Excretion Of Porphyrin Precursors Research Articles

Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 - 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until one year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 (IQR 4.4-21.9) mmol/mol creatinine) than in controls (3.8 (1.2-9.8)) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2x ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions. This article is protected by copyright. All rights reserved.

Pathogenesis of acute encephalopathy in acute hepatic porphyria

Acute encephalopathy (AE) can be a manifestation of an acute porphyric attack. Clinical data were studied in 32 patients during AE with or without polyneuropathy (PNP) together with 12 subjects with PNP but no AE, and 17 with dysautonomia solely. Brain neuroimaging was done in 20 attacks during AE, and PEPT2 polymorphisms were studied in 56 subjects, 24 with AE. AE manifested as a triad of seizures, confusion and/or blurred vision. Symptoms lasting 1–5 days manifested 3–19 days from the onset of an attack. 55% of these patients had acute PNP independent of AE. Posterior reversible encephalopathy syndrome (PRES) was detected in 42% of the attacks. These patients were severely affected and hyponatremic (88%). Reversible segmental vasoconstriction was rare. There was no statistical difference in hypertension or urinary excretion of porphyrin precursors among the patients with or without AE. In 94% of the attacks with AE, liver transaminases were elevated significantly (1.5 to fivefold, P = 0.034) compared to a normal level in 87% of the attacks with dysautonomia, or in 25% of patients with PNP solely. PEPT2*2/2 haplotype was less common among patients with AE than without (8.3% vs. 25.8%, P = 0.159) and in patients with PNP than without (9.5% vs. 22.9%, P = 0.207), suggesting a minor role, if any, in acute neurotoxicity. In contrast, PEPT2*2/2 haplotype was commoner among patients with chronic kidney disease (P = 0.192). Acute endothelial dysfunction in porphyric encephalopathy could be explained by a combination of abrupt hypertension, SIADH, and acute metabolic and inflammatory factors of hepatic origin.

High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach.

Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP.

Computational disease model of phenobarbital-induced acute attacks in an acute intermittent porphyria mouse model

IntroductionAcute intermittent porphyria (AIP) is characterized by hepatic over-production of the heme precursors when aminolevulinic acid (ALA)-synthase 1 is induced by endogenous or environmental factors. The aim of this study was to develop a semi-mechanistic computational model to characterize urine accumulation of heme precursors during acute attacks based on experimental pharmacodynamics data and support the development of new therapeutic strategies. MethodsMale AIP mice received recurrent phenobarbital challenge starting on days 1, 9, 16 and 30. 24-h urine excretion of ALA, porphobilinogen (PBG) and porphyrins from challenges D1, D9 and D30 constituted the training data set to build the mechanistic model using the population approach. In a second study, porphyrin and porphyrin precursor excretion from challenge D16 were used as a validation data set. ResultsThe computational model presented the following features: (i) urinary excretion of ALA, PBG and porphyrins was governed by unmeasured circulating heme precursor amounts, (ii) the circulating amounts of ALA and PBG were the precursors of circulating amounts of PBG and porphyrins, respectively, and (iii) the phenobarbital effect linearly increased the synthesis of circulating ALA and PBG levels. The model displayed good parameter precision (coefficient of variation below 32% in all parameters), and adequately described the experimental data. Finally, a theoretical hemin effect was implemented to illustrate the applicability of the model to dosage optimization in drug therapies. ConclusionsA semi-mechanistic disease model was successfully developed to describe the temporal evolution of urinary heme precursor excretion during recurrent biochemical-induced acute attacks in AIP mice. This model represents the first computational approach to explore and optimize current and new therapies.

Systemic messenger RNA as an etiological treatment for acute intermittent porphyria.

Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.

DOUBLE PORPHYRIA: LITERATURE REVIEW AND ANALYSIS OF CLINICAL OBSERVATION

A brief review of the literature on the problem of double porphyria and analysis of its own observation is presented. For more than 10 years patient B was observed for more than 10 years with a verified diagnosis of acute intermittent porphyria, which manifested with acute pain abdominal syndrome, neurological disorders in the form of peripheral polyneuropathy and hemiparesis of lower extremities, and hypertension syndrome was also noted. The observed clinical symptoms corresponded to an acute porphyrin crisis in the manifestation and / or relapse of acute intermittent porphyria. The diagnosis was confirmed by a quantitative determination of the excretory profile of porphyrin precursors (δ-aminocaproic acid, porphobilinogen) and porphyrin fractions (uroporphyrin, coproporphyrin). Their concentrations are significantly (especially porphyrin precursors) exceeding the control values, which is the cardinal diagnostic criterion of acute intermittent porphyria. Against the backdrop of persistent clinical and biochemical remission of acute intermittent porphyria, symptoms of photosensitization of the skin (blisters, erosion, pigment spots) on the dorsal surface of the hands began to appear in 4 years. Later, hypertrichosis was formed in the temporo-periorbital region. The constellation type of the excretory profile of porphyrins began to change. Against the backdrop of persistent increased excretion of porphyrin precursors (δ-aminolevulinic acid and porphobilinogen), a progressive increase in the excretion of the fraction of uroporphyrin was observed, which became dominant (up to 58% of the total content of porphyrins). Such a prolonged observation in the dynamics allowed us to state the appearance of a new variant of the porphyrin exchange disturbance, which, taking into account clinical symptoms, corresponded to another form of hepatic porphyria, namely, late cutaneous porphyria. The clinical and biochemical changes in the excretory profile of the parameters of porphyrin metabolism registered in the dynamics of observation may indicate the occurrence of a combined enzymatic defect characteristic of double porphyria. In our case, a manifestation of late cutaneous porphyria was noted against a background of compensated acute intermittent porphyria.

Renal Failure Affects the Enzymatic Activities of the Three First Steps in Hepatic Heme Biosynthesis in the Acute Intermittent Porphyria Mouse

Chronic kidney disease is a long-term complication in acute intermittent porphyria (AIP). The pathophysiological significance of hepatic overproduction of the porphyrin precursors aminolevulinate acid (ALA) and porphobilinogen (PBG) in chronic kidney disease is unclear. We have investigated the effect of repetitive acute attacks on renal function and the effect of total or five-sixth nephrectomy causing renal insufficiency on hepatic heme synthesis in the porphobilinogen deaminase (PBGD)-deficient (AIP) mouse. Phenobarbital challenge in the AIP-mice increased urinary porphyrin precursor excretion. Successive attacks throughout 14 weeks led to minor renal lesions with no impact on renal function. In the liver of wild type and AIP mice, 5/6 nephrectomy enhanced transcription of the first and rate-limiting ALA synthase. As a consequence, urinary PBG excretion increased in AIP mice. The PBG/ALA ratio increased from 1 in sham operated AIP animals to over 5 (males) and over 13 (females) in the 5/6 nephrectomized mice. Total nephrectomy caused a rapid decrease in PBGD activity without changes in enzyme protein level in the AIP mice but not in the wild type animals. In conclusion, high concentration of porphyrin precursors had little impact on renal function. However, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure.

Sustained Enzymatic Correction by rAAV-Mediated Liver Gene Therapy Protects Against Induced Motor Neuropathy in Acute Porphyria Mice

Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.

Acute Intermittent Porphyria Presented with Recurrent Abdominal Pain and Hypertension

Acute intermittent porphyria (AIP) is a rare disorder characterized biochemically by the increased excretion of porphyrins and porphyrin precursors, including delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). AIP has variable clinical manifestations, such as acute abdominal pain, vomiting, nausea, constipation, peripheral neuropathy, seizures, tachycardia, and hypertension. A 16-year-old girl presented with recurrent abdominal pain, vomiting, hypertension, seizures, hypercholesterolemia, and red urine. AIP was confirmed by clinical features and increased 24-hour urine ALA and PBG. AIP should be considered in the differential diagnosis of patients who have abdominal pain, hypertension, and seizures when the results of all other tests are normal. (Korean J Pediatr Gastroenterol Nutr 2011; 14: 81∼85)

Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria

Acute intermittent porphyria (AIP) is characterized by hepatic porphobilinogen deaminase (PBGD) deficiency resulting in a marked overproduction of presumably toxic porphyrin precursors. Our study aimed to assess the protective effects of bone marrow transplantation or PBGD gene transfer into the liver against phenotypic manifestations of acute porphyria attack induced in an AIP murine model. Lethally irradiated AIP mice were intravenously injected with 5x10(6) nucleated bone marrow cells from wild type or AIP donor mice. To achieve liver gene transfer, AIP mice received via hydrodynamic injection plasmids expressing human PBGD or luciferase, driven by a liver-specific promoter. Erythrocyte PBGD activity increased 2.4-fold in AIP mice receiving bone marrow cells from normal animals. Nevertheless, phenobarbital administration in these mice reproduced key features of acute attacks, such as massively increased urinary porphyrin precursor excretion and decreased motor coordination. Hepatic PBGD activity increased 2.2-fold after hydrodynamic injection of therapeutic plasmid. Mice injected with the luciferase control plasmid showed a high excretion of porphyrin precursors after phenobarbital administration whereas just a small increase was observed in AIP mice injected with the PBGD plasmid. Furthermore, motor disturbance was almost completely abolished in AIP mice treated with the therapeutic plasmid. PBGD deficiency in erythroid tissue is not associated with phenotypic manifestations of acute porphyria. In contrast, PBGD over-expression in hepatocytes, albeit in a low proportion, reduced precursor accumulation, which is the hallmark of acute porphyric attacks. Liver-directed gene therapy might offer an alternative to liver transplantation applicable in patients with severe and recurrent manifestations.

Nitric oxide and the clinical manifestations of acute porphyria

The porphyrias comprise a clinically and genetically heterogenous group of diseases mostly arising from a genetically determined dysfunction of specific enzymes along the pathway of haeme biosynthesis. This leads to a pathological accumulation and measurable excretion of porphyrins and/or porphyrin precursors, which is considered the cause of the clinical features related to this group of diseases. However, acute porphyria can present with varied symptoms, which have some features in common with other diseases where nitric oxide has been shown to play a role. The article describes the possibility of nitric oxide depletion in porphyria contributing to its clinical manifestations.

Safety, Pharmacokinetics and Pharmocodynamics of Recombinant Human Porphobilinogen Deaminase in Healthy Subjects and Asymptomatic Carriers of the Acute Intermittent Porphyria Gene Who Have Increased Porphyrin Precursor Excretion

Acute intermittent porphyria is an autosomal dominant disorder caused by deficient activity of the third enzyme in the haem biosynthetic pathway, porphobilinogen deaminase. It is characterised by acute, potentially life-threatening neurological attacks that are precipitated by various drugs, reproductive hormones and other factors. During acute attacks, the porphyrin precursors 5-aminolevulinic acid and porphobilinogen accumulate and are excreted at high concentrations in the urine. Current treatment is based on glucose loading and parenteral haem replenishment, which reduce the accumulation of 5-aminolevulinic acid and porphobilinogen. Recently, a new form of treatment based on porphobilinogen deaminase enzyme replacement therapy has been shown to be effective in an acute intermittent porphyria mouse model which, during phenobarbital (phenobarbitone) induction of haem biosynthesis, mimics the biochemical pattern of acute porphyric attacks. The objective of the present study was to investigate the safety, pharmacokinetics and pharmacodynamics of recombinant human porphobilinogen deaminase (P 9808), administered to healthy subjects and asymptomatic porphobilinogen deaminase-deficient subjects with high concentrations of porphobilinogen, the substrate of porphobilinogen deaminase. Forty individuals participated in this two-part study: 20 asymptomatic porphobilinogen deaminase-deficient subjects (both male and female) with > or =4 times the upper reference urinary porphobilinogen level, and 20 healthy male subjects. Four different doses of recombinant human porphobilinogen deaminase were studied (0.5, 1, 2 and 4 mg/kg bodyweight). Part A included 12 asymptomatic porphobilinogen deaminase-deficient subjects, and the enzyme was administered in an open-label, single-dose design. Part B included 20 asymptomatic porphobilinogen deaminase-deficient subjects and 20 healthy subjects. The same enzyme dosages were administered as divided doses every 12 hours for 4 consecutive days in a randomised, double-blinded, placebo-controlled design. The washout period between Parts A and B was 2 weeks. The concentrations of recombinant human porphobilinogen deaminase and titres of antibodies against recombinant human porphobilinogen deaminase were analysed by ELISA. Plasma porphobilinogen and 5-aminolevulinic acid concentrations were analysed using a novel liquid chromatography-tandem mass spectrometry method. Urinary porphobilinogen, 5-aminolevulinic acid and porphyrin concentrations, as well as plasma porphyrin concentrations, were analysed using standard methods. The pharmacodynamic effect of the enzyme was studied through changes in plasma porphobilinogen concentrations. No serious adverse events were observed. Seven subjects (four healthy men and three asymptomatic porphobilinogen deaminase-deficient subjects) developed antibodies against recombinant human porphobilinogen deaminase but did not experience allergic manifestations. The mean elimination half-lives of the highest doses of recombinant human porphobilinogen deaminase ranged between 1.7 and 2.5 hours for both healthy men and asymptomatic porphobilinogen deaminase-deficient subjects. The area under the plasma concentration-time curve was proportional to the respective dose. In asymptomatic porphobilinogen deaminase-deficient subjects, plasma porphobilinogen concentrations decreased below measurable levels almost instantaneously after administration of any dose of the enzyme. The effect lasted for approximately 2 hours, after which the plasma porphobilinogen concentration slowly increased, reaching about 70% of the initial values 12 hours after administration. There was no effect on plasma 5-aminolevulinic acid concentrations, and there was a transitory increment in porphyrin concentrations. The corresponding concentrations of metabolites in the urine reflected the pattern observed in the plasma. The recombinant human porphobilinogen deaminase enzyme preparation was found to be safe to administer and effective for removal of the accumulated metabolite porphobilinogen from plasma and urine. The pharmacokinetic profile of recombinant human porphobilinogen deaminase showed dose proportionality, and the elimination half-life was about 2.0 hours for the two highest doses. Thus, clinical grounds were established for investigation of the therapeutic efficacy of the enzyme during periods of overt disease in patients with acute intermittent porphyria.

Variations in Porphobilinogen and 5-Aminolevulinic Acid Concentrations in Plasma and Urine from Asymptomatic Carriers of the Acute Intermittent Porphyria Gene with Increased Porphyrin Precursor Excretion

The heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate during overt crises of acute intermittent porphyria (AIP), and high excretion of these metabolites often continues in the asymptomatic phase. We measured concentrations of PBG and ALA and investigated the correlation between these metabolites in plasma and urine in 10 asymptomatic AIP carriers with high excretion and in 5 healthy individuals. We quantified plasma concentrations with an HPLC-mass spectrometric method and urine concentrations with ion-exchange chromatography. The mean (SD) plasma concentrations of PBG and ALA in the AIP carriers were 3.1 (1.0) and 1.7 (0.7) micromol/L, respectively. The mean 8-h urinary excretion amounts of PBG and ALA in the AIP carriers were 102 (25) and 56 (18) micromol, respectively, whereas the corresponding values for healthy individuals were 2.9 (0.7) and 9.3 (1.2) micromol. The correlations between PBG and ALA values in plasma and urine of the AIP carriers were 0.678 and 0.856, respectively. The mean PBG/ALA ratio was approximately 2.0 in both plasma and urine for the AIP carriers and 0.3 in urine for the healthy individuals. The renal clearance rates for PBG and ALA were 71 (15) and 70 (13) mL/min, respectively. The described HPLC-mass spectrometric method enabled characterization of variations in plasma PBG and ALA in AIP carriers during an 8-h period. The renal clearances were similar for both metabolites. This method could be used to monitor AIP patients during treatment.

Liver transplantation as a cure for acute intermittent porphyria

Acute intermittent porphyria occasionally causes frequent and crippling acute neurovisceral attacks associated with increased hepatic production of porphyrin precursors, resulting in long-term damage, poor quality of life, and shortened life expectancy. There has been no cure for this condition, but replacement of deficient hepatic enzymes might restore excretion of porphyrin precursors to normal and prevent acute attacks. We aimed to treat severe acute intermittent porphyria in a 19-year-old woman by liver transplantation. After the transplant, concentrations of haem precursors in the patient's urine returned to normal, and 1.5 years later her quality of life was good. Our report suggests some hope of cure for selected patients with severe forms of this disease.

Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients

Objectives: To describe the biochemical and clinical features in hereditary coproporphyria (HCP). Design and method: Within the last 20 years, we investigated 53 patients (male:female = 1:2.5; age = 8–86 years) suffering from HCP. We describe the characteristic levels of urine, and fecal porphyrins and their precursors in hereditary coproporphyria and present the clinical features. Especially, we measured the coproporphyrin isomers I and III. Results and conclusion: The group of hereditary coproporphyria patients exhibited a significantly higher ( p < 0.0001) excretion of urinary porphyrin precursors, δ-aminolevulinic acid (median = 84 μmol/24 h) and porphobilinogen (median = 39 μmol/24 h), as compared to controls (δ-aminolevulinic acid: 22 μmol/24 h, porphobilinogen: 3 μmol/24 h; median, n = 20). The median of coproporphyrin in urine (1315 nmol/24 h) and feces (1855 nmol/g) were enhanced 12- and 168-fold, as compared to healthy subjects (urinary coproporphyrin: 106 nmol/24 h, fecal coproporphyrin: 11 nmol/g; median, n = 20). During therapy on one female patient, with IV application of heme arginate, a considerable decline of porphyrin precursors and porphyrin excretion was observed. The examination of urinary and fecal coproporphyrin isomers I and III revealed an excessive elevation of the coproporphyrin isomer III of 87% in urine and 94% in feces, respectively (normal: urinary isomer III = 69–83% and fecal isomer III = 25–40%). In feces the increase of isomer III caused an inversion of the physiologic coproporphyrin isomer III:I ratio that could be recognized in all various stages in hereditary coproporphyria and in children. Acute attacks of hereditary coproporphyria are accompanied by an acute polysymptomatic clinical syndrome, and this is associated with high levels of urinary porphyrin precursors. On review of our patients, the highest percentage had abdominal pain (89%), followed by neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

Porphyrias.

The porphyrias are a heterogeneous group of metabolic disorders caused by genetic defects of the enzymes involved in heme biosynthesis. The diseases are characterized by excessive accumulation and excretion of porphyrin or porphyrin precursors. The disorders have been classified as cutaneous, hepatic, or neuropsychiatric according to the organ system involved. This review describes the enzymes of the heme biosynthetic pathway along with the clinical features and management of the porphyrias.

Management of the acute porphyrias.

Three hepatic porphyrias--acute intermittent porphyria, hereditary coproporphyria and variegate porphyria--are characterized by episodic acute attacks that consist of various neuro-psychiatric symptoms and signs, such as abdominal pain, vomiting, constipation, hypertension and tachycardia associated with increased excretion of porphyrins and porphyrin precursors. Peripheral neuropathy is manifested as pain in the extremities, and it may progress to a severe motor neuropathy. Measurement of porphobilinogen in the urine gives a prompt diagnosis during acute attacks. Attacks are often induced by precipitating factors such as drugs, alcohol, infection, fasting or changes in sex-hormone balance, and they should be eliminated when a patient is treated during an attack. Heme, the end biosynthetic product, is the most effective therapy for restoration of porphyrin biosynthesis to normal, and it is usually infused at 3 mg/kg daily for 4 days. Adequate calories are necessary and parenteral nutrition with carbohydrates may be necessary. Attacks may also require therapy for hypertension, pain and epileptic seizures. Strict avoidance of all precipitating factors may not be necessary in the asymptomatic phase.

HEPATIC PORPHYRIAS

The porphyrias are metabolic disorders characterized by abnormal heme biosynthesis with excessive accumulation and excretion of porphyrias or porphyrin precursors. Defects in the enzymes of the heme biosynthetic pathway result in porphyria. Several of the disorders have been classified as hepatic because the major site of the biochemical defect has been localized to the liver. This article describes the enzymes of the heme biosynthetic pathway, the clinical features of the hepatic porphyrias and management of the disorders.

Effect of chronic anesthesia on the drug-metabolizing enzyme system and heme pathway regulation

1. 1. The effect of chronic enflurane or isoflurane anesthesia on hepatic heme regulation and the drug-metabolizing system in mice treated or not with phenobarbital (PB) was investigated. 2. 2. Δ-Aminolevulinic acid synthetase was induced 50–170% in all cases. Urinary porphyrin precursor excretion was also enhanced, but these values were lower when animals also received PB. 3. 3. Cytochrome (CYT) P-450 levels were enhanced in animals treated with enflurane whether or not they were given PB. 4. 4. Gluthatione- S-transferase activity was induced by enflurane (138%) or isoflurane (174%), and even more in animals receiving PB also. Sulfatase activity was increased more than 60% with anesthetics. Isoflurane produced a 50% increase of β-glucuronidase activity and a 35% diminution of tryptophan pyrrolase. 5. 5. The association between anesthetics and PB produced diverse effects on the metabolizing enzyme system. 6. 6. Data suggest that both anesthetics, chemically related, could act through two different mechanisms, however, with the same final effect: heme pathway deregulation.

Heterogeneity of acute intermittent porphyria: a subtype with normal erythrocyte porphobilinogen deaminase activity in Germany.

Patients with acute intermittent porphyria can be subdivided into three groups, according to the porphobilinogen deaminase activity in their erythrocytes. The first group has lowered, the second overlapping and the third normal porphobilinogen deaminase activity. Of 385 acute intermittent porphyria patients 5% had normal porphobilinogen deaminase activity. Gene carriers of acute intermittent porphyria, which have normal porphobilinogen deaminase activity but display slight, moderate or high aberrations of excretion, are recognized by analysis of urinary haem precursors and faecal porphyrins. Six individuals suffering from acute intermittent porphyria were detected in three families with normal porphobilinogen deaminase. There were no differences in the latent and clinical phases of acute intermittent porphyria between patients with lowered and those with normal porphobilinogen deaminase. One female with normal activity in erythrocytes, in which the porphyria disease process is triggered by barbiturates and carbamazepine, is presented. After therapy with high doses of glucose and omission of inducing agents, this woman was free of symptoms, and the excretion of different urinary porphyrin precursors and porphyrins decreased by between 65 and 93%.