Review
Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder characterized by a deficiency in heme biosynthesis. Heme biosynthesis occurs throughout the body, but it is most prominent in the erythroblastic system and liver. AIP is a hepatic porphyria whereby the liver is the source of toxic heme metabolites. Clinical manifestations of AIP result from a genetic mutation that leads to partial function of porphobiliogen deaminase (PBGD). This causes an accumulation of upstream, neurotoxic metabolites. Symptoms include but are not limited to peripheral neuropathies, autonomic neuropathies and psychiatric manifestations. AIP can be life threatening and clinical signs and symptoms are often heterogeneous and non-specific. Therefore, it is important to be able to recognize these patients to make a prudent diagnosis and offer appropriate therapy. Here, we review the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of AIP including the role of liver transplantation.
PubMed: 31908464
DOI: 10.2147/TCRM.S180161 -
Liver Transplantation : Official... Apr 2021Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT)...
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.
Topics: Female; Humans; Liver Transplantation; Male; Porphyria, Acute Intermittent; Quality of Life; Registries; Retrospective Studies
PubMed: 33259654
DOI: 10.1002/lt.25959 -
International Journal of Molecular... Jul 2022During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight... (Review)
Review
During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight enzyme-catalyzed pathway within each developing erythroid cell. A large body of data exists to explain the transcriptional regulation of the heme biosynthesis enzymes, but until recently much less was known about alternate forms of regulation that would allow the massive production of heme without depleting cellular metabolites. Herein, we review new studies focused on the regulation of heme synthesis via carbon flux for porphyrin synthesis to post-translations modifications (PTMs) that regulate individual enzymes. These PTMs include cofactor regulation, phosphorylation, succinylation, and glutathionylation. Additionally discussed is the role of the immunometabolite itaconate and its connection to heme synthesis and the anemia of chronic disease. These recent studies provide new avenues to regulate heme synthesis for the treatment of diseases including anemias and porphyrias.
Topics: Erythropoiesis; Gene Expression Regulation; Heme; Humans; Porphyrias
PubMed: 35806474
DOI: 10.3390/ijms23137467 -
Blood Nov 2023The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors...
The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors that upregulate hepatic 5-aminolevulinic acid synthase 1 (ALAS1) activity. Induction of hepatic ALAS1 leads to the accumulation of porphyrin precursors, in particular 5-aminolevulinic acid (ALA), which is thought to be the neurotoxic mediator leading to acute attack symptoms such as severe abdominal pain and autonomic dysfunction. Patients may also develop debilitating chronic symptoms and long-term medical complications, including kidney disease and an increased risk of hepatocellular carcinoma. Exogenous heme is the historical treatment for attacks and exerts its therapeutic effect by inhibiting hepatic ALAS1 activity. The pathophysiology of acute attacks provided the rationale to develop an RNA interference therapeutic that suppresses hepatic ALAS1 expression. Givosiran is a subcutaneously administered N-acetylgalactosamine-conjugated small interfering RNA against ALAS1 that is taken up nearly exclusively by hepatocytes via the asialoglycoprotein receptor. Clinical trials established that the continuous suppression of hepatic ALAS1 mRNA via monthly givosiran administration effectively reduced urinary ALA and porphobilinogen levels and acute attack rates and improved quality of life. Common side effects include injection site reactions and increases in liver enzymes and creatinine. Givosiran was approved by the US Food and Drug Administration and European Medicines Agency in 2019 and 2020, respectively, for the treatment of patients with AHP. Although givosiran has the potential to decrease the risk of chronic complications, long-term data on the safety and effects of sustained ALAS1 suppression in patients with AHP are lacking.
Topics: Humans; Aminolevulinic Acid; RNA Interference; Quality of Life; Porphyrias, Hepatic; Pain; Heme; Porphyrias
PubMed: 37027823
DOI: 10.1182/blood.2022018662 -
British Journal of Haematology Feb 2017Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms,... (Review)
Review
Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light-protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non-porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated.
Topics: Chronic Disease; Disease Management; Humans; Porphyria, Acute Intermittent
PubMed: 27982422
DOI: 10.1111/bjh.14459 -
Molecular Genetics and Metabolism Nov 2023Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway....
Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease.
Topics: Humans; Porphobilinogen; Porphyrias, Hepatic; Porphobilinogen Synthase; Heme
PubMed: 37542766
DOI: 10.1016/j.ymgme.2023.107670 -
Hepatology Communications Feb 2019The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types... (Review)
Review
The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%-3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long-term complications. Their first-degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down-regulate ALA synthase-1 and/or wild-type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders.
PubMed: 30766957
DOI: 10.1002/hep4.1297 -
Actas Dermo-sifiliograficas Oct 2015Skin manifestations associated with chronic kidney disease are very common. Most of these conditions present in the end stages and may affect the patient's quality of... (Review)
Review
Skin manifestations associated with chronic kidney disease are very common. Most of these conditions present in the end stages and may affect the patient's quality of life. Knowledge of these entities can contribute to establishing an accurate diagnosis and prognosis. Severe renal pruritus is associated with increased mortality and a poor prognosis. Nail exploration can provide clues about albumin and urea levels. Nephrogenic systemic fibrosis is a preventable disease associated with gadolinium contrast. Comorbidities, such as diabetes mellitus and secondary hyperparathyroidism, can lead to acquired perforating dermatosis and calciphylaxis, respectively. Effective and innovative treatments are available for all of these conditions.
Topics: Calciphylaxis; Comorbidity; Hair Diseases; Humans; Nail Diseases; Nephrogenic Fibrosing Dermopathy; Porphyria Cutanea Tarda; Prognosis; Pruritus; Renal Insufficiency, Chronic; Skin; Skin Diseases; Therapies, Investigational
PubMed: 26093993
DOI: 10.1016/j.ad.2015.05.007 -
Lakartidningen Sep 2016The attack of acute porphyria Based on in silico evidence of pharmacokinetic, pharmacodynamic, and physiologic properties, have approximately 1 300 medicinal drugs... (Review)
Review
The attack of acute porphyria Based on in silico evidence of pharmacokinetic, pharmacodynamic, and physiologic properties, have approximately 1 300 medicinal drugs been assessed with regard to the specific risk to carriers of acute porphyria. The classifications have been published in booklet form, together with prophylactic advice to the carriers and suggestions for doctors in charge of their care. The risk-classifications rest on the behavior of the drug in an extended molecular model of the attack of acute porphyria. In this, symptoms are effects of 5-aminolevulinate (ALA) produced in surplus after acceleration of enzyme-deficient heme biosynthesis, taking place during induction of drug-metabolizing cytochromes P450 and triggered by hepatocellular nuclear receptors, activated by the drug. The process is enhanced by glucagon- and sirtuin-dependent molecular processes activated in stress and cellular energy deficit, and enhanced and prolonged by auto-generating ALA.
Topics: Algorithms; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Porphyria, Acute Intermittent
PubMed: 27622758
DOI: No ID Found