heme-arginate and Porphyria--Acute-Intermittent

Topics: Arginine; Combined Modality Therapy; Diagnosis, Differential; Female; Genetic Predisposition to Disease; Heme; Hemin; Humans; Interdisciplinary Communication; Intersectoral Collaboration; Middle Aged; Porphobilinogen; Porphyria, Acute Intermittent; Prognosis; Recurrence; Risk Factors

Topics: 5-Aminolevulinate Synthetase; Analgesics, Opioid; Antipsychotic Agents; Arginine; Benzodiazepines; Ferrochelatase; Haloperidol; Heme; Humans; Hydroxymethylbilane Synthase; Olanzapine; Pirenzepine; Plasma Exchange; Porphyria, Acute Intermittent; Prognosis

The porphyrias comprise a group of disorders of the haem biosynthesis pathway that can present with acute neurovisceral symptoms, skin lesions or both. Acute porphyrias present with severe abdominal pain, confusion and seizures which may be life-threatening. Specific treatment with haem preparations should be instituted as soon as possible following confirmation of increased excretion of porphobilinogen in the urine. Supportive treatment includes opiate analgesia, monitoring for and treating complications such as hypertension and hyponatraemia. Follow-up should include counselling on lifestyle modification involving avoidance of alcohol, smoking and known porphyrogenic drugs and diet. Identification and counselling of at risk relatives is essential. The cutaneous porphyrias result from porphyrin-induced photosensitivity and can present with either acute photosensitivity or skin fragility and blisters. All cutaneous porphyrias can be alleviated by avoidance of sunlight. Treatment of erythropoietic protoporphyria involves administering large doses of beta-carotene, which may improve tolerance to sunlight. Porphyria cutanea tarda can be effectively treated by phlebotomy or low dose chloroquine. Congenital erythropoietic porphyria is a rare, early onset, severe, photomutilating condition for which bone marrow transplantation has been shown to be successful.

Topics: Arginine; beta Carotene; Chloroquine; Estrogens; Ethanol; Heme; Humans; Phlebotomy; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyrias; Sunlight

Haem preparations are now available for the specific treatment of attacks of acute porphyria. This review focuses on their use in this uncommon but life-threatening medical emergency.

Topics: Adolescent; Adult; Analgesics, Opioid; Arginine; Clinical Trials as Topic; Dietary Carbohydrates; Female; Heme; Humans; Male; Porphobilinogen; Porphyria, Acute Intermittent; Pregnancy; Pregnancy Complications; Treatment Outcome

In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values.

Topics: Adult; Anxiety; Arginine; Depression; Family; Female; Germany; Heme; Hospitalization; Humans; Male; Porphyria, Acute Intermittent; Prospective Studies; Quality of Life; Surveys and Questionnaires

Acute intermittent porphyria (AIP) is a metabolic disease affecting hepatic heme biosynthesis. The clinical course in overt disease is characterized by acute attacks of neurovisceral symptoms. Treatment is based on symptomatic relief together with carbohydrate loading and in more severe attacks heme therapy. During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine. These metabolites represent the acute phase reactants confirming an ongoing attack and are used to evaluate therapeutic measures. The aim of this study was to measure PBG and ALA in plasma and urine during an acute attack and to match the biochemical pattern with the clinical and therapeutical course.. Three consecutive AIP patients were included during four acute attacks. Plasma PBG and ALA were measured by a LC-MS method and in urine by ion-exchange chromatography. The patients received symptomatic and glucose treatment at admission to hospital, and four days later, if necessary, heme therapy.. In the three attacks that required heme therapy, plasma PBG concentrations had further increased after admission (p=0.01). In the patient that did not require heme therapy, plasma PBG had decreased after admission.. Biochemical monitoring of an acute attack was more accurately reflected by plasma PBG than plasma ALA or urinary PBG and ALA. Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks.

Topics: Acute Disease; Adult; Aminolevulinic Acid; Arginine; Biomarkers; Chromatography, Ion Exchange; Drug Monitoring; Female; Glucose; Heme; Humans; Male; Porphobilinogen; Porphyria, Acute Intermittent; Sensitivity and Specificity

Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10-129 vs median tHcy: 14.5 μmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 μmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-β-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.

Topics: Acetylgalactosamine; Adult; Arginine; Cystathionine beta-Synthase; Female; Folic Acid; Heme; Homeostasis; Homocysteine; Homocystinuria; Humans; Hydroxymethylbilane Synthase; Hyperhomocysteinemia; Male; Methionine; Middle Aged; Porphyria, Acute Intermittent; Pyridoxal Phosphate; Pyrrolidines; Young Adult

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC-MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.

Topics: 5-Aminolevulinate Synthetase; Acetylgalactosamine; Adult; Arginine; Colitis; Colon, Sigmoid; Controlled Clinical Trials as Topic; Drug Hypersensitivity; Female; Fibrosis; Heme; Hepatocytes; High-Throughput Nucleotide Sequencing; Homocysteine; Humans; Hydroxymethylbilane Synthase; Hyperhomocysteinemia; Male; Models, Biological; Pancreatitis; Porphyria, Acute Intermittent; Pyrrolidines

A 20-year-old Japanese woman had an attack of acute intermittent porphyria (AIP). Magnetic resonance imaging (MRI) revealed symmetrical lesions in the cerebrum and cerebellar hemisphere, corresponding to posterior reversible encephalopathy syndrome (PRES). Our administration of heme arginate gradually improved the clinical condition associated with AIP and the level of metabolite of nitric oxide (NO), which is a vascular dilator. Repeated MRI and magnetic resonance angiography revealed exacerbated PRES, part of which showed a small infarction, accompanied by progressive vasoconstriction. These findings suggest that the recovery of NO by heme replacement alone is insufficient for preventing brain damage during an AIP attack.

Topics: Arginine; Female; Heme; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Porphyria, Acute Intermittent; Posterior Leukoencephalopathy Syndrome; Young Adult

Acute intermittent porphyria (AIP) is a rare metabolic disease involving a defect in haem biosynthesis resulting in the accumulation and excessive secretion of porphyrins and its precursors. Acute attacks present with episodes of severe abdominal pain, nausea, confusion and severe life-threatening seizures. A high index of suspicion is required for the initial diagnosis of AIP.

Topics: Abdominal Pain; Administration, Intravenous; Adolescent; Arginine; Heme; Humans; India; Male; Porphobilinogen; Porphyria, Acute Intermittent; Seizures; Treatment Outcome

Topics: Abdominal Pain; Adolescent; Arginine; Cholelithiasis; Chronic Disease; Diagnosis, Differential; Female; Heme; Humans; Porphyria, Acute Intermittent; Porphyrins; Tomography, X-Ray Computed

Acute intermittent porphyria, the most common porphyria affecting the nervous system, typically presents with neurovisceral crises followed by a motor neuropathy. We describe a 23-year-old black South African man presenting with a progressive stuttering, lower motor neuron syndrome developing over months. He had not experienced pain or neuropsychiatric symptoms. One year after symptom onset he was bed-bound with a flaccid quadriparesis. There was marked amyotrophy, but without fasciculations. Sensation was intact apart from a hypo-aesthetic patch over the thigh. Electrophysiological investigations showed an active motor axonopathy. Urinary porphyrins, delta-aminolaevulinic acid and porphobilinogen were elevated. Mutation analysis revealed the c445C>T (R149X) mutation in the porphobilinogen deaminase gene. The patient responded dramatically to haem arginate and could walk with assistance 2 weeks later. We identified the first molecularly confirmed acute intermittent porphyria in a black South African. The clinical presentation mimicked a progressive lower motor neuron syndrome.

Topics: Arginine; Heme; Humans; Hydroxymethylbilane Synthase; Male; Muscular Atrophy, Spinal; Porphyria, Acute Intermittent; Young Adult

Acute neurovisceral attacks of porphyria can be life threatening. They are rare and notoriously difficult to diagnose clinically, but should be considered, particularly in female patients with unexplained abdominal pain, and associated neurological or psychiatric features or hyponatraemia. The diagnosis might be suggested by altered urine colour and can be confirmed by finding an elevated porphobilinogen concentration in fresh urine protected from light. Severe attacks require treatment with intravenous haem arginate and supportive management with safe drugs, including adequate analgesia. Intravenous glucose in water solutions are contraindicated as they aggravate hyponatraemia, which can prove fatal.

Topics: Abdominal Pain; Adolescent; Analgesics; Arginine; Disease Management; Fatal Outcome; Female; Hallucinations; Heme; Humans; Hyponatremia; Monitoring, Physiologic; Porphobilinogen; Porphyria, Acute Intermittent; Water-Electrolyte Balance

A survey was posted to 27 women with acute porphyria about complications and outcome of pregnancy. Fifteen women returned the completed questionnaire and the pregnancies were characterised depending on the timing of diagnosis of porphyria. Four women were diagnosed with porphyria before the first pregnancy, five during a pregnancy and six after pregnancy. Five women were diagnosed with porphyria from family studies and the remaining ten were diagnosed when they presented with acute symptoms. There were a total of 33 pregnancies and 23 live births. Four women reported symptoms associated with porphyria during pregnancy. Two women received treatment with haem arginate during pregnancy with one of them having haem arginate therapy weekly with no adverse effect either to her or the baby. One woman had acute pain and skin symptoms during pregnancy but was not diagnosed until after delivery, and another reported acute symptoms during pregnancy. There were no differences, compared to the general population, between birth weight and miscarriage rate, and there were few obstetric complications with only one patient having pre-eclampsia at 37 weeks gestation. These results show that pregnancy is typically uncomplicated in acute porphyria, and that problems are more likely if the porphyria has not been diagnosed previously. We found that administration of haem arginate during pregnancy is safe and its continuous use during pregnancy has no detrimental effect on the outcome of pregnancy.

Topics: Abortion, Spontaneous; Adolescent; Adult; Arginine; Child; Female; Heme; Humans; Live Birth; London; Middle Aged; Porphyria, Acute Intermittent; Pregnancy; Pregnancy Complications; Retrospective Studies; Surveys and Questionnaires; Time Factors; Treatment Outcome; Young Adult

The porphyrias are a heterogeneous group of metabolic diseases resulting from a variable catalytic defect of one of the eight enzymes involved in the heme biosynthesis pathway; they are mostly inherited diseases, but in some circumstances the metabolic disturbance may be acquired. The specific patterns of tissue overproduction (and hence accumulation and excretion) of toxic heme precursors, associated with each enzymatic deficiency, are responsible for the characteristic biochemical and clinical features of each of these diseases. Moreover, even in the presence of a specific inherited enzymatic defect, many different environmental factors (such as drugs, calorie restriction, hormones, sunlight exposition, infections, etc.) often play a key role in triggering the clinical expression of the various forms of porphyrias. The porphyrias are often misdiagnosed diseases, due their multiform clinical manifestations, able to mimic many other more common diseases. For this reason, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially for the forms presenting with acute and life-threatening clinical features. According to the clinical features, the porphyrias can be classified into neuropsychiatric (characterized by neurovisceral crises involving autonomic and central nervous system but also the liver and the kidney with possible consequences in terms of neurological, psychic, cardiac, respiratory, liver and kidney functions), dermatological (mostly presenting with cutaneous lesions due to photosensitivity), and mixed forms. From a strictly clinical point of view, porphyrias presenting with neurovisceral attacks are also referred as acute porphyrias: they are the object of the present review. An accurate diagnosis of acute porphyria requires knowledge and the use of correct diagnostic tools, and it is mandatory to provide a more appropriate therapeutic approach and prevent the use of potentially unsafe drugs, able to severely precipitate these diseases, especially in the presence of life-threatening symptoms. To date, availability of a relatively stable haem preparation (haem arginate) has significantly improved the treatment outcome of acute porphyric attacks, so the knowledge about the diagnosis and the management of these diseases may be relevant for physicians working in internal medicine, neurology and emergency units.

Topics: Arginine; Diagnostic Errors; Emergency Medicine; Heme; Humans; Internal Medicine; Porphyria, Acute Intermittent

Acute porphyrias are caused by enzyme defects along the heme synthesis pathway. Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine. This article gives an overview over drugs that are recommended in patients with acute hepatic porphyrias and represents a compilation of four so far existing lists.

Topics: 5-Aminolevulinate Synthetase; Arginine; Drug-Related Side Effects and Adverse Reactions; Heme; Humans; Liver Transplantation; Porphyria, Acute Intermittent

Topics: Adult; Arginine; Female; Follow-Up Studies; Heme; Humans; Infant, Newborn; Male; Porphobilinogen; Porphyria, Acute Intermittent; Porphyrins; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Factors

Neurologic disorders represent the most severe complications of acute intermittent porphyria (AIP). Cognitive disturbances, bulbar and spinal weakness appear as the most critical neurological complications as they may lead to death or definitive motor weakness. A 38-year-old woman was admitted for an acute and painful tetra paresis occurring after a laparoscopy for an ovarian cyst. She also complained of abdominal pain treated with noramidopyrine, tachycardia, hypertension and hyponatremia. The electrophysiological examination showed a motor axonal neuropathy. The increase of Urine ALA at 268 micromol/l (N<38) and of at 235 micromol/l (N<5) strongly suggested AIP that was further confirmed by PBG desaminase deficiency in red cells. Thanks to the prescription of heme arginate (HA) at the dose of 3 mg/kg/day for 4 days, pain resolved immediately and motor function began to improve since the second day of treatment concurrently to a dramatic decrease of both urine ALA and PBG concentrations. Motor recovery was complete after 12 months of evolution. This case illustrates the potential severity of acute porphyric neuropathy when precipitating factors (noramidopyrine, surgery) are present in previously undiagnosed AIP. Moreover, motor neuronal function improved while HA therapy was initiated 22 days after the clinical onset of weakness. This tempts us to propose HA therapy at any stage of acute porphyric neuropathy.

Topics: Adult; Arginine; Electrodiagnosis; Electrophysiology; Female; Heme; Humans; Laparoscopy; Motor Neuron Disease; Nervous System Diseases; Neural Conduction; Ovarian Cysts; Peripheral Nerves; Porphyria, Acute Intermittent; Postoperative Complications; Quadriplegia

Topics: Abortion, Induced; Arginine; Female; Heme; Humans; Porphyria, Acute Intermittent; Pregnancy; Pregnancy Complications, Infectious

Acute intermittent porphyria is the most common type of porphyria occurring in Poland. Its characteristic feature is periods of remissions and aggravations. Aggravation or an attack of the disease is caused by many endogenous and exogenous factors, among others by hormonal contraceptives.. This article describes the case of an acute intermittent porphyria attack in a 28 years old female patient resulting from the use of a few, contraindicated drugs (metamizole, nospa, desogestrel in case of porphyria, urinary tract infection, as well as a spontaneous abortion two months earlier). The attack included abdominal pain, vomiting, reduction in muscle strength in limbs and it was complicated by seizures caused by hyponatraemia. High excess haem precursors in urine was observed. During hospitalization, the patient ceased to take harmful drugs and she was given haem arginate, glucose and symptomatic drugs, and she recovered completely.. In the described case there were a few porphyrogenous factors whose action was observed, among which the most important was desogestrel. Due to this conclusion, a change in contraceptive therapy that would exclude hormonal contraception was suggested.

Topics: Adult; Arginine; Contraceptives, Oral, Synthetic; Desogestrel; Female; Glucose; Heme; Humans; Porphyria, Acute Intermittent; Saline Solution, Hypertonic; Treatment Outcome

Four forms of porphyria may present clinically with the acute attack, an episodic, severe, and potentially life-threatening manifestation characterized by abdominal and neurologic symptoms. We describe our experience with 112 consecutive attacks observed and treated in 25 patients with the 2 most common forms of acute porphyria in Cape Town, South Africa; 25 attacks in 10 patients with variegate porphyria and 87 attacks in 14 patients with acute intermittent porphyria. The remaining patient experienced more than 100 sequential, severe, and poorly remitting attacks, which are not included in our analysis. In our population, the relative risk of an acute attack in acute intermittent porphyria compared with that in variegate porphyria was 14.3 (confidence intervals, 6.3-32.7). Patients with variegate porphyria were significantly older (median age at first attack, 30 yr) than those with acute intermittent porphyria (median age at first attack, 23.5 yr; p < 0.0001), and demonstrated an equal sex ratio, whereas the male:female ratio in acute intermittent porphyria was 2:12 (p < 0.0001). There was a significant difference in the incidence of factors precipitating the acute attack. Drug exposure was a frequent precipitant of the acute attack in variegate porphyria, whereas hormonal factors were more important in acute intermittent porphyria (p < 0.00001). Patients with acute intermittent porphyria also showed a trend to earlier and more frequent recurrent acute attacks following the initial admission. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate requirement were all significantly higher in patients with acute intermittent porphyria. No significant difference in the frequency of serious complications or in outcome could be shown. We describe our experience with treatment with heme arginate, and provide evidence that heme arginate results in a prompt and statistically significant improvement in symptoms. The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment.

Topics: Abdominal Pain; Acute Disease; Adult; Age Factors; Arginine; Epidemiologic Methods; Female; Heme; Humans; Hypertension; Male; Porphyria, Acute Intermittent; Porphyria, Variegate; Precipitating Factors; Psychotic Disorders; Remission, Spontaneous; Sex Factors; South Africa; Tachycardia

Abdominal pain is a common complaint for visits to ED. Among the causes of abdominal pain, the acute porphyria may confuse emergency physicians. With wide range of unspecific symptoms and signs, acute porphyria is rarely considered as a differential diagnosis of acute abdomen in ED. Some patients even receive unnecessary surgery. There are 32 patients who visited the ED of National Taiwan University Hospital because of acute porphyric attacks over the past 13 years. Ten patients (3 males and 7 females) were diagnosed with acute porphyria for the first time at ED. The onset of age ranged from 17 to 55 years (mean, 32 years). All of our patients presented with abdominal pain but without fever, dermatologic, and neurologic symptoms that are typically presented in acute porphyria. On the average, most of them repeatedly sought for medical help because of persistent symptoms for 4 times before being definitely diagnosed and thus receiving the optimal treatment. Meanwhile, all patients needed at least 2 kinds of analgesic, and most of them needed narcotic analgesia for pain control before diagnosis. The most commonest point of tenderness is over epigastrium (7 of 10 patients). The laboratory and image studies of our patients were of no diagnostic value for acute porphyria, except for Watson-Schwartz test. In summary, our study revealed that when a patient after puberty with repetitive visits because of severe abdominal pain without reasonable causes and needs narcotics for pain control, acute porphyria should be taken into consideration.

Topics: Abdominal Pain; Adolescent; Adult; Age of Onset; Analgesia; Arginine; Diagnostic Errors; Emergency Medicine; Emergency Service, Hospital; Female; Glucose; Heme; Humans; Hyponatremia; Infusions, Intravenous; Male; Middle Aged; Porphyria, Acute Intermittent; Retrospective Studies; Seizures; Taiwan; Treatment Outcome

To characterize patients with various nosological unities [symbol: see text] of porphyria in accordance with their age, clinical symptoms, provoking factors, therapy and outcome.. Patients with acute intermittent porphyria (43), hereditary coproporphyria (8), variegate porphyria (3), porphyria cutanea tarda (7), hepatoerythropoietic porphyria (1), and hereditary erythropoietic porphyria (2) were studied. One patient was suspected of porphyria caused by deficiency of delta-aminolevulenic acid dehydrogenase.. The patients were from the CIS. The overwhelming majority of them were young and middle-aged subjects. Rapid development of the disease and severe neurological symptoms were predominantly observed in patients with acute forms of porphyria.. Early diagnosis of porphyrin metabolism disorders makes it possible to decrease abruptly the number of cases leading to severe complications, disability, and fatal outcome. The use of inexpensive methods of screening of porphyrin metabolism disorders provides a promising approach to solving this problem. These methods should be used in municipal hospitals. In addition, asymptomatic carriers of defective gene should be revealed at the preclinical stage using various methods of molecular genetic assay.

Topics: Acute Disease; Adolescent; Adult; Arginine; Chronic Disease; Female; Heme; Humans; Inosine Diphosphate; Middle Aged; Octreotide; Plasmapheresis; Porphyria, Acute Intermittent; Porphyria, Erythropoietic; Porphyrias; Porphyrins

Topics: Abdominal Pain; Arginine; Colic; Diagnosis, Differential; Heme; Humans; Porphyria, Acute Intermittent

We report a case of acute intermittent porphyria (AIP) in a 45-year-old woman. Her first attack occurred at the age of 38. Because of escalating cyclical premenstrual attacks, the following 2 years, depletion of the endogenous sex hormone was considered as haeme arginate treatment proved insufficient. Gonadotropin releasing hormone agonist treatment with low-dose oestradiol add back was quite successful initially but was abandoned after 18 months when progesterone add back precipitated a severe attack. Following hysterectomy and oophorectomy at age 42 and oestradiol add back, a remarkable monthly regularity of attacks ensured periodically but with milder symptoms. Two years after surgery, preceded by six attack-free months, a puzzling symptom-shift occurred, from abdominal pain, back and thigh pain during the attacks, to solely severe distal extensor paresis in the arms. Haeme arginate treatment interrupted the progress of the paresis almost immediately and motor function improved considerably up to the 9-month follow-up. Electrophysiological examination revealed only motor neuropathy, consistent with axonal degeneration. Subsequently the symptoms changed yet again, to sensory disturbances with numbness and dysesthesia as the primary expression followed by rather mild abdominal pain. However, cyclical attacks occurred, despite absence of endogenous ovarial hormone production, possibly attributable to impaired oestrogen metabolism in the liver, or adrenal oestrogen production. Treatment comprising oophorectomy, low-dose oestradiol add back and haeme arginate infusion for 2 days on the appearance of early AIP symptoms is now quite successful affording improvement in life quality.

Topics: Abdominal Pain; Adult; Arginine; Disease Progression; Estradiol; Female; Heme; Humans; Hysterectomy; Middle Aged; Ovariectomy; Paresis; Periodicity; Porphyria, Acute Intermittent; Progesterone; Recurrence

Topics: Adult; Anaphylaxis; Arginine; Female; Heme; Hemin; Humans; Porphyria, Acute Intermittent

Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-aminolevulinic acid synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 micromol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 micromol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study.

Topics: 5-Aminolevulinate Synthetase; Acute Disease; Aminolevulinic Acid; Animals; Arginine; Cytosol; Drug Combinations; Female; Heme; Heme Oxygenase (Decyclizing); Injections, Intraperitoneal; Liver; Metalloporphyrins; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Phenobarbital; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Reference Values; RNA, Messenger

Acute intermittent porphyria (AIP) is an autosomal-dominant disease caused by a deficiency of porphobilinogen (PBG) deaminase. Patients with AIP present with neurological syndromes such as autonomic neuropathy, peripheral axonal neuropathy or central nervous system dysfunction. We report serial MRI of a patient with AIP who had cortical and subcortical cerebral changes. A 29-year-old woman with a 6-month history of AIP had an attack with severe hyponatraemia and generalised convulsions, treated with haem arginate and supportive therapy. MRI showed central pontine and extrapontine myelinolysis and cortical laminar necrosis. These are not common in AIP, but are likely to have been caused by rapid correction of hyponatraemia and by vasospasm, which could be induced by AIP.

Topics: Adult; Arginine; Brain; Female; Fluid Therapy; Heme; Humans; Hyponatremia; Myelinolysis, Central Pontine; Necrosis; Porphyria, Acute Intermittent; Saline Solution, Hypertonic; Seizures; Vasospasm, Intracranial

5-Aminolevulinic acid dehydratase (ALAD) activity in two patients with compound heterozygous 5-aminolevulinic acid dehydratase deficiency porphyria was studied over the last 20 years. The patients' enzyme activity was <10% from 1977 to 1997. An acute crisis in each patient was successfully treated by infusion of glucose and heme arginate. After this therapy both urinary 5-aminolevulinic acid (ALA) and total porphyrins were diminished to 65% in patient B. In patient H, ALA was decreased to 80%, and total porphyrins were reduced to 15% after treatment with heme arginate and glucose. The patients remained free of symptoms after this therapy. Family studies of patient B showed cross-reactive immunological material (CRIM), in which the maternal mutation is CRIM(+), whereas the paternal mutation is CRIM(-). Incubation of erythrocyte lysates with ALA decreased porphyrin formation, whereas incubation with porphobilinogen produced porphyrin concentrations within reference values in both patients, confirming that ALAD activity is rate-limiting in these cells.

Topics: Adolescent; Aminolevulinic Acid; Arginine; Biomarkers; Erythrocytes; Follow-Up Studies; Glucose; Heme; Humans; Male; Mutation; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrins

We report on a patient with acute intermittent porphyria (AIP) who, during treatment with hypertonic glucose, developed peripheral neuropathy. Once haeme-arginate was started, the progression of the neuropathy was attenuated. This suggests that hypertonic glucose may be inadequate in preventing the development of neuropathy in a patient with porphyria. However, haeme-arginate, if started early, can attenuate the progression of porphyric neuropathy.

Topics: Adult; Arginine; Glucose Solution, Hypertonic; Heme; Humans; Male; Peripheral Nervous System Diseases; Porphyria, Acute Intermittent

Acute intermittent porphyria (AIP) is a hereditary disease characterized biochemically by a defect in the heme pathway enzyme porphobilinogen deaminase. There is wide variability in the neurologic clinical expression of AIP, and the disorder remains latent in most gene carriers. The natural history of the disease and results in a porphyric rat model suggest a significant relationship between tryptophan metabolites and clinical expression of the disease. In the present study, we examined urine and blood tryptophan metabolite levels in AIP women before, during and after acute attacks and treatment by heme arginate. Heme arginate treatment promptly decreased total tryptophan levels (from 69 +/- 9, to 44 +/- 5, mean +/- SEM, mumole/l, p < 0.001), serotonin blood levels (from 629 +/- 103, to 356 +/- 80, nmole/l, p < 0.01) and the urinary excretion of 5-HIAA (from 3.9 +/- 0.6, to 2.2 +/- 0.4, mumole/mmole creatinine, p < 0.01). The plasma level of melatonin was found much lower than the normal control level at night (86.2 +/- 70.3, vs the normal range, 409 +/- 78.9, pmole/l +/- SEM) and day time (38.8 +/- 22.0, vs 75 +/- 13.7). Heme arginate treatment did not influence melatonin levels. Our results support the involvement of abnormal tryptophan metabolism in the pathophysiology of AIP acute attacks. Low melatonin plasma levels in porphyric women suggest that the defect of the pineal hormone may be responsible for the recurrent aspect of porphyric attacks. A desynchronization of biological rhythms in AIP patients may increase the inducibility of hepatic ALA synthase to environmental risk factors and, specially, to sex steroid hormones.

Topics: Adult; Arginine; Circadian Rhythm; Female; Heme; Humans; Melatonin; Porphyria, Acute Intermittent; Recurrence; Tryptophan

We investigated the efficacy of early administration of heme arginate in acute porphyric attacks.. The series consisted of 51 consecutive acute attacks in 22 patients with acute intermittent porphyria and in two patients with variegate porphyria referred to a hospital in France or in Finland. Four attacks were associated with pareses, and 47 attacks were not. Heme in a dose of 250 mg or 3 mg/kg was started within 24 hours after admission in 37 (72.5%) of the attacks and within 4 days in 49 (96%) of the attacks. During all except five attacks, four daily infusions were given.. The mean (+/- SD) duration of abdominal or nonabdominal pain was 2.5 +/- 0.97 days, and opiates were stopped an average of 2.8 +/- 0.72 days after the first heme infusion was started. All patients responded. In 46 (90%) of the attacks, the total hospitalization time was 7 days or less. The mean urinary excretion of porphobilinogen decreased to 16.2% +/- 7.7% and that of 5-aminolevulinic acid to 11.6% +/- 5.6% of pretreatment values. The only side effect was moderate thrombophlebitis in one patient.. Favorable responses in every attack suggest specific effects of heme. In patients with acute attacks, heme therapy should be started immediately on admission.

Topics: Adult; Aged; Arginine; Female; Heme; Humans; Length of Stay; Male; Middle Aged; Porphyria, Acute Intermittent; Time Factors; Treatment Outcome