Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.

[Study on relationships between biomarkers in workers with low-level occupational lead exposure].

OBJECTIVE: To investigate the lead exposure, its effects, and the relationships between biomarkers of susceptibility in the workers with low-level occupational lead exposure, and to explore its sensitivity and practical value to evaluate the health hazard. METHODS: The concentrations of lead fume and lead dust in workplaces of a lead acid storage battery enterprise in Jiangsu Province, China, were measured by occupational health monitoring method. The blood samples of 233 workers with occupational lead exposure and 76 non-occupational lead exposure were collected to measure the blood lead (Pb-B) level using graphite furnace atomic absorption spectrometry (GFAAS), the zinc Protoporphyrin (ZPP) level with blood fluorescence assay, and the delta-aminolevulinic acid dehydratase (ALAD) concentration by a spectrophotometer, and to determine the gene polymorphism of ALAD with TaqMan real-time polymerase chain reaction. At the same time, their urine samples were collected to measure urine lead (Pb-U) concentration with GFAAS and delta-aminolevulinic acid (ALA-U) concentration with a spectrophotometer. The correlations between the above indices were analyzed by multiple linear regression method. RESULTS: The concentration of lead fume in 18 testing sites and the concentration of lead dust in 30 testing sites were 0.002-0.019 mg/m3 and 0.004-0.013 mg/m3, respectively. Pb-B level was positively correlated with Pb-U concentration (r=0.62, P<0.01) and ZPP level (r=0.47, P<0.01) and was negatively correlated with ALAD concentration (r=-0.77, P<0.01) in 233 workers with occupational lead exposure. Among 233 workers, 218 (93.6%) had ≤70 µg/L Pb-U, and 15 (6.9%) had ≥400≥g/L Pb-B. Pb-B level was not correlated with ZPP level as Pb-B level was <190 µg/L (r=0.18, P=0.068 ), while Pb-B level was positively correlated with ZPP level as Pb-B level was ≥190 µg/L (r=0.36, P<0.01). Pb-U concentration was positively correlated with ALA-U concentration (r=0.49, P<0.01) and ZPP level (r=0.47, P<0.01). ZPP level was negatively correlated with ALAD concentration (r=-0. 19, P<0.01), and was positively correlated with ALA-U concentration (r=0.27, P<0.01). ALAD concentration was not correlated with ALA-U concentration (r =-0. 11, P>0.05). And in 233 workers with occupational lead exposure, there were no significant differences in Pb-B level, ZPP level, and ALAD activity between the workers with ALAD1-2 genotype and the workers with ALAD1-1 genotype (P>0.05). In 76 workers with non-occupational lead exposure, there was no significant difference in Pb-B level between the workers with ALAD1-2 genotype and the workers with ALAD1-1 genotype (P >0.05). The workers with ALAD1-2 genotype had a significantly lower ALAD activity, and a significantly higher ZPP level compared with those ALAD1-1 genotype (P<0.01). CONCLUSION: In the workers with low-level occupational lead exposure, ZPP level is positively correlated with Pb-B level when Pb-B level was ≥190 µ/L. ALAD could be used as an effect biomarker of low Pb-B level. ALAD gene polymorphism shows different effects on the Pb-B level and the toxic effects between the workers with occupational lead exposure and the workers with non-occupational lead exposure.

Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver.

Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and ALA and PBG concentrations were increased ~3- and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.

Role of delta-aminolevulinic acid in the symptoms of acute porphyria.

BACKGROUND: Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative. METHODS: We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome. RESULTS: Although each of these conditions has characteristic urine biochemistry, all exhibit excess delta-aminolevulinic acid. Moreover, in all, treatment with hemin reduces delta-aminolevulinic acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective. CONCLUSIONS: There is now convincing evidence that delta-aminolevulinic acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-aminolevulinic acid synthase-1, the enzyme that catalyzes delta-aminolevulinic acid formation. Delta-aminolevulinic acid synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria.

Hepatocyte transplantation ameliorates the metabolic abnormality in a mouse model of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder characterized by insufficient porphobilinogen deaminase (PBGD) activity. When hepatic heme synthesis is induced, porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate, which causes clinical symptoms such as abdominal pain, neuropathy, and psychiatric disturbances. Our aim was to investigate if hepatocyte transplantation can prevent or minimize the metabolic alterations in an AIP mouse model. We transplanted wild-type hepatocytes into PBGD-deficient mice and induced heme synthesis with phenobarbital. ALA and PBG concentrations in plasma were monitored, and the gene transcriptions of hepatic enzymes ALAS1, PBGD, and CYP2A5 were analyzed. Results were compared with controls and correlated to the percentage of engrafted hepatocytes. The accumulation of ALA and PBG was reduced by approximately 50% after the second hepatocyte transplantation. We detected no difference in mRNA levels of PBGD, ALAS1, or CYP2A5. Engraftment corresponding to 2.7% of the total hepatocyte mass was achieved following two hepatocyte transplantations. A lack of precursor production in less than 3% of the hepatocytes resulted in a 50% reduction in plasma precursor concentrations. This disproportional finding suggests that ALA and PBG produced in PBGD-deficient hepatocytes crossed cellular membranes and was metabolized by transplanted cells. The lack of effect on enzyme mRNA levels suggests that no significant efflux of heme from normal to PBGD-deficient hepatocytes takes place. Further studies are needed to establish the minimal number of engrafted hepatocytes needed to completely correct the metabolic abnormality in AIP and whether amelioration of the metabolic defect by partial restoration of PBGD enzyme activity translates into a clinical effect in human AIP.

Biochemical, radiologic, ultrastructural, and genetic evaluation of iron overload in acute leukemia and iron-chelation therapy.

Iron overload in hereditary hemochromatosis and hematologic malignancy has unfavorable effects on morbidity. Herein, 53 children (age 108.4±58.3 mo, 25 girls and 28 boys) with acute myeloblastic and lymphoblastic leukemia, who received 4 different chemotherapy protocols, were evaluated for iron overload throughout chemotherapy. Iron overload arose: (1) before chemotherapy, which was dependent on neither chemotherapy nor packed red blood cell transfusions and (2) after chemotherapy, which was dependent on the duration and nature of chemotherapy and partially on transfusion of packed red blood cells. Iron overload was documented in 75% of patients with a ferritin level >1000 ng/mL, by liver and heart magnetic resonance imaging, and they were administered iron-chelation therapy with success. Three of 10 radiologically iron-overloaded patients were heterozygous for H63D mutation. Aminolevulinic acid and porphobilinogen levels were normal. Light microscopic examination of the bone marrow revealed increased iron granules in erythroblasts, platelets, and megakaryocytes, iron-laden macrophages, free iron in the matrix, dyshematopoiesis, and apoptotic cells. Electron microscopic examination revealed iron-laden secondary lysosomes and autolysosomes in normoblasts and iron-laden primary granules in promyelocytes, irrelevant to the ferritin level, implying autophagia due to chemotherapy as a source of the excess iron. We think that iron overload, which is an important complication of acute leukemia, should be evaluated separately from "transfusion overload," and the management principles specific to leukemia should be implemented.

Function of the liver and bile ducts in humans exposed to lead.

Lead is very common in the environment, and it is therefore important to characterize its possible adverse health effects. The aim of this study was to evaluate the impact of lead exposure on selected functions of the liver and bile ducts in people who are chronically exposed to the metal because of their occupations. To provide this information, the activity of specific enzymes and the bilirubin concentration were determined in blood serum, and morphological parameters of the liver and bile ducts were evaluated using the ultrasonic imaging method. Healthy male employees of a lead-zinc processing facility (n = 145) who were occupationally exposed to lead were divided into two subgroups as a function of the lead concentrations in blood (PbB): low lead exposure (PbB = 20-35 µg/dl; n = 57) and high lead exposure (PbB = 35-60 µg/dl; n = 88). Human exposure to lead compounds was found to cause liver enlargement and to activate inflammatory reactions with the characteristics of moderate cholestasis within the bile ducts, while no characteristics of necrotic damage of hepatic cells were noted. It seems that lipid peroxidation can be one of the toxic mechanisms of lead which induce moderate cholestasis. The effects depend on the extent of the lead exposure and were greater in subjects with higher exposure levels, particularly subjects with PbB values greater than 35 µg/dl.

Imported occupational lead poisoning: report of four cases.

BACKGROUND: In most industrialized countries, occupational lead poisoning has become increasingly rare, however this metal remains a serious health hazard in the rest of the world. REPORT OF CASES: We observedfour male patients (aged 35 / 54 years) who had suffered recurrent abdominal pain due to recent lead exposure (for 7 to 13 months) in two Chinese battery recycling plants. On their return to Italy, three of them presented normocytic, normochromic anaemia. The diagnosis was confirmed by high lead levels in the blood and urine, decreased erythrocyte delta-aminolevulinic acid dehydratase (ALA-D), raised erythrocyte zinc protoporphyrin (ZP), and elevated urinary excretion of b-aminolevulinic acid (ALA-U) and porphyrins. Chelation with EDTA resulted in increased urinary lead excretion, improvement of the clinical picture, decreased ZP, and progressive normalization of the other lead biomarkers (Pb-B, ALA-D, ALA-U, urinary porphyrins). CONCLUSIONS: Temporary work in developing countries may result in imported lead poisoning. Differential diagnosis of this unusual condition requires careful medical history collection and specific toxicological analysis. Preventive measures for workers going abroad are needed.

Direct and simultaneous quantitation of 5-aminolaevulinic acid and porphobilinogen in human serum or plasma by hydrophilic interaction liquid chromatography-atmospheric pressure chemical ionization/tandem mass spectrometry.

Serum/plasma concentrations of 5-aminolaevulinic acid (ALA) and porphobilinogen (PBG) are elevated in patients with acute hepatic porphyrias, especially during acute attacks. Current assays require lengthy sample pre-treatment and derivatization steps. We report here a rapid, sensitive and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry method for the direct and simultaneous quantitation of ALA and PBG in serum or plasma following simple protein precipitation with acetonitrile and centrifugation prior to injection. ALA and PBG were detected using selected reaction monitoring mode, following positive atmospheric pressure chemical ionization. Calibration was linear from 0.05 to 50 µmol/L for ALA and PBG. For both analytes, imprecision (relative standard deviation) was <13% and accuracy (percentage nominal concentrations) was between 92 and 107%. The method was successfully applied to the measurement of ALA and PBG in serum or plasma samples for the screening, biochemical diagnosis and treatment monitoring of patients with acute hepatic porphyrias.

Occupational risk assessment of oxidative stress and genotoxicity in workers exposed to paints during a working week.

OBJECTIVES: Paints are complex mixtures of solvents and metals that can induce health damages in workers exposed to them. The aim of the present work was to evaluate possible oxidative and genotoxic effects in workers exposed to paints. MATERIAL AND METHODS: Peripheral blood and buccal cell samples were collected from 33 workers exposed to paints and 29 non-exposed workers (controls) during an ordinary working week (Monday morning and Friday evening). Oxidative markers were assessed using thiobarbituric acid assay, carbonylated proteins, superoxide dismutase and catalase activities. Hippuric acid and delta-aminolevulinic acid were determined as biomarkers of toluene and lead exposure, respectively. Genotoxicity was measured through comet assay and micronucleus (MN) frequencies. RESULTS: The exposed group showed higher hippuric acid and delta-aminolevulinic acid levels (Friday samples) and lower superoxide dismutase activity (Monday samples) in relation to control group. DNA damage index (comet assay) was higher in the exposed group, both in Monday and Friday samples, compared to the control group. No differences were observed in frequency of micronuclei (MN) between the groups, either in lymphocytes or buccal cells. However, the exposed group presented an increase (Monday samples) in nuclear buds frequency in lymphocytes - a marker of gene amplification - as well as an increase in condensed chromatin in the buccal cells (Monday and Friday samples), suggesting induction of apoptosis. Furthermore, a decrease in the nuclear division index (Friday samples) was observed in the exposed group, indicating that paint exposure induces cytostatic effects in lymphocytes. CONCLUSION: The results suggest that individuals exposed to paints have increased levels of DNA damage.

A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen.

Accurate determinations of 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) in physiologic fluids are required for the diagnosis and therapeutic monitoring of acute porphyrias. Current colorimetric methods are insensitive and over-estimate ALA and PBG due to poor specificity, while LC-MS/MS methods increase sensitivity, but have limited matrices. An LC-MS/MS method was developed to simultaneously determine ALA and PBG concentrations in fluids or tissues which were solid phase extracted, butanol derivatized, and quantitated by selective reaction monitoring using (13)C(5), (15)N-ALA and 2,4-(13)C(2)-PBG internal standards. ALA was separated from interfering compounds on a reverse phase C8-column. For ALA and PBG, the matrix effects (87.3-105%) and process efficiencies (77.6-97.8% and 37.2-41.6%, respectively) were acceptable in plasma and urine matrices. The assay was highly sensitive for ALA and PBG (LLOQ=0.05 µM with 25 µL urine or 100 µL plasma), and required ∼4 h from extraction to results. ALA and PBG accuracy ranged from 88.2 to 110% (n=10); intra- and inter-assay coefficients of variations were <10% for urine and plasma. In clinical applications, patients with mutation-confirmed acute porphyrias had normal to slightly increased urinary ALA and PBG levels when asymptomatic, and high levels during acute attacks, which decreased with hemin therapy. In AIP mice, baseline ALA and PBG levels in urine, plasma, and liver were increased after phenobarbital induction 28-/63-, 42-/266-, and 13-/316-fold, respectively. This LC-MS/MS method is rapid, specific, highly sensitive, accurate, and simultaneously measures ALA and PBG in urine, plasma, and tissues permitting porphyria clinical diagnoses, therapeutic monitoring, and research.

Co-administration of meso 2,3-dimercaptosuccinic acid monoesters reduces arsenic concentration and oxidative stress in gallium arsenide exposed rats.

1. Gallium arsenide (GaAs), a semiconductor, exerts toxicity as a result of its constitutive moieties; that is, gallium and arsenic that becomes dissociated after exposure. The present study focuses on reducing arsenic concentration from the target organs using monoesters of meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination. 2. Animals were exposed to GaAs (0.0014 mol/kg, orally for 8 weeks) and then treated with monoisoamyl DMSA (MiADMSA), monocyclohexyl DMSA (MchDMSA) or monomethyl DMSA (MmDMSA) either individually (0.3 mmol/kg, orally) or in combination (0.15 mmol/kg each, orally) for five consecutive days. 3. GaAs exposure significantly inhibited blood δ-aminolevulinic acid dehydrogenase (ALAD), suggesting alterations in the heme synthesis pathway. Whereas a significant increase in blood, liver and kidney reactive oxygen species accompanied by an increase in lipid peroxidation points to the involvement of oxidative stress in GaAs toxicity. 4. GaAs also significantly disturbed glutathione metabolism. Hepatic and renal catalase activity decreased significantly, whereas hepatic and renal superoxide dismutase activity, as well as serum transaminases activity, showed marginal increase. Treatment with MiADMSA in combination with MchDMSA showed better therapeutic efficacy compared with other treatments in the aforementioned variables. 5. Co-administration of MiADMSA with MchDMSA provided better therapeutic effects, including reduction of arsenic burden, compared with all other treatments.

Pathological role of aminolevulinate in uremic patients.

Previous reports have demonstrated that δ-aminolevulinate (ALA) can promote iron release from horse spleen ferritin under conditions of high serum ALA levels in uremia; therefore, we speculated that the accumulated ALA in uremic patients would stimulate iron release from ferritin, resulting in accelerated oxidative stress and uremic complications. We measured the plasma ALA of uremic patients and examined the ALA-induced iron release from human ferritin. The participants consisted of 30 hemodialysis patients and 14 healthy subjects. Plasma malondialdehyde was measured as a surrogate marker of lipid peroxidation. The plasma exchange effluent from two patients who had undergone plasma exchange (for the treatment of systemic lupus erythematosus and acute myeloblastic leukemia) was collected and treated to obtain the human ferritin-rich fraction. Iron release from ferritin was examined using bathophenanthroline sulfate. The influence of antioxidants and different pH levels on iron release were investigated. Plasma ALA and malondialdehyde concentration in the hemodialysis patient was significantly higher than that in healthy subjects. ALA was positively correlated with malondialdehyde. The abundance of iron release was dependent on the ALA concentration and incubation time. Iron release at the high pH of 7.6 was decreased compared with that at pH 7.4. Citrate increased iron release at pH 7.4, but citrate-stimulated iron release was totally abolished at pH 7.6. Our study suggests that ALA accumulation may have a role to play in certain complications in uremic patients, such as oxidative stress, by releasing iron from ferritin.

Comparison of blood lead and blood and plasma δ-aminolevulinic acid concentrations as biomarkers for lead poisoning in cattle.

Lead (Pb) concentrations in whole blood and δ-aminolevulinic acid (ALA) concentrations in plasma and whole blood from 37 cattle with suspected Pb exposure were determined in order to investigate the usefulness of ALA as a biological indicator for Pb poisoning in cattle. Cows were divided into 4 groups based on blood Pb, as follows: <30 ppb (group 1), 30-100 ppb (group 2), 100-300 ppb (group 3), and >300 ppb (group 4). The derivatization reaction for ALA was improved by a greater than 2-fold measure in whole blood and by a 10-fold measure in plasma by adding 75 and 50 µl of 0.1 N HCl, respectively. Blood Pb concentrations ranged from <25 ppb to 1,006 ppb (185.5 ± 254.9 ppb), with 17 samples containing >50 ppb Pb. Delta-aminolevulinic acid concentrations in whole blood and plasma ranged from <62.7 ppb to 96.9 ppb (77.4 ± 8.4 ppb) and from <5.0 ppb to 24.0 ppb (4.6 ± 3.8 ppb), respectively. Whole blood ALA did not correlate with blood lead concentrations in any group. Increase in plasma ALA concentration was dependent on blood Pb concentration. There was no correlation between blood Pb concentration and plasma ALA concentration in group 2 (n  =  4), but correlation coefficients were 0.736 in group 3 and 0.807 in group 4, respectively. The correlation coefficient was increased to 0.851 when groups 3 and 4 were combined. Based on these observations, in cattle, plasma ALA is a more reliable biological biomarker for Pb exposure than is blood ALA.

[Acute intermittent porphyria and inappropriate ADH syndrome]. / Porfiria aguda intermitente y síndrome de secreción inadecuada de ADH.

A 44-year-old woman complained of abdominal pain of 4 days' duration accompanied by vomiting and painful urination. The admitting physician noted neurologic signs consistent with axonal polyneuropathy and hyponatremia. In the absence of other explanations for the syndrome, SIADH was diagnosed. Because of the nonspecific nature of the observations, the patient was assessed by various specialists and admitted to the anesthetic recovery unit due to worsening of neurologic signs and suspicion of acute intermittent porphyria. The diagnosis was confirmed by laboratory findings of elevated d-aminolevulinic acid and porphobilinogen levels and normal stool porphyrins. The patient improved with intravenous hematin infused over 4 days.

Successful treatment of extreme acute lead intoxication.

Severe acute lead intoxications are rare and are associated with accidental or purposeful ingestion. There were only few cases of severe to fatal poisonings reported in literature in children. We report a case of acute lead intoxication in a child with extremely high lead blood level of 20.4 micromol/L (422.7 microg/dL), who was treated with chelation and in whom significant organ dysfunction did not develop. Documented significant high level above 3.37 micromol/L (corresponding to 70 microg/dL) in this patient persisted for approximately 24 h. Adequate, single or combined chelatation therapy in early phase of acute lead poisoning is essential for the further patient's outcome.

Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Porphyrin precursors and porphyrins in three patients with acute intermittent porphyria and end-stage renal disease under different therapy regimes.

Porphyrin precursors and porphyrins were measured in three patients with recurrent attacks of acute intermittent porphyria and end-stage renal disease (ESRD): two patients on hemodialysis and one on peritoneal dialysis. Plasma porphobilinogen (PBG) and porphyrins were considerably increased in the three patients. In a previous study, the mean urinary and plasma PBG/ALA ratio in biochemically active AIP patients with conserved renal function was 2.0 (normal 0.3) and plasma porphyrin levels were normal (< 10 nmol/L). In this study we show that the progression to ESRD was paralleled by an increase in urinary and plasma PBG/ALA ratio reaching levels above 6 and higher. Plasma porphyrin increased to levels above 1000 nmol/L causing cutaneous lesions resembling porphyria cutanea tarda. The porphyrin precursors were readily filtered by dialysis membranes but not the porphyrins. The development of kidney failure was a devastating complication in these AIP patients with chronic active disease, leading to unavoidable deterioration of peripheral veins, progression of peripheral neuropathy, dialysis treatment and secondary cutaneous lesions. The clinical course could not be reversed by medical treatment in any of the cases. Today, combined liver and kidney transplantation should be considered as a therapeutic option.

Prenatal exposure to lead, delta-aminolevulinic acid, and schizophrenia: further evidence.

BACKGROUND: A previously conducted study of prenatal lead exposure and schizophrenia using delta-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959-1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life. OBJECTIVES: In the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959-1966). Using similar methods, in this study we found results that suggest a comparable association in this cohort. METHODS: We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education. RESULTS: The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 microg/dL of blood Pb was 1.92 (95% confidence interval, 1.05-3.87; p = 0.03). CONCLUSION: Although several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.