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A 23-year-old woman, with 6-week-old intrauterine gestation, presented with severe diffuse abdominal pain of 3 days duration which was intermittent and crampy in nature associated with generalised weakness of all limbs. There was no history of bleeding per-vagina, fever, rashes, diarrhoea

The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

Background Pregnancy in women with acute hepatic porphyria (AHP) has historically been associated with significant morbidity. Clinical outcomes have been the focus of previous reports on porphyria and maternal health, with little data available on the levels of heme precursors during pregnancy. We present the results of a follow-up program for women with AHP in the Swedish cohort who were pregnant between 2001 and 2020. Methods Thirty-three women with AHP were monitored during forty-four pregnancies resulting in forty-four single births. Seven of thirty-three women had a clinical history of acute attacks that required hospitalization. Results Four women experienced acute porphyria attacks during pregnancy, and one during the puerperium. Seven women developed hypertension and four pregnancies ended with preeclampsia. There were no maternal or fetal pre- or postnatal deaths. One infant had a congenital cardiac anomaly. In thirty-two of the thirty-eight pregnancies in which we measured heme precursors in the urine during pregnancy, the levels were increased. Conclusion Our observations align with contemporary reports that pregnancy in patients with AHP is frequently uncomplicated. Excretion of heme precursors increased during pregnancy, but this did not manifest as a higher frequency of clinical porphyria manifestations. The involvement of porphyria specialists in the patients' maternal care is recommended for reducing risk and improving the probability of good pregnancy outcomes. This article is protected by copyright. All rights reserved.

Acute hepatic porphyrias (AHP) are a group of four different rare to ultra-rare, severely debilitating, and sometimes fatal diseases that significantly impact patients' lives: 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Based on literature estimates, a conservative estimate of the number of AHP patients in Belgium requiring treatment, defined as patients experiencing recurrent attacks and/or chronic debilitating symptoms, is likely limited to 11-34 patients. These patients face a considerable unmet need, as there is currently no pharmaceutical treatment available that effectively prevents attacks and has an impact on other chronic symptoms of the disease.A panel consisting of the two European Porphyria Network1 (EPNet) centers in Belgium (Center for inborn errors of metabolism of UZ Leuven and the 'Centre Belge des Porphyries' of Erasme Hospital and LHUB-ULB) participated in an advisory board on 24 January 2020. Representatives of the sponsoring pharmaceutical company, Alnylam Pharmaceuticals, organized and attended the meeting. The objective of the meeting was to obtain expert input on the state-of-the-art clinical practice of AHP in Belgium. Following this meeting, this expert consensus statement was drafted, in collaboration with and coordinated by the EPNet centers in Belgium. This statement provides an overview of the state-of-the art in AHP, by means of a concise overview of AHP pathophysiology, clinical manifestations, and burden of disease, (Belgian) epidemiology, treatments, and proposed organization of care. ispartof: ACTA CLINICA BELGICA vol:77 issue:4 pages:735-741 ispartof: location:England status: published

Acute hepatic porphyrias (AHPs) are a group of rare genetic disorders that affect the enzymes of the heme biosynthetic pathway. Patients have a varied presentation, but attacks of severe abdominal ...

Background Porphyrias are a group of rare diseases leading to dysregulation in heme biosynthesis and the accumulation of heme precursors, including porphyrinogens, which in their oxidized states [porphyrins] are reddish or purple. Acute hepatic porphyrias (AHP) comprise four diseases that cause acute debilitating neurovisceral attacks. Despite diagnostic advances, AHP is often undiagnosed or misdiagnosed due to a lack of disease awareness, low clinical suspicion, variable presentation, and nonspecific symptoms that mimic more common diseases. Delays in diagnosis and treatment increase the risk of serious acute and chronic complications. Aim In order to assess whether symptoms alone or in combination might be utilized as important indicators or “purple flags” that, when present, should alert clinicians to suspect AHP and pursue specific diagnostic testing, we conducted a comprehensive review of the literature on AHP, including cohort studies and case reports over two epochs, from 1980 to 2006 and from 2012 to 2018. Results We found that severe abdominal pain, with or without acute central nervous system manifestations and peripheral neuropathy, continues to be recognized the most frequent symptom. Hyponatremia, change in urine color, and certain chronic symptoms were also identified as features that should raise suspicion of AHP. To improve diagnosis of AHP, clinicians need to take a broad perspective, including demographic data and medical history, into consideration. Conclusions The clinical features of AHP continue to be severe pain, especially pain in the abdomen. Other features that should raise suspicion are autonomic, peripheral, or central neuropathies, hyponatremia, and red-purple urine color.

Introduction Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. ENVISION is an ongoing phase 3 study, evaluating efficacy and safety of givosiran in symptomatic AHP patients. Objective Describe efficacy and safety resuts of the ENVISION 18-month OLE period. Methods Exploratory efficacy (composite porphyria attacks, ALA/PBG levels, hemin use, and missed days of work) and safety measures in the OLE were assessed. Analyses were descriptive and represent the timepoint after which all patients completed at least their Month 18 visit (01/10/2020). Results Ninety-four patients completed the DB period, and 93 patients entered the OLE (placebo/givosiran = 46; givosiran/givosiran = 47). Mean exposure to givosiran was 12.97 [SD = 3.6] months for placebo/givosiran and 18.86 [3.6] months for givosiran/givosiran, with maximum exposure of 25.1 months. Continued treatment in givosiran/givosiran patients led to a median annualized attack rate (AAR) of 0.58 (range: 0–16.2) through Month 18. Patients in the placebo/givosiran group had an AAR of 1.62 (range: 0–11.8) after receiving givosiran for ≥12 months during the OLE period, compared with 10.65 (range: 0–51.6) whilst receiving placebo during the 6-month DB period. Sustained ALA/PBG lowering during the OLE was accompanied by sustained reductions in hemin use, and more than half of the placebo/givosiran patients experienced 0 days of hemin use. There was a decrease in the number of work days missed in the past 4 weeks at Month 6 (mean = 6.7 days [SD = 7.8], n = 20/46) compared with Month 18 (2.5 [5.1], n = 23/46), for patients in the placebo/givosiran group who were able to work. The most common related adverse events (AEs) observed during givosiran treatment were injection site reactions, nausea and fatigue. Hepatic and renal AEs were both reported in 17% of patients each during givosiran treatment. No new safety concerns occurred in the OLE period. Conclusion In the ongoing OLE period of the ENVISION study, patients receiving long-term treatment with givosiran demonstrated a durable response in clinical efficacy, across a wide range of clinical parameters. Following the initial 6 months of givosiran treatment during the OLE, placebo/givosiran patients had a similar clinical response to that observed in givosiran/givosiran patients in the OLE period through Month 18. The safety profile of givosiran remained acceptable and consistent with that previously observed.

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.

Porphyria are a group of metabolic disorders caused by altered activity of enzymes in the heme biosynthesis pathway. Acute hepatic porphyria (AHP) are due to hepatic overproduction of the porphyrin precursors, delta aminolevulinic acid, and porphobilinogen, and the symptoms are probably caused primarily by injury to the nervous system. However, abdominal pain and nausea can be observed. Porphyria cutanea tarda (PCT) is the most common of the porphyria with a prevalence of 5–10 per 100 000 people (D. Montgomery Bissell, K. E. et al. N Engl J Med 2017; 377: 862–872). In PCT, deficient enzymatic activity of uroporphyrinogen decarboxylase (UROD) in the liver leads to cutaneous phototoxicity after sun exposure. The most important susceptibility factors include hepatitis C virus infection, alcohol consumption, smoking, estrogen use, and genetic factors like UROD mutation and HFE mutations (S. Jalil et al. Clin Gastroenterol Hepatol 2010; 8: 297–302). In ultrasonography (US) of PCT patients, the liver can be normal, exhibit fibrotic or cirrhotic changes, or rarely demonstrates hyperechogenic focal alterations (M. Nishiyama et al. Abdom Radiol 2017; 42: 1813–1818). We report two cases of patients with rare findings not previously diagnosed with any porphyria.

Background This study used quantitative and qualitative research methods to analyze how acute hepatic porphyria (AHP) affects patients with varying annualized porphyria attack rates. The overall impact of AHP on patients and caregivers, including their quality of life, was explored. The nature and treatment of acute attacks, experiences of long-term heme arginate treatment and access to other appropriate treatment, and the extent of and treatment for chronic symptoms were also investigated within this study. Methods Patient and caregiver data were collected via an online survey of members of the British Porphyria Association, followed by an optional 1-h telephone interview. Results Thirty-eight patients and 10 caregivers responded to the survey. Of those, 10 patients and three caregivers completed follow-up interviews. Overall, 19 patients (50%) had experienced an acute attack within the previous 2 years, and the severity and types of symptoms experienced during or between acute attacks varied considerably. There were no clear definitions among patients for ‘mild’ or ‘severe’ attacks. Treatments and treatment settings used to manage attacks also varied. Following unsatisfactory care experiences at hospitals, some patients reported avoiding further hospital services for later attacks. Therefore, using settings of care as a measure of attack severity should be avoided. Ninety-four percent of patients also experienced chronic symptoms, which were as varied as acute attacks. Pain was the predominant chronic symptom and was managed with opioids in severe cases. Regardless of AAR, porphyria heavily impacted the daily lives of patients and caregivers. Although patients experiencing frequent attacks generally endured a greater impact on their daily life, patients with less frequent attacks also experienced impacts on all domains (social, leisure activities, relationship with family, relationships, psychological wellbeing, finances, employment, and study). Caregivers were most affected in the finance, relationships with family, and employment domains, and just over half of the caregivers reported a moderate impact on their psychological wellbeing. Conclusions/implications The burden of illness with AHP is high across all patients, regardless of frequency of attacks, and AHP negatively affects patients and caregivers alike.

Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.

© 2021 Elsevier B.V. All rights reserved., Porphyrias are a set of rare inherited metabolic disorders, each of them representing a defect in one of the eight enzymes in the haem biosynthetic pathway resulting in the accumulation of organic compounds called porphyrins. Acute hepatic porphyrias (AHP) are those in which the enzyme deficiency occurs in the liver, of which acute intermittent porphyria is by far the most common subtype. Neurology of the AHP is still challenging in practice, and patients rarely receive the correct diagnosis early in the disease course. For AHP, which primarily affects the central and peripheral nervous system, the cause of symptoms seems to be the increased production of neurotoxic precursors, in particular delta-aminolaevulinic acid and porphobilinogen. Neurological complications usually result from severe episodes of acute attacks. The neurologic hallmark of porphyrias is an acute predominantly motor axonal neuropathy resembling a Guillain-Barré syndrome that generally occurs after the onset of other clinical features such as abdominal pain and central nervous system manifestations. Neuropsychiatric syndromes, seizures, encephalopathy, and cerebrovascular disorders are among the possible central nervous system presentations. Therapeutic approach to AHP is divided into management and prophylaxis of an acute attack, including long standing options such as intravenous hematin and new therapeutic agents such as givosiran.

Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.

Zusammenfassung. Unter dem Begriff «Porphyrie» wird eine Gruppe von acht Stoffwechselerkrankungen zusammengefasst, welche in Folge einer gestörten Hämbiosynthese entstehen. Die Einteilung der verschiedenen Formen erfolgt anhand der klinischen und biochemischen Merkmale. Dieser Artikel fokussiert auf die akuten (hepatischen) Porphyrien (AHP), die durch eine ähnliche Pathophysiologie und klinische Symptomatik gekennzeichnet sind. Typisch sind akute, das autonome Nervensystem betreffende Symptome; starke, kolikartige, teilweise ausstrahlende Oberbauchschmerzen, Übelkeit, Erbrechen, Hypertonie, Tachykardie, Obstipation und Hyponatriämie. Die Diagnose einer AHP wird aufgrund einer mindestens fünffach erhöhten Ausscheidung von Porphobilinogen (PBG) im Urin gestellt. Therapie der Wahl ist die Zufuhr von Kohlenhydraten, die Gabe von humanem Häm, die Elimination und Vermeidung von schubauslösenden Triggerfaktoren und eine begleitende symptomorientierte Therapie, im Besonderen eine suffiziente Analgesie.

Acute intermittent porphyria (AIP) is the most common and severe form of porphyrias. This is a dominant inherited disorder with low penetrance, caused by mutations in gene coding hydroxymethylbilane synthase (HMBS). We present the results of our long-term genetic study of AIP patients and their relatives (N = 153 and 302, respectively). We detected 88 HMBS gene mutations, 24 of which never described before. To identify additional factors conditioning AIP manifestation, we carried out whole exome sequencing on the group of AIP patients (N = 6). Mutation spectra of different patients virtually did not overlap. In 5 out of 6 patients, we found defects in genes regulating nervous system (UNC13A, ALG8, FBXO38, AGRN, DOK7, SCN4A). As usually acute AIP attacks have various neurological symptoms, we proposed a hypothesis of possible contribution of mutations in such genes in AIP manifestation.

Acute intermittent porphyria (AIP), an autosomal dominant inborn error of metabolism, is the most common and severe form of the acute porphyrias. Attacks of severe abdominal pain, often with hypertension, tachycardia, are cardinal features of AIP, often requiring hospital admissions. Frequent recurrent attacks of AIP, defined as >3 attacks in one year, during which at least one attack requires intravenous heme therapy, are associated with significant morbidity, lost productivity, and health care burden. We report two patients with such frequent attacks of AIP, who have been managed with prophylactic heme therapy on a weekly basis. We describe results particularly in relation to symptom control, biochemical findings, health care costs, quality of life, and utilization of resources. During 11-month duration of weekly prophylactic heme infusions, we observed a 100% decrease in acute attacks and inpatient admissions in one subject and a 75% decrease in the other. During this time, we also observed a significant decrease in the number of emergency room visits. The decrease in number of acute attacks requiring hospital admission was associated with significantly decreased health care costs and improved quality of life. Reduction of both emergency room visits and hospital admissions decreased the utilization of health care services. Outpatient weekly infusions were also noted to be associated with better reimbursements and reduced overall costs of health care for the subjects. Both our subjects also endorsed better symptom control, quality of life and better understanding of disease. Thus, prophylactic heme therapy, through a multi-disciplinary approach, decreases the incidence of acute attacks, decreases health care costs and leads to better patient satisfaction and quality of life. Keywords: Acute hepatic porphyria, Health care costs, Health-related quality of life, Heme therapy, Prophylactic therapy

Background Acute hepatic porphyria (AHP) is a family of rare genetic diseases, the most common being acute intermittent porphyria (AIP). AHP results from enzyme deficiencies involved in haem synthesis, leading to accumulation of neurotoxic haem intermediates, aminolaevulinic acid (ALA) and porphobilinogen (PBG), causing potentially life-threatening attacks and chronic symptoms. Patients afflicted by AHP often remain without a proper diagnosis for up to 15 years due to lack of awareness and testing. First-line diagnostic biochemical tests include measuring spot urinary ALA and PBG as both are elevated in the majority of AHP patients. Aims The study aimed to describe physicians experience diagnosing AHP and characterize patients globally, including Canada. Methods Physicians (n=175) who actively managed AHP patients (with and without recurrent attacks) in the preceding year were recruited from 9/2017–10/2017 to complete an online survey collecting information on demographics, familiarity with AHP and diagnostic tests, perspective on symptoms important to diagnosis, referral patterns, and treatment preferences. Physicians also completed a chart review of 546 patients and reported anonymized data on demographics, medical history, attacks, and symptoms. Data was analysed using descriptive statistics. Results Canadian physicians (n=15) practiced a mean of 19.7 years, 67% worked in community settings, and 53% were gastroenterologists. Symptoms informing AHP diagnosis included fatigue (93%), sensory loss (87%), mental confusion (87%), Abdominal pain (80%), red/dark urine (80%), vomiting (73%). AHP diagnostic tests considered informative for diagnosis included urinary ALA (87%) and PBG (80%); however, several non-specific tests were also commonly considered informative of AHP. Chronic symptoms reported included fatigue (75%), nausea/vomiting (70%), weakness (66%), pain (58%), anxiety (54%), diarrhea (41%), constipation (40%). Canadian physicians reported a mean of 58% AHP patients they manage being initially misdiagnosed. Global patients (n=546) were aged 40 years (mean), female (52%), with AIP (83%). Canadian patients (n=38) were aged 41 years (mean), female (61%), with AIP (78%). Patients had mean of 3.4 attacks and 1.6 hospitalizations in the past year. Conclusions This study highlights the challenges diagnosing AHP due to non-specificity of symptoms and limited understanding of diagnostic procedures. Due to the frequent presentation of gastrointestinal symptoms, AHP should be included in gastroenterologists’ differential diagnosis of patients presenting with non-specific abdominal pain. Among patients diagnosed with AHP, both acute attacks and chronic symptoms were reported, implicating both in the disease. Funding Agencies Alnylam Pharmaceuticals

Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years.Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method.The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p = 0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years.Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer.

Background: Porphyria variegata (VP) is one of the hepatic porphyrias that results from the deficiency of protoporphyrinogen oxidase, an enzyme in the heme synthesis pathway. The name porphyria variegata refers to its many presentations, which include various neuropsychiatric and cutaneous manifestations. Emergency department (ED) presentations due to VP are most commonly neuropathic abdominal pain. Case Report: We present the case of a 57-year-old woman presenting to an ED with abdominal pain consistent with prior VP attacks. In addition to analgesics and supportive care, infusion of intravenous dextrose resulted in improvement in her symptoms. Conclusion: Intravenous dextrose and heme administration remain the first-line treatment for abdominal pain attributable to known acute hepatic porphyria attacks. Recently, the mechanism of action of carbohydrates in treating porphyria has been elucidated. Current information on this illness and ED management are discussed.

Variegate porphyria is an acute hepatic porphyria resulting from a partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in haem biosynthesis. Cutaneous symptoms and acute neurovisceral attacks are well-known clinical characteristics of the disease. Less studied, however, is the risk of developing hepatocellular carcinoma, an aggressive type of liver cancer. We describe here two Swiss patients with variegate porphyria and this serious complication. Common risk factors, including alcohol over-consumption or chronic hepatitis, were absent in both patients. Interestingly, one patient carried mutation 1082-1083insC in the PPOX gene, a prevalent sequence deviation in the Swiss variegate porphyria population, which was also found in a French patient with variegate porphyria and hepatocellular carcinoma. Recent studies indicate that individuals with acute hepatic porphyria have a 36- to 61-fold increased risk of manifesting hepatocellular carcinoma. The incidence rate ratio in the Swiss population was estimated to be 34, comparable with those found in the French and Finnish populations. Because this tumour is associated with a rising mortality, we suggest regular screening for hepatocellular carcinoma in all patients with variegate porphyria.

A 28-year-old female was admitted to intensive medical care as an emergency with tetraplegia and respiratory paralysis. Acute hepatic porphyria of the hereditary coproporphyria type was diagnosed which was associated with epilepsy in the history. The polysymptomatology could be traced back for 12 years. From the spectrum of 46 wrong diagnoses a three-dimensional symptom complex of abdominal, neuropsychiatric and cardiovascular complaints and findings could be documented. The patient was ill for a total of more than 128 weeks, had been admitted to 14 different hospitals on 21 occasions and had undergone repeated surgery without improvement of her complaints. Porphyria diagnostics had not been considered previously.

The porphyrias are predominantly inherited metabolic disorders, which result from a specific deficiency of one of the eight enzymes along the pathway of haem biosynthesis. Historically, they have been classified into hepatic and erythropoietic forms, based on the primary site of expression of the prevailing dysfunctional enzyme. From a clinical point of view, however, it is more convenient to subdivide them into acute and non-acute porphyrias, thereby primarily considering the potential occurrence of life-threatening acute neurovisceral attacks. Unrecognised or untreated, such an acute porphyric attack is associated with a significant mortality of up to 10%. The acute hepatic porphyrias comprise acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase deficiency porphyria. Making a precise diagnosis may be difficult because the different types of porphyrias may show overlapping clinical and biochemical characteristics. To date, the therapeutic possibilities are limited and mainly symptomatic. In this overview we report on what is currently known about pathogenesis, clinic, diagnostics, and therapy of the acute hepatic porphyrias. We further point out actual and future challenges in the management of these diseases.

Mechanisms that cause Alzheimer’s disease (AD), an invariably fatal neurodegenerative disease, are unknown. Important recent data indicate that neuronal heme deficiency may contribute to AD pathogenesis. If true, factors that contribute to the intracellular heme deficiency could potentially alter the course of AD. The porphyrias are metabolic disorders characterized by enzyme deficiencies in the heme biosynthetic pathway. We hypothesize that AD may differ significantly in individuals possessing the genetic trait for an acute hepatic porphyria. We elaborate on this hypothesis and briefly review the characteristics of the acute hepatic porphyrias that may be relevant to AD. We note the proximity of genes encoding enzymes of the heme biosynthesis pathway to genetic loci linked to sporadic, late-onset AD. In addition, we suggest that identification of individuals carrying the genetic trait for acute porphyria may provide a unique resource for investigating AD pathogenesis and inform treatment and management decisions.

A 22-year-old para I/gravida II developed psychiatric symptoms at 8 weeks of gestation. Subsequently neurological symptoms with seizures developed leading to a status epilepticus with continuing seizures at week 14. Anticonvulsive therapy had little effect in alleviating the seizures and the condition of the patient rapidly deteriorated. A sudden reddening of her urine lead to the diagnosis of acute hepatic porphyria confirmed by laboratory tests. After extensive discussion with the patient’s family it was decided to terminate the pregnancy at week 16. Within hours after pregnancy termination the seizures stopped and the patient recovered without any neurological deficits. Acute hepatic porphyria can be triggered by pregnancy and usually presents with gastrointestinal symptoms and personality changes. In its rare neurological manifestation it can lead to untreatable convulsions which leave no option but to terminate the pregnancy.

A 22-years old, 55 kg female patient in the twelfth week of pregnancy developed neuropsychiatric syndromes and in the following status epilepticus. Raised porphyrines and porphyrine precursors were found in the patient's urine. Despite intravenous glucose infusions and appropriate medication no reduction in seizure-frequency and neuropsychiatric syndromes was observed. An abortion was induced. After the interruption and starting of haem arginate therapy, seizure activity stopped and porphyrine precursors returned to normal levels, and after 6 weeks the patient was discharged in excellent clinical condition. This report describes a status epilepticus caused by acute hepatic porphyria, triggered by pregnancy, in a 22-years old woman. To our knowledge this is the first report of induced abortion as successful treatment in acute hepatic porphyria induced status epilepticus.

A new form of acute hepatic porphyria with double genetic defect--deficiency of porphobilinogen deaminase and coproporphyrinogen oxidase--is described. Among 17 studied family members this double enzymatic deficiency was found in five individuals, deficiency of porphobilinogen deaminase in four, and deficiency of coproporphyrinogen oxidase in two. Only the proband had an attack of porphyria. Apart from the proband, all family members had normal urinary PBG excretion. Increased faecal coproporphyrin excretion was found in three people. The results obtained suggest that deficiency of porphobilinogen deaminase and coproporphyrinogen oxidase can be inherited independently. coproporphyrinogen oxidase can be inherited independently.

Antipyrine kinetics following a single oral dose were obtained in porphyric patients in attack and in remission and in controls. The clearance of antipyrine was significantly lower during an acute porphyric attack (median: 0.34 ml min-1 kg-1; range: 0.1-0.71, P less than 0.05) than in patients in remission (median: 0.53 ml min-1 kg-1; range: 0.28-0.87) or controls (median: 0.52 ml min-1 kg-1; range: 0.32-0.93). There was a significant negative correlation between weight-adjusted antipyrine clearance and the urinary excretion of the porphyrin precursors, delta-aminolaevulinic acid (r = 0.86, P less than 0.001) and porphobilinogen (r = 0.82, P less than 0.002). These data suggest that the more severe the porphyric attack, the greater the impairment of hepatic monooxygenase activity.

Patients with acute hepatic porphyria present with abdominal pain and neurologic abnormalities. Although tho disease is uncommon, the emergency physician will occasionally encounter a patient with porphyria. The relevant pathophysiology of acute hepatic porphyria and the treatment of the patient with acute hepatic porphyria are reviewed.

The acute hepatic porphyrias are diseases in which the production of heme is deficient because of inherited abnormalities in specific enzymes of the heme synthetic pathway.1 The goal of therapy for...

In this study we examined the case histories of 163 living and 82 deceased adult Finnish patients with acute hepatic porphyria. There were 184 patients with acute intermittent porphyria and 61 patients with variegate porphyria. Among the 124 of the 163 living patients, who were traced 1984-1985, no hepatocellular carcinoma was found. Among the 82 deceased patients the cause of death was porphyria in 29 (36%), cardiovascular disease in 23 (29%) and hepatocellular carcinoma in 7 (9%). Of the 7 patients with hepatocellular carcinoma, 6 had acute intermittent porphyria and one had variegate porphyria. In acute hepatic porphyria, as compared with the total population, the calculated risk of hepatocellular carcinoma is increased 61-fold.

Hepatic porphyrias are disorders of heme synthesis characterized by genetically determined lesions of one of the key enzymes of heme synthesis. In carriers of such lesions, several factors (drugs, environmental chemicals, or diet) precipitate acute and often fatal attacks of neurologic dysfunction, which are promptly relieved by intravenous infusion of heme. However, the mechanism of such heme-induced amelioration remains elusive. To probe this mechanism, the biochemical events triggered by acute hepatic heme deficiency were examined in an animal model of chemically induced porphyria. Acute hepatic heme depletion in porphyric rats was found to impair hepatic tryptophan pyrrolase activity which, in turn, elevated tryptophan and 5-hydroxytryptamine turnover in the brain. These alterations in porphyric rats were dramatically reversed by parenteral heme administration. These findings suggest that increased tryptophan and 5-hydroxytryptamine in the nervous system may be responsible for the neurologic dysfunctions observed in humans with acute attacks of hepatic porphyria.

Summary The efficacy of hematin has been evaluated in eight patients with acute intermittent porphyria: six with acute attacks and two with chronic subacute symptoms. Hematin suppressed the chemical signs of porphyria in all patients and the symptoms in those with acute attacks. The clinical response to hematin occurred uniformly on the third or fourth day of treatment, suggesting that a stereotypic response to this form of therapy can be defined. Hematin had no effect on chronic subacute symptoms. The indications for hematin therapy, its rationale and the details of its administration are reviewed.

A 14-year-old boy had suffered from intermittent acute hepatic porphyria, myoclonic convulsions and mental retardation (Lennox-Gastaut syndrome). The porphyria was treated by stopping the administration of phenobarbitone and phenytoin. Sodium valproate at a dose of 70 mg/kg per day lessened the severity and frequency of convulsive crises.

Seizures may occur in acute intermittent porphyria or other hepatic porphyrias. Management is difficult, because barbiturates and hydantoins exacerbate the porphyric state. We studied one patient with major motor seizures and acute intermittent porphyria. The seizure disorder was exacerbated by phenytoin and did not respond to a high-carbohydrate diet or to intravenous hematin. Clonazepam was ineffective in treating the seizures and, in high doses, seemed to exacerbate the porphyria. Both clonazepam and valproate were porphyrinogenic in experimental test systems. Because both drugs may exacerbate the acute hepatic porphyrias, bromide remains the drug of choice to treat these seizures.