Long-Term Health Effects of PCBs and Related Compounds: A Comparative Analysis of Patients Suffering from Yusho and the General Population.

Yusho, which refers to a mass poisoning caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans, was first reported in October 1968 in Japan. Yusho patients suffer from various symptoms; however, after 40 years, some emerging symptoms have been attributed to aging. The prevalence of symptoms and diseases among Yusho patients and the general population was compared in this study. The data obtained from the survey among Yusho patients (1131 patients) by the Ministry of Health, Labour, and Welfare of Japan in 2008 were compared with the data from a survey conducted among the general population. When selecting the comparison group, the age and residential area (prefecture) were taken into account to match the baseline characteristics of Yusho patients. A logistic regression analysis was performed to identify the association between Yusho and the prevalence of symptoms and was adjusted for various potential confounding factors (age, sex, body mass index, cigarette smoking, frequency of drinking, and walking time). Skin pigmentation and acneiform eruption were found to be characteristic symptoms of Yusho and were more prevalent in these patients. Other symptoms and diseases associated with Yusho included orthostatic hypotension, hypohidrosis, dysgeusia, Basedow's disease, hoarseness, cardiac insufficiency, tachycardia, eczema, and hair loss. Symptoms related to aging, such as general fatigue, arthralgia, and numbness in the extremities, were significantly higher in Yusho patients after adjusting for age and lifestyle. This study demonstrated that, 40 years after the outbreak of Yusho, the prevalence of various symptoms and diseases in Yusho patients, including age-related diseases, was higher than that in the general population.

Cutaneous Porphyrias: Causes, Symptoms, Treatments and the Danish Incidence 1989-2013.

Porphyrias are rare diseases caused by altered haem synthesis leading to the accumulation of different haem intermediates. Neurovisceral attacks may occur in acute porphyrias, while photosensitivity is the presenting symptom in cutaneous porphyrias. We present here an overview of symptoms and a flowchart for the diagnosis of cutaneous porphyrias, with recommendations for monitoring and an update of treatment options. From the Danish Porphyria Register, we present the incidences and approximate prevalences of cutaneous porphyrias within the last 25 years. A total of 650 patients with porphyria cutanea tarda were identified, 73 with erythropoietic protoporphyria, 9 with variegate porphyria, 4 with hereditary coproporphyria and one with congenital erythropoietic porphyria. The total incidence of all porphyrias was ~0.52/100,000 per year.

[Lessons from Field Studies].

During my academic career for more than 40 years, I was involved in 18 epidemiological field studies, partially or fully. Among these field studies, four (1. Medical services in remote rural areas in Okinawa, 2. Yusho episode, 3. JICA Onchocerciasis Control Project in Guatemala, and 4. Miyako cohort study in Fukuoka) are introduced in this paper, including the latest situation after the presentation. Through these field works experienced by the author, the following lessons were gained. 1. Strong human reliance between researchers and the targeted population is essential in carrying out epidemiological surveys successfully in the field. 2. Data obtained from the survey should be carefully examined and analyzed so that those data may reflect the real situation.

Porphyria Diagnostics-Part 1: A Brief Overview of the Porphyrias.

Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and excretion of porphyrins and their precursors. Precisely which of these chemicals builds up depends on the type of porphyria. Porphyria is not a single disease but a group of nine disorders: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), δ-aminolevulinic acid dehydratase deficiency porphyria (ADP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP). Each porphyria results from overproduction of heme precursors secondary to partial deficiency or, in XLP, increased activity of one of the enzymes of heme biosynthesis. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the most common porphyria, PCT, has a prevalence of 1 in 10,000, the most common acute porphyria, AlP, has a prevalence of ∼1 in 20,000, and the most common erythropoietic porphyria, EPP, is estimated at 1 in 50,000 to 75,000. CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less. Only six cases of ADP are documented. The current porphyria literature is very exhaustive and a brief overview of porphyria diseases is essential in order for the reader to better appreciate the relevance of this area of research prior to undertaking biochemical diagnostics procedures. This unit summarizes the current knowledge on the classification, clinical features, etiology, pathogenesis, and genetics of porphyria diseases.

Pseudoporphyria: discussion of etiologic agents.

Pseudoporphyria describes a photodistributed bullous disorder with negative urinary, fecal, and serum porphyrin studies. Although pseudoporphyria is thought to be extremely rare (less than 100 reported cases4-5), we propose that this entity is underreported. One author (KB) has seen four cases of pseudoporphyria in the past four years. We describe a patient with nonpruritic, nonpainful bulla on the dorsum of his hands. Biopsy revealed a split at the dermal-epidermal junction; laboratory tests and urinary porphyrin evaluation were negative.

Individuals' half-lives for 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in blood: correlation with clinical manifestations and laboratory results in subjects with Yusho.

BACKGROUND: In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long. OBJECTIVES: To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood. METHODS: Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression. RESULTS: A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy. CONCLUSIONS: Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF.

Pseudoporphyria induced by dialysis treated with oral N-acetylcysteine.

Pseudoporphyria is a rare bullous dermatosis that clinically and histopathologically is similar to porphyria cutanea tarda. It mainly affects patients with chronic renal failure on peritoneal dialysis or hemodialysis. Medications can also be involved in the etiology. Diagnosis and management of this condition is a challenge for dermatologists. The authors report a case of pseudoporphyria related to dialysis with favorable outcome after the use of oral N-acetylcysteine.

Pseudoporfiria induzida pela diálise tratada com N-acetilcisteína oral / Pseudoporphyria induced by dialysis treated with oral N-acetylcysteine

Pseudoporfiria é dermatose bolhosa rara, semelhante clínica e histopatologicamente à porfiria cutânea tardia. Acomete, principalmente, pacientes renais crônicos em diálise peritoneal ou hemodiálise. Medicamentos também podem ser envolvidos na etiologia. O diagnóstico e o manejo desta entidade é um desafio para os dermatologistas. Os autores demonstram um caso de pseudoporfiria, relacionada à diálise, com evolução favorável após o uso de N-acetilcisteína oral.

Pseudoporphyria is a rare bullous dermatosis that clinically and histopathologically is similar to porphyria cutanea tarda. It mainly affects patients with chronic renal failure on peritoneal dialysis or hemodialysis. Medications can also be involved in the etiology. Diagnosis and management of this condition is a challenge for dermatologists. The authors report a case of pseudoporphyria related to dialysis with favorable outcome after the use of oral N-acetylcysteine.

Hemodialysis-associated pseudoporphyria resistant to N-acetylcysteine.

We report a 33-year-old female patient who had hemodialysis-associated pseudoporphyria which did not respond to treatment with oral N-acetylcysteine. She responded favorably to treatment with the anti-malarial drug, chloroquine. The case is being reported to highlight the difficulty in interpreting the urinary porphyrin assays in patients on hemodialysis. Additionally, the current literature on pseudoporphyria disorders in patients with end-stage renal disease is briefly discussed.

Porfiria cutânea tardia esporádica associada ao uso de estrógenos: relato de caso e revisão de literatura / Sporadic late cutaneous porphyria associated estrogen use: a case report and literature review

Porfiria é a designação de um grupo de doenças enzimáticas que afetam a síntese do heme. São sete os tipos de porfiria, que se diferenciam pela enzima afetada. A porfiria cutânea tardia é acarretada pela deficiência da enzima uroporfirinogênio descarboxilase, gerando manifestações cutâneas e hepáticas aos portadores. Fatores como estrógenos, álcool, HIV, HCV, juntamente com o ferro podem desencadear a doença que é diagnosticada principalmente por análise urinária. O tratamento se dá por flebotomia e administração de cloroquina. No caso relatado a paciente, 54 anos, apresentou bolha na mão esquerda e após alguns meses foi diagnosticada porfiria cutânea tardia, por análise histopatológica alterada e eliminação anormal de uroporfirinas urinárias. O provável fator desencadeante foi o estrógeno, devido à eliminação de possível causa por outros fatores. Após tratamento com cloroquina e eliminação do fator causal, houve remissão da doença.

Porphyria is the designate of an enzyme group of diseases that affect the synthesis of heme. There are seven types of porphyria, which differ by the enzyme affected. Porphyria cutanea tarda is caused for the deficiency of the enzyme uroporphyrinogen descarboxylase, generating skin expression disorders and liver patients. Factors such as estrogens, alcohol, HIV, HCV, getting together with iron can cause the disease is mainly diagnosed by urinalysis. The treatment is done by phlebotomy and administration of chloroquine. In that case related the patient, 54 years old, presented blister on his left hand and after a some months was diagnosed tarda cutaneous porphyria, through histopathology and altered abnormal urinary elimination uroporphyrin. The probable factor precipitating was estrogen, due to elimination of possible causes for other factors. After treatment with chloroquine and elimination of the causal factor, there was remission of the disease.

[Porphyrias]. / Porphyrien.

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria and Doss porphyria belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological and cardiovascular symptoms. The diagnosis is based on a tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like Porphyria cutanea tarda, Erythropoietic protoporphyria and Congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin up to severe liver damage. The location of the deficient enzyme within the heme biosynthesic pathway determines the pattern of the accumulated porphyrins. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.

[Clinical significance of ontogenetic abnormalities of hemoglobin synthesis].

Hemoglobin consists of four globin chains linked by 4 hem molecules. Differences between hemoglobin species are due to dissimilarity of amino acid sequence in globin chains accounting for different solubility, affinity to oxygen, and interaction with nitrogen. The hem component is the same in all hemoglobins. Anomalous activity of hem-synthesizing enzymes leads to porphyria. The number of molecular defects associated with porphyria has recently increased which necessitated improvement of diagnostic and therapeutic methods. Factors promoting hemoglobin synthesis in patients with hemoglobinopathies may be used to alleviate symptoms of the disease. Measurement of hemoglobin in premature newborns helps to estimate their oxygen status and minimize the risk of toxic oxygen action. Porphyrias and hemoglobinopathies must be end-points of differential diagnosis. Modern techniques allow for earlier diagnosis of disturbed hemoglobin synthesis and improvement of relevant therapeutic strategies.

The porphyrias: pathophysiology.

Porphyrias are a group of inherited and acquired metabolic disorders due to a defect in haem biosynthesis. An enzymatic defect at different steps of haem synthesis leads to tissue accumulation and excessive excretion of porphyrins and/or their toxic precursors. The specific patterns of accumulation determine the variety of clinical manifestations, ranging from acute neurovisceral attacks to skin lesions and liver disease. Most enzyme defects represent partial deficiencies, while familial cases are linked to autosomal or recessive traits. The incomplete penetrance of the genetic defects often requires the triggering or aggravating effect of host-related or environmental factors. While genetics has a role in confirming clinical suspicion and in family screening, biochemical and clinical studies are still central in the diagnosis.

[Clinical and biochemical syndromes of cadmium-induced acute porphyrinopathy].

AIM: To study the specific features of porphyrin metabolic disturbances in cadmium poisoning. MATERIAL AND METHODS: The paper describes a patient who has developed clinical and biochemical syndromes of acute porphyrinopathy after exposure to cadmium-containing paint the vapors. The levels of delta-aminolevulinic acid, porphobilinogen, coproporphyrin, and uroporphyrin in urine and those of coproporphyrin and protoporphyrin in feces were measured. The concentrations of lead, cadmium, and copper were determined in whole blood and urine; selective screening of amino acids for hereditary metabolic diseases was made. RESULTS: The clinical signs of acute porphyrinopathy developed in the patient mimicked those of acute porphyries known by the current classification. The biochemical syndrome more corresponded to lead poisoning. However, the blood and urinary lead levels were not greater than the normal values, but the blood showed a 4-fold increase in cadmium, which seemed to induce porphyrin dysmetabolism.

[Oxidative stress in porphyria and carriers].

UNLABELLED: We sought to establish a causal relationship between oxidative stress and porphyria in patients and carriers. We reported changes in urinary porphyrin concentrations related to 8-hydroxy-2'-deoxyguanosine. METHODS: We measured urinary 8-hydroxy-2'-deoxyguanosine concentration in porphyria patients and carriers with multifactorial inheritance as a possible marker of attack. The porphyria types included 10 patients with porphyria cutanea tarda, 5 with variegate porphyria, 8 with hereditary coproporphyria, 7 with congenital erythropoietic porphyria, 5 with erythropoietic protoporphyria, 5 with acute intermittent porphyria, 7 erythropoietic protoporphyria carriers, and 7 acute intermittent porphyria carriers. RESULTS: Urinary porphyrin concentrations in these patients were significantly higher than those in healthy subjects (p<0.001). Urinary 8-hydroxy-2'-deoxyguanosine concentrations were significantly high in dermatopathy porphyria types namely porphyria cutanea tarda (p<0.001), variegate porphyria (p<0.05), hereditary coproporphyria (p<0.05), congenital erythropoietic phyria (p<0.05), and erythropoietic protoporphyria (p<0.001). CONCLUSION: These results reveal that urinary 8-hydroxy-2'-deoxyguanosine concentration in cutis porphyria types is a good predictor of attack and abatement.