Attacks Of Porphyria Research Articles

Acute Intermittent Porphyria: Mutation Analysis and Identification of Gene Carriers in a German Kindred by PCR-DGGE Analysis

Acute intermittent porphyria (AIP) is the most frequent acute porphyria. Symptomatic patients and asymptomatic gene carriers are characterized by a reduction of their porphobilinogen-deaminase (PBG-D) activity to 50%, which is sufficient for porphyrin biosynthesis. PBG-D is encoded by two different mRNAs which are expressed in a tissue-specific manner. In classical AIP, the enzyme activity is reduced in erythroblasts and all other heme-forming body cells, whereas in the variant form of AIP, the PBG-D activity in erythroid tissues remains normal. Acute porphyria attacks can occur in gene carriers when the biosynthesis of heme is increased by drugs, low calory intake, alcohol consumption or infections. Under these conditions, PBG-D cannot convert the precursors adequately so that PBG and δ-aminolevulinate accumulate. This may lead to neurovisceral symptoms and other neurological complications which are potentially life threatening. In patients with AIP, mutation analysis by PCR-DGGE (denaturing gradient gel electrophoresis) is becoming increasingly important since it also permits rapid identification of their presymptomatic relatives. Using this technique, more than 120 mutations have been identified in the PBG-D gene. When identified, the family members are informed about their genetic predisposition and are taught how to prevent porphyric attacks. Here, I illustrate this preventive strategy by describing a German kindred of an affected patient with the variant form of AIP with 17 family members.

Treatment of seizures in acute intermittent porphyria: safety and efficacy of gabapentin

Treatment of seizures in acute intermittent porphyria represents a therapeutic dilemma. Patients needing chronic therapy often experience acute porphyric attacks due to increased hepatic metabolism induced by the antiepileptic drugs themselves. Gabapentin is a new antiepileptic drug not appreciably metabolized by the liver in humans, and it appears to be safe and effective in the maintenance therapy of epilepsy in these patients. We report a patient affected by partial and generalized seizures in the course of acute intermittent porphyria, who was safely and successfully treated with gabapentin.

Liver metabolism of porphyrins and haem.

The liver is an active site for the biosynthesis of haem and porphyrinogens/porphyrins, which are intermediates of the haem biosynthetic pathway, because haem is required for functional activity of the cytochrome P 450 system and other critical hepatic haemoproteins. The production of hepatic haem is regulated primarily through the activity of aminolaevulinic acid synthase which is the first and normally rate-limiting enzyme of the pathway. This is, in turn, controlled by a putative regulatory haem pool. Hepatic haem can be repleted by the intravenous administration of haem, which is the basis for haem therapy in patients with acute porphyric attacks. The liver catabolizes haem to bilirubin through microsomal haem oxygenase activity and excretes haem into bile along with porphyrins. Biliary excretion of porphyrins increases significantly in patients with some types of porphyria. In protoporphyria this may cause liver damage as a result of protoporphyrin toxicity. The delineation of the pathway for protoporphyrin excretion into bile should facilitate therapy in protoporphyria by identifying ways in which protoporphyrin excretion can be enhanced.

Variegate porphyria.

Variegate porphyria is an autosomal dominant inherited trait resulting in decreased activity of protoporphyrinogen oxidase. It is characterized clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. The disease is found worldwide but has an exceptionally high frequency in South Africa. The gene for human protoporphyrinogen oxidase has been identified and sequenced, and several mutations in the protoporphyrinogen oxidase gene sequence have been identified. In South Africa, fewer patients now present with acute attacks, leaving a greater proportion with skin disease or asymptomatic disease. Acute attacks of variegate porphyria appear to be less easily provoked and to be milder than those associated with acute intermittent porphyria.

Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria.

Some patients with acute hereditary porphyrias have seizures and require anticonvulsant therapy, but many anticonvulsants induce exacerbations of the hepatic porphyrias. Recently, several new anticonvulsants have become available. Among these are gabapentin, vigabatrin, felbamate, lamotrigine, and tiagabine. Little is known about their potential for induction of porphyric attacks. We used a cell culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of these new anticonvulsants on porphyrin accumulation. Treatment of the cells with deferoxamine (250 microM) led to a partial block in heme synthesis, simulating the conditions encountered in human beings with porphyria. Concomitant exposure of these cells to phenobarbital (2 mM) strongly induced accumulation of porphyrins, serving as a positive control in this model. Cells were treated for 20 hours with increasing doses (3.2 to 1,000 microM) of the newer anticonvulsants, with or without deferoxamine. For most of these anticonvulsants 5 to 100 microM is representative of the concentrations achieved in humans with therapeutic doses. Porphyrins were measured spectrofluorometrically as uro-, copro-, and protoporphyrins. Results were confirmed by high-pressure liquid chromatography. Neither vigabatrin nor gabapentin treatment, with or without deferoxamine, led to any increase in porphyrin accumulation. Similar doses of felbamate (with deferoxamine) led to a marked increase in (mainly proto-) porphyrin levels, qualitatively and quantitatively almost identical to the accumulation produced by phenobarbital. Lamotrigine or tiagabine (with deferoxamine) caused similar porphyrin accumulation. Tiagabine treatment up to 100 microM (with deferoxamine) also resulted in very high levels of predominantly proto-porphyrin. In contrast to the other anticonvulsants tested, tiagabine without deferoxamine led to mild porphyrin accumulation. In the presence of deferoxamine, phenobarbital, felbamate, lamotrigine, or tiagabine, but not gabapentin or vigabatrin, increased levels of the mRNA of ALA synthase, the first and rate-controlling enzyme of porphyrin synthesis. Such enzyme induction is a sine qua non for acute porphyric attacks. We conclude that neither vigabatrin nor gabapentin is porphyrogenic, whereas felbamate, lamotrigine, and, especially, tiagabine lead to much accumulation of porphyrins. The latter three anticonvulsants, therefore, may precipitate or exacerbate acute porphyric attacks in humans. We recommend use of vigabatrin or gabapentin, but not felbamate, lamotrigine, or tiagabine, in patients with acute porphyria and seizures.

Plasmapheresis combined with somatostatin is a successful treatment of porphyrias.

During acute attacks of hepatic porphyria, levels of polypeptides, vasoactive intestinal peptides, neurotensin, substance P, pancreatic polypeptide, gastrin releasing polypeptide, gastrin, and motilin increased in the circulation while the clinical symptoms were evident. However, somatostatin decrease was not detected. Somatostatin belongs to a group of regulatory peptides that antagonize the action of endogenous steroid hormones, and decreasing their bioavailability decreases the rate of synthesis of delta-aminolevulinate synthase, alpha-aminolevunilic acid (ALA), and polypeptides. Plasma exchange was conducted in courses for 2 consecutive days every 28 days (total of 6 courses), removing more than 100% of the patient plasma each time. Between the 2 courses of plasmapheresis, subcutaneous injections of somatostatin (100-500 mcg) were administered. A lasting disappearance of pain and complete remission were obtained in all 7 patients treated. Plasmapheresis combined with somatostatin may be considered as a treatment of porphyria exacerbation.

Mortality in patients with acute intermittent porphyria requiring hospitalization: a United States case series.

Acute intermittent porphyria (AIP) is a genetic disorder in which patients may have life threatening attacks of neurologic dysfunction. This study examined the prognosis during the past 50 years of patients in the United States who required hospitalization for porphyric attacks. The cumulative survival was determined for 136 patients with AIP who were hospitalized for porphyric attacks between 1940 and 1988. Diagnosis was established on the basis of clinical symptoms, in combination with increased urinary excretion of porphobilinogen. The patient group had an average age of 32 years (range 9 to 75) at diagnosis and consisted of 43 males and 93 females. At follow-up, 19 males (44%) and 31 females (33%) were decreased. The standardized mortality ratio for the 136 patients, compared to an age-matched hypothetical population experiencing USA 1970 Census Death Rates was 3.2, with a 95% confidence interval of 2.4-4.0. Most deaths occurred during the initial porphyric attack (20% of deaths) or a subsequent attack (38% of deaths). Suicide was also common (five deaths). Comparison was made between 50 patients who were diagnosed before 1971, the year in which hematin therapy became available, and 86 patients who were diagnosed afterward. There was improved survival in the latter group, particularly after 10 years from the time of diagnosis, but this did not reach statistical significance. In conclusion, the proportionate increase in mortality due to symptomatic AIP was three-fold compared to the general population during the past 50 years. The major cause of the increased mortality was the porphyric attack itself.

Visual evoked potential and neurological development infants of diabetic mothers

This chapter discusses the inherited neuropathies with autonomic involvement. Fabry's disease or Anderson–Fabry's disease (angiokeratoma corporis diffusum) is an X-linked inherited slowly progressive metabolic disorder with protean and nonspecific clinical manifestations. Unlike many other lysosomal storage diseases, most patients remain clinically silent during the first few years of life. Cerebrovascular disease secondary to multifocal abnormalities of large and small vessels, including transient ischemic attacks and stroke, may also occur. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria) are a group of autosomal dominant inherited metabolic disorders that manifest as acute or subacute, severe, life-threatening motor neuropathy, abdominal pain, autonomic dysfunction, and neuropsychiatric manifestations. The neurologic manifestations of all forms of the acute porphyrias are identical. Symptoms of the acute attack include severe abdominal pain, nausea, vomiting, constipation, diarrhea, urinary frequency and hesitancy, urine discoloration, labile hypertension, tachycardia, excessive sweating, pain in limbs and back, and convulsions. The most effective treatment of porphyria attacks is the administration of hematin intravenously. With modern intensive care techniques and the advent of hematin therapy, the mortality rate for acute intermittent porphyrias is less than 10%.

Genetics and anaesthesia

Genetic diseases are of considerable interest to the anaesthesiologist, particularly those that provoke abnormal responses to medication. Three of the most important disorders: malignant hyperthermia, porphyria and cholinesterase deficiency are reviewed here. Malignant hyperthermia is a hereditary syndrome that affects skeletal muscle. Its presence is indicated by an episode of muscle hypermetabolism after exposure to certain drugs. Generally transmitted as an autosomal dominant trait with variable penetrance, on occasion it appears to be recessive or even multigenic. An acute episode is characterized by hypercapnia, tachycardia, hyperthermia, muscle contracture and tachypnoea. The most reliable diagnostic test is that of contracture. The specific therapy is dantrolene. Different types of acute porphyria share common features; they are transmitted by autosomal dominant inheritance with variable penetrance. The factors that might trigger an attack of porphyria are hormonal changes, dehydration, stress and infection; however, enzyme-inducing drugs are the principal triggering factors. In most cases of porphyria, the patient can be anaesthetized with relative safety since measures can be taken to identify susceptible individuals and potentially porphyrinogenic agents. In the presence of inhibited, diminished or genetically atypical plasma cholinesterase levels, prolonged block can be produced. The presence of an individual with absent or near zero cholinesterase activity in an apparently normal family would alert us to the existence of abnormal genes. Genetic studies are necessary to identify possible atypical variants and thus prevent adverse reactions.

Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.

Treatment of complex partial status epilepticus unmasking acute intermittent porphyria in a patient with resected anaplastic glioma

We report a 42-year-old woman with an established complex partial seizure disorder, who presented in refractory complex partial status epilepticus, the treatment of which with lorazepam, phenytoin, carbamazepine, and pentobarbital precipitated an attack of acute intermittent porphyria (AIP). The subsequent clinical course and management with gabapentin is discussed.

Anesthetic Considerations in Porphyrias

Four hereditary types of porphyria are now classified as acute porphyrias. Enzymatic defects result in accumulation of porphyrin precursors (usually ALA and PGB). The quantity of these precursors may be normal or slightly increased in latent periods but increase to toxic levels during a porphyric crisis. Iatrogenic induction of ALA synthetase by administration of certain triggers (classically barbiturates) is only one of several factors which contribute to porphyric crisis. Signs and symptoms of acute porphyric attack consist primarily of neurologic dysfunction, which occurs secondary to neurotoxicity of ALA or diminished intraneuronal heme levels. Appropriate anesthetic management of porphyria requires knowledge of the type of porphyria (acute vs non-acute), assessment of latent versus active (crisis) phase, awareness of clinical features of porphyric attack, and knowledge of safe pharmacologic intervention.

Anesthetic Considerations in Porphyrias

Anesthetic Considerations in Porphyrias

Effects of mifepristone (RU-486) on heme metabolism and cytochromes P-450 in cultured chick embryo liver cells, possible implications for acute porphyria.

Mifepristone (RU-486), a potent progesterone receptor antagonist and inducer of cytochromes P-450, is currently in use in Europe, particularly as a post-coital oral contraceptive. Soon it will be available in the United States, as well. Since progesterone has been implicated in the pathogenesis of acute attacks of porphyria, the use of RU-486 or related compounds might be considered in porphyric patients. However, as with other cytochrome P-450 inducers, RU-486 may have the ability to precipitate or exacerbate attacks of acute porphyria. The acute porphyrias in relapse are associated with an increase in activity of delta-aminolevulinic acid synthase, the first and normally rate-controlling enzyme in heme biosynthesis. We have used primary cultures of chick embryo liver cells to test the ability of RU-486 to induce delta-aminolevulinic acid synthase activity and mRNA, cytochromes P-450, porphyrin accumulation, and heme oxygenase. We found that RU-486, at concentrations observed in human plasma after a single oral dose, induced the mRNA and activity of delta-aminolevulinic acid synthase, both by itself and in the presence of deferoxamine, a potent iron chelator that inhibits ferrochelatase. RU-486 and deferoxamine together also produced significant accumulations of protoporphyrin. These results indicate that RU-486 may pose a risk in patients with known acute porphyria and should be used with caution. RU-486 increased the concentration of total cytochrome P-450, and the activity of erythromycin demethylase, an activity specifically catalyzed by cytochrome P-450 3A. Unlike several other porphyrogens (e.g. hydantoins, barbiturates), RU-486 does not produce accumulation of uroporphyrin or induction of heme oxygenase in chick embryo liver cells.

Acute hereditary coproporphyria induced by the androgenic/anabolic steroid methandrostenolone (Dianabol)

Acute attacks of porphyria can be induced by certain drugs. We report a case of acute coproporphyria induced by methandrostenolone. This is the first report of acute porphyria induced by an androgenic, anabolic steroid.

Acute Intermittent Porphyria in Pregnancy and Puerperium

Acute intermittent porphyria (AIP) is considered to be the most severe form of acute porphyria. Our patient was first diagnosed with AIP during late pregnancy and early puerperium. Porphyrinogenic drugs were discontinued and a high carbohydrate infusion was given to abort the attack. Subsequent attacks required treatment by a specific hematin therapy. An acute porphyric attack in a primigravida who is not known to have AIP constitutes a great challenge as it is difficult to differentiate between AIP and eclampsia.

Treatment of the porphyrias.

There are seven porphyrias which are caused by defective functions of the enzymes in the haem biosynthesis. Pathogenic mechanisms and symptoms differ greatly in individual porphyrias and, consequently, most of them require a specific therapy. Clinically, the three most important entities are acute porphyric attack, porphyria cutanea tarda and protoporphyria. For an acute porphyric attack the treatment of choice is administration of haem; the other measures are elimination of precipitating factors and symptomatic therapy for many associated symptoms. Porphyria cutanea tarda is controlled by removal of iron by phlebotomies or with low-dose chloroquine. Skin symptoms in protoporphyria can be alleviated with betacaroten but there is no effective procedure to normalize disturbed porphyrin metabolism; hepatic failure seen in some patients may need a liver transplantation. The only effective treatment in congenital erythropoietic porphyria is probably a bone marrow transplantation. No satisfactory treatment is available for very rare delta-aminolevulinic acid dehydrase deficiency porphyria.

Early Administration of Heme Arginate for Acute Porphyric Attacks

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.

Early administration of heme arginate for acute porphyric attacks

<h3>Background:</h3> We investigated the efficacy of early administration of heme arginate in acute porphyric attacks. Methods: 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. <h3>Results:</h3> 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. <h3>Conclusion:</h3> Favorable responses in every attack suggest specific effects of heme. In patients with acute attacks, heme therapy should be started immediately on admission. (Arch Intern Med. 1993;153:2004-2008)

Acute intermittent porphyria with pancreatitis and pancreatic fistula

Objective To report a case of acute intermittent porphyria and acute, relapsing pancreatitis with pancreatic fistula. Design Single case report and review of the literature. Setting Medical department of a community hospital. Patient A 39-year-old woman with recurrent attacks of abdominal pain. On the first occasion, she was diagnosed as having acute pancreatitis. During the second episode of abdominal pain, a diagnosis of acute intermittent porphyria could be established and a pancreatico-peritoneal fistula was documented by endoscopic retrograde cholangiopancreatography. Outcome The patient was discharged from hospital without symptoms. Conclusion To our knowledge, this is the first reported case of acute intermittent porphyria with acute pancreatitis and pancreatic fistula. This report adds to the scarce data on the association of porphyria and pancreatitis. Acute intermittent porphyria may be obscured by the presence of acute pancreatitis, especially when there is a delay between the onset of abdominal pain and laboratory evaluation, since an increase in pancreatic enzyme levels occurs late in the course of a porphyric attack.