Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.

Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report.

Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

Late-onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation.

Deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria (CEP). The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission. In a few patients, a late-onset CEP-like phenotype without UROS mutations appears to be associated with a myelodysplastic syndrome. We report a 60-year-old man with late-onset signs of cutaneous porphyria and accumulation in urine, plasma and faeces of type I porphyrin isomers characteristic of CEP. Analysis of DNA from peripheral leucocytes, skin and bone marrow aspirate showed that he was a heterozygous carrier of a Cys73Arg (c.217 T>C) mutation within UROS. Sequencing of cDNA from peripheral blood confirmed heterozygosity and expression of the normal allele. Measurement of UROS enzymatic activity in erythrocytes showed values ~70% of normal, indirectly indicating expression of the normal allele. Differently from other cases of late-onset uroporphyria, the patient did not present thrombocytopenia or any evidence of a myelodysplastic syndrome. Five years of clinical follow-up showed persistence of skin signs and increased excretion of porphyrins, independently of lifestyle factors or changes in medication regimes. We hypothesize acquired mosaicism (in the bone marrow) affecting the UROS gene. Thus, unstable cellular clones initiated overproduction of isomer I porphyrins leading to a CEP phenotype. This could be explained either by a clonal expansion of the porphyric (Cys73Arg) allele or by loss of function of the normal allele. Cellular turnover would facilitate release of uroporphyrins into circulation and subsequent skin lesions. This is the first case of a CEP heterozygous carrier presenting clinical manifestations.

Increased serum hepcidin levels in patients with porphyria cutanea tarda.

BACKGROUND: Increased iron stores- are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down-regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. OBJECTIVE: To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. METHODS: Hepcidin levels were measured by a competitive enzyme-linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). RESULTS: The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin-6 (IL-6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. CONCLUSION: Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse.

Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene.

BACKGROUND: Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria that results from a deficiency of uroporphyrinogen decarboxylase (UROD). The disease is caused by homoallelism or heteroallelism for mutations in the UROD gene. OBJECTIVE: To study a 19-year-old woman from Equatorial Guinea, one of the few cases of HEP of African descent and to characterize a new mutation causing HEP. METHODS: Excretion of porphyrins and residual UROD activity in erythrocytes were measured and compared with those of other patients with HEP. The UROD gene of the proband was sequenced and a new mutation identified. The recombinant UROD protein was purified and assayed for enzymatic activity. The change of amino acid mapped to the UROD protein and the functional consequences were predicted. RESULTS: The patient presented a novel homozygous G170D missense mutation. Porphyrin excretion showed an atypical pattern in stool with a high pentaporphyrin III to isocoproporphyrin ratio. Erythrocyte UROD activity was 42% of normal and higher than the activity found in patients with HEP with a G281E mutation. The recombinant UROD protein showed a relative activity of 17% and 60% of wild-type to uroporphyrinogen I and III respectively. Molecular modelling showed that glycine 170 is located on the dimer interface of UROD, in a loop containing residues 167-172 that are critical for optimal enzymatic activity and that the carboxyl side chain from aspartic acid is predicted to cause negative interactions between the protein and the substrate. CONCLUSIONS: The results emphasize the complex relationship between the genetic defects and the biochemical phenotype in homozygous porphyria.

The association between porphyria cutanea tarda and diabetes mellitus: analysis of a long-term follow-up cohort.

BACKGROUND: An association between porphyria cutanea tarda (PCT) and diabetes mellitus (DM) is widely reported, but the pathogenetic link remains unknown. OBJECTIVES: To investigate the natural history of DM in the setting of PCT and to determine which PCT features and risk factors may be associated with the development of DM. METHODS: This retrospective longitudinal study included 81 Spanish patients with PCT with at least 10 years of strict follow-up. Patients attended our Porphyria Unit for follow-up visits and the data were collected in the period 2004-2008. We classified patients into two groups: patients with glucose metabolism alterations (GMA: DM or impaired fasting glucose), and patients without. PCT features and PCT and DM risk factors were retrieved from clinical charts and compared between groups. RESULTS: We identified 33 patients (41%) with GMA, of whom 27 (82%) developed GMA a long time after the diagnosis of PCT (mean 12·7 years). In bivariate analysis, these patients had significantly higher mean serum ferritin at diagnosis (651 vs. 405 ng mL(-1); P = 0·005), a higher prevalence of persistently elevated serum ferritin (52% vs. 15%; P < 0·001 for trend) and a higher prevalence of family history of DM (48% vs. 19%; P = 0·004). In multivariate analysis, persistently elevated serum ferritin [odds ratio (OR) 10·66, 95% confidence interval (CI) 1·95-58·19; P = 0·006] and family history of DM (OR 4·82, 95% CI 1·34-17·33; P = 0·016) remained significantly associated with the presence of GMA. CONCLUSIONS: GMA are highly prevalent in patients with PCT and mostly develop a long time after the diagnosis of PCT. Persistent hyperferritinaemia seems to be a risk biomarker of GMA in patients with PCT, probably in the setting of chronic iron overload and hepatic inflammation. Strict long-term monitoring of glucose metabolism and serum ferritin may be advisable in the routine follow-up of patients with PCT.

Role of two nutritional hepatic markers (insulin-like growth factor 1 and transthyretin) in the clinical assessment and follow-up of acute intermittent porphyria patients.

OBJECTIVE: Acute intermittent porphyria (AIP) is caused by a deficiency of hydroxymethylbilane synthase. Clinical manifestations are abdominal pain and neurovisceral symptoms, accompanied by overproduction of heme-precursors in the liver, which frequently remains long-lasting in AIP patients. We tested the hypothesis that this condition may be associated with alterations of hepatic proteins known to be either increased or decreased in serum according to diverse pathological conditions including malnutrition, inflammation or liver disease. DESIGN: Serum proteins were analyzed in 26 biochemically active AIP patients that were classified according to the EPI (European Porphyria Initiative) guidelines as follows: (i) patients who presented a single acute attack having remained so far free of clinical symptoms; (ii) patients who present recurrent attacks or chronic symptoms associated with exacerbations of AIP. RESULTS: Most of the serum proteins were within normal limits, however insulin-like growth factor 1 (IGF-1) was decreased in 53.8% of AIP patients (z-score = -2.86 +/- 0.37) and transthyretin (prealbumin) was found significantly decreased in 38.5% of them. The IGF-1 z-score was lower in group B versus group A patients (-2.66 vs. -1.43; P = 0.024). The coincident decrease of both IGF-1 and transthyretin was associated with worsening of the clinical condition. CONCLUSIONS: This first study in humans suggests that the clinical expression AIP is associated with a state of under-nutrition and/or with hepatic inflammation due to the sustained accumulation of heme-precursors. We propose the use of both IGF-1 and transthyretin as biomarkers of disease morbidity/severity for the clinical follow-up of AIP patients.

Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives.

Porphyria cutanea tarda (PCT) arises from decreased hepatic activity of uroporphyrinogen decarboxylase (UROD). Both genetic and environmental factors interplay in the precipitation of clinically overt PCT, but these factors may vary between different geographic areas. Decreased activity of UROD in erythrocytes was used to identify patients with UROD mutations among a group of 130 Spanish PCT patients. Nineteen patients (14.6%) were found to harbor a mutation in the UROD gene. Eight mutations were novel: M1I, 5del10, A22V, D79N, F84I, Q116X, T141I and Y182C. Five others were previously described: F46L, V134Q, R142Q, P150L and E218G. The new missense mutations and P150L were expressed in Escherichia coli. D79N and P150L resulted in proteins that were localized to inclusion bodies. The other mutations produced recombinant proteins that were purified and showed reduced activity (range: 2.3-73.2% of wild type). These single amino acid changes were predicted to produce complex structural alterations and/or reduced stability of the enzyme. Screening of relatives of the probands showed that 37.5% of mutation carriers demonstrated increased urinary porphyrins. This study emphasizes the role of UROD mutations as a strong risk factor for PCT even in areas where environmental factors (hepatitis C virus) have been shown to be highly associated with the disease.

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Genetic studies in variegate porphyria in Spain. Identification of gene mutations and family study for carrier detection.

BACKGROUND: First, to establish the mutations of the protoporphyrinogen-oxidase (PPOX) gene in four Spanish patients with variegate porphyria (VP). Second, study of carrier status detection in the families, including a four-generation Balearic family. Third, evaluation of the results of carrier detection screening methods. DESIGN: Blood samples of four patients and of 139 members belonging to four families, including four generations of a Balearic family were processed for mutation analysis of the 13 exons of PPOX gene. Biochemical studies were performed together (blood and faecal porphyrin analysis) and plasma fluorescence scanning for 626 nm peak emission detection. A questionnaire regarding clinical manifestations was submitted to all family members studied. RESULTS: Single strand conformational analysis (SSCP) of DNA allowed the detection of the following mutations: W224R, 746delT: exon 7, 1077-1082insC: exon 10, and IVS6+2T-->A. Mutation was present in 19 of the 139 members of the families studied. Clinical manifestations or biochemical alterations were checked in the carriers detected and found as not relevant or not present. Only 11 members of the 19 mutation-bearing individuals showed plasma fluorescence PV peak positivity. CONCLUSION: Demonstration of gene mutation is the most reliable means of detecting carriers in studies of variegate porphyria families. DNA analysis is the most sensitive carrier detection method and also allows transmission behaviour of the genetic defect to be established in successive generations of the affected families.

Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation.

Acute intermittent porphyria (AIP) is a metabolic disease with a variable prevalence among different countries. In some areas of southern Europe it remains to be fully evaluated. We undertook a genetic and biochemical study of 16 unrelated Spanish AIP patients and relatives. The genetic analyses showed they harboured the following mutations in the porphobilinogen deaminase gene: R173W, G111R, L278P, L238P, R116W, R26C, 340insT, 730delCT, 691del30bp, and IVS14+1g>a. The mutation R173W was found in 6 patients (37.5%), including the only patients of our series with >3 recurrent porphyria attacks. While in clinical remission, all AIP patients exhibited sustained increased excretion of porphyrins and precursors. PBG excretion showed a high between-subject variation and was not related to erythrocyte PBG deaminase activity. The study of family members allowed the identification of 22 asymptomatic AIP carriers. These included 8 persons harbouring the R173W mutation belonging to four different families. Six of these latent AIP subjects showed increased PBG elimination, and in two the urinary levels were >10-fold the normal limit. These results reinforce the hypothesis that the R173W mutation may have a high biochemical and clinical penetrance among AIP patients.

Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years.

BACKGROUND: A genetic component of early-onset lung cancer has been suggested. The role of metabolic gene polymorphisms has never been studied in young lung cancer cases. Phase 1 and Phase 2 gene polymorphisms are involved in tobacco carcinogens' metabolism and therefore in lung cancer risk. METHODS: The effect of metabolic gene polymorphisms on lung cancer at young ages was studied by pooling data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. All primary lung cancer cases of both sexes who were Caucasian and

Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1.

Human microsomal epoxide hydrolase (mEH) catalyzes a key step in the biotransformation of benzo[a]pyrene that yields the highly mutagenic (+)-anti-7,8-diol-9,10 epoxide (BPDE). Two polymorphisms have been described in the coding region of the mEH gene (EPHX1) that produce two protein variants: 113Tyr-->113His (exon 3) and 139His-->139Arg (exon 4). We performed a case-control study among Northwestern Mediterranean Caucasians to investigate a possible association between these EPHX1 variants and lung cancer risk. Both EPHX1 polymorphisms were analyzed in a group of lung cancer patients (n=176) and in a control group of healthy smokers (n=187). The results showed a significantly decreased risk for the rare homozygous 113His/113His (adjusted odds ratio (OR): 0.44, 95% confidence interval (CI): 0.27-0.71) and 139Arg/139Arg (adjusted OR: 0.55, 95% CI: 0.33-0.91) compared with the major wild-types 113Tyr/113Tyr and 139His/139His, respectively, as the references. Thereafter, we analyzed the EPHX1 variants in combination with three glutathione S-transferase polymorphic genes (GSTM1, GSTT1, and GSTP1) and we found a significant overepresentation of cancer patients with a combination of exon 3 113Tyr/113Tyr EPHX1 and exon 5 105Ile/105Ile GSTP1 (adjusted OR: 2.34, 95% CI: 1.21-4.52). The polymorphic site within the exon 5 of GSTP1 results in a Ile-->Val substitution, and the isoleucine GSTpi isoform has been found in vitro to be less active than the valine isoform towards the conjugation of BPDE. The 113 Tyr/Tyr EPHX1 encodes for a high-activity mEH. Our results agree with these observations in vitro and suggest that a genetically determined combination of a high-activity mEH and a low-activity GSTpi may increase lung cancer risk among smokers.

Association between serum concentrations of hexachlorobenzene and polychlorobiphenyls with thyroid hormone and liver enzymes in a sample of the general population.

OBJECTIVES: Hexachlorobenzene (HCB) is a highly lipophilic organochlorine compound of widespread environmental occurrence, that accumulates in the biological system. It affects the porphyrine metabolism, thyroid hormones, and the liver function in animals. Although HCB is one of the most common organochlorine compound in humans, little investigation on its health effects has been done. Polychlorobiphenyls (PCBs) are also widespread toxic environmental contaminants. The aim of the present study was to investigate the association of serum HCB and PCB concentrations with thyroid hormone status and liver enzymes in human. METHODS: Thyroid stimulating hormone (TSH), total and free thyroxine (T4), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were measured as biological markers of thyroid and liver function in a rural population sample older than 14 years (n=192, except for TSH with n=608) highly exposed to HCB. Serum concentrations of HCB were measured by gas chromatography coupled to electron capture detection. RESULTS: After adjustment for confounding variables, there was a significant negative association between serum HCB concentrations and total T4 (a decrease of 0.32 microg/dl per each unit, ln ng/ml, of increase of HCB) and a positive association with GGT (a relative increase of 10 % per each ln unit of increase of HCB), although most subjects (92%) were within the normal range for both T4 and GGT. These associations were not modified after adjustment for total lipid content or for other organochlorine compounds. The association of T4 and GGT with PCB was smaller although significant. No association was found with the other biochemical markers. CONCLUSIONS: These results suggest that the internal dose of HCB of this population may reflect a subtle metabolic effect on thyroid function and an enzymatic induction activity. Further studies are needed to evaluate the health impact of these effects in more susceptible populations, such as infants.

Excretion of hexachlorobenzene and metabolites in feces in a highly exposed human population.

A set of 53 individuals from a population highly exposed to airborne hexachlorobenzene (HCB) were selected to study the elimination kinetics of this chemical in humans. The volunteers provided blood, 24-hr urine, and feces samples for analysis of HCB and metabolites. The serum HCB concentrations ranged from 2.4 to 1,485 ng/mL (mean +/- SD, 124 +/- 278), confirming that this human population has the highest HCB blood levels ever reported. All analyzed feces samples contained unchanged HCB (range, 11-3,025 ng/g dry weight; mean +/- SD, 395 +/- 629). The HCB concentration in feces strongly correlated with HCB in serum (r = 0.85; p < 0.001), suggesting an equilibrium in feces/serum that is compatible with a main pulmonary entrance of the chemical and low intestinal excretion of nonabsorbed foodborne HCB. The equilibrium is also compatible with a nonbiliary passive transfer of the chemical to the intestinal lumen. Two HCB main metabolites, pentachlorophenol (PCP) and pentachlorobenzenethiol (PCBT), were detected in 51% and 54% of feces samples, respectively. All urine samples contained PCP and PCBT, confirming the conclusions of a previous study [Environ Health Perspect 105:78-83 (1997)]. The comparison between feces and urine showed that whereas daily urinary elimination of metabolites may account for 3% of total HCB in blood, intestinal excretion of unchanged HCB may account for about 6%, thus showing the importance of metabolism in the overall elimination of HCB. The elimination of HCB and metabolites by both routes, however, appears to be very small (< 0.05%/day) as compared to the estimated HCB adipose depots. Features of HCB kinetics that we present in this study, i.e., nonsaturated intestinal elimination of HCB and excretion in feces and urine of inert glutathione derivatives, may explain, in part, the absence of porphyria cutanea in this human population heavily exposed to HCB.

Genetic polymorphism of glutathione S-transferase P1 gene and lung cancer risk.

OBJECTIVES: The human GSTTP1 gene is polymorphic with an A-->G transition in exon 5 causing a replacement 105 Ile-->Val in the GSTP1 protein. The two isoforms, encoded by the alleles GSTP1*A and GSTP1*B, respectively, show different catalytic efficiencies towards some carcinogenic epoxides. In this study we have addressed the possible role of the Ile105Val GSTP1 polymorphism in lung cancer susceptibility. METHODS: The polymorphic site was genotyped by RFLP in a group of lung cancer patients (n = 164) and in two control groups (healthy smokers, n = 132; general population, n = 200). All patients and controls were Northwestern Mediterranean Caucasians of the same ethnic origin. RESULTS AND CONCLUSIONS: The cancer patients showed frequencies of GSTP1*A/A; GSTP1*A/B and GSTP1*B/B (50%, 38%, 11%, respectively) very similar to those of both control groups (healthy smokers: 48%, 41%, 11%). After adjusting for age, sex and smoking status, no association was found between the GSTP1*B allele and lung cancer risk (OR: 1.18; 95% CI: 0.67-2.07). The Ile105val GSTP1 polymorphism was also analysed in combination with the GSTM1 and GSTT1 genes. The results showed that allelism at GSTP1 did not increase the risk associated with the GSTM1 or GSTT1 deletions.

Urinary porphyrin excretion in a human population highly exposed to hexachlorobenzene.

BACKGROUND: Data from an epidemic reported in Turkey (1955-1959) is the only information about the relationship between hexachlorobenzene (HCB) intake and porphyria cutanea tarda in humans. No information is available on the HCB threshold exposure level to induce porphyria cutanea tarda. OBJECTIVES: To study HCB serum levels and urinary porphyrin excretion in the inhabitants of a village located near an organochlorine compound factory with high HCB concentrations in the air and to detect possible alterations in urinary porphyrin excretion and examine their relationship with HCB serum levels. DESIGN: Cross-sectional study. SETTING: Unit of Porphyrias of a tertiary care facility in Barcelona, Spain. PARTICIPANTS: Six hundred four inhabitants of the village who were older than 14 years provided serum and urine samples (185 participants were factory workers). MAIN OUTCOME MEASURES: Serum HCB was analyzed by gas chromatography coupled to electron capture detection. Quantification of urinary total porphyrins was performed by spectrofluorimetry. Porphyrin profile was determined by high-pressure liquid chromatography. RESULTS: Hexachlorobenzene was detected in all serum samples (mean, 39.8 ng/mL; range, 1.1-1616.0 ng/mL), and levels were higher in factory workers. Mean +/- SD level urinary total porphyrin average concentration was 98 +/- 69 nmol/L (range, 9-1009 nmol/L). Only the urine sample with the highest porphyrin concentration showed an increase of highly carboxylated porphyrins, with a typical profile of porphyria cutanea tarda. In the remaining 603 urine samples, coproporphyrin was the predominant fraction. CONCLUSION: The airborne exposure to and increased body burden of HCB in the Flix village population are not enough to trigger a significant alteration of the heme biosynthesis pathway.

Health effects of chronic high exposure to hexachlorobenzene in a general population sample.

Hexachlorobenzene, an organochlorine compound that accumulates in humans, is widespread throughout the environment. In this study, we describe the health status of inhabitants of a rural village that surrounds an electrochemical factory characterized by high levels of hexachlorobenzene in the air. During 1994, we conducted a cross-sectional study of 1 800 inhabitants in the south of Catalonia, Spain, who were older than 14 y of age. We obtained information on lifestyles and occupational and medical histories via questionnaire. Self-reported health outcomes were validated against clinical records and cancer registry data. Serum levels of hexachlorobenzene were very high in males who worked in the electrochemical factory (geometric mean = 54.6 ng/ml in randomized participants). Levels were lower among subjects who had never worked in the electrochemical factory (females, 14.9 ng/ml; males, 9.0 ng/ml). Levels of other organochlorine compounds (i.e., beta-hexachlorocy-clohexane, 2,2-bis[p-chlorophenyl]-1,1-dichloroethylene) were in the same range found in other communities. Perceived health, prevalence of self-reported common chronic conditions, and porphyria cutanea tarda, thyroid pathology, Parkinson's disease, cancer, and reproductive outcomes were within the ranges observed in other studies. Employment in the plant, however, was associated with having any of the a priori selected health outcomes that were potentially related to exposure to hexachlorobenzene (odds ratio for cancer prevalence = 1.9; 95% confidence interval = 0.5, 7.6). Our population of workers and nonworkers had the highest levels of hexachlorobenzene ever described. The results suggest that exposure to hexachlorobenzene did not affect the general health status of the this population, but it was associated with specific health effects of the most highly exposed subjects.