Mortality in Yusho patients exposed to polychlorinated biphenyls and polychlorinated dibenzofurans: a 50-year retrospective cohort study.

BACKGROUND: In 1968, the Yusho incident resulted in accidental exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and related compounds in Japan. This study updated the risk of mortality in Yusho patients. METHODS: We obtained updated cohort data for all Yusho patients for the period 1968-2017. We calculated standardized mortality ratios (SMRs) for all-cause and cause-specific mortality over a 50-year follow-up period compared with the general population in Japan. RESULTS: A total of 1664 Yusho patients with 63,566 person-years of follow up were included in the analysis. Among males, excess mortality was observed for all cancers (SMR: 1.22, 95% confidence interval [CI]: 1.02 to 1.45) and lung cancer (SMR: 1.59, 95% CI: 1.12 to 2.19). Among females, increased mortality was observed for liver cancer (SMR: 2.05, 95% CI: 1.02 to 3.67). No significant increase was seen in non-cancer-related mortality compared with the general population. CONCLUSIONS: Carcinogenic risk in humans after exposure to PCBs and PCDFs remains higher among Yusho patients. Our findings suggest the importance of care engagement and optimum management to deal with the burden of Yusho disease.

Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases.

We evaluated the prognosis of acute porphyria among 206 adult Finnish patients with acute intermittent porphyria (AIP) or variegate porphyria (VP). The series represents all known patients with these porphyrias in Finland. Of the 47 patients who had a total of 117 acute attacks during the period 1967-1989, 6 died during an attack and 21 attacks were associated with paresis; the frequency of severe attacks was significantly smaller than before 1967 (p = 0.00002). Most pareses and deaths occurred because of a delay in diagnosis and inappropriate treatment of porphyria. For those patients who were symptom-free at the time of diagnosis (1365 follow-up years), the risk of the first subsequent attack was significantly smaller than for those who had had an acute attack before the diagnosis of porphyria (1047 follow-up years, p = 0.005). In addition, milder symptoms of porphyria were more common among those who had had previous attacks than among those who had not (p less than 0.00001). In AIP the risk of attacks correlated with the excretion of porphobilinogen in the urine during remission among adults (p = 0.03); a low rate of excretion predicted freedom from acute attacks. A regular use of many precipitating drugs was never associated with symptoms of porphyria. Two percent of the surgical operations and 4% of the pregnancies were associated with acute attacks. Nearly one-third of the women had symptoms of porphyria associated with the menstrual cycle, but these seldom proceeded to an acute attack. Forty-six percent of the women had used sex-hormone preparations regularly; 2 of them (4.5%) experienced associated acute attacks. Patients with AIP or VP showed increased incidences of hepatocellular carcinoma, and probably also chronic renal failure and hypertension.

[Neurologic disorders in acute intermittent porphyria]. / Zaburzenia neurologiczne w ostrej przerywanej porfirii.

In a material of 28 patients with acute intermittent porphyria and 2 with mixed porphyria neurological disturbances occurring in acute attach and the degree of their persistence during remission were analysed. The obtained results indicate that the symptoms of acute attach are neurogenic. In the acute phase of the disease a reversible disturbance of function develops in the first place in the nerve fibres with acetylcholine-type of impulse transmission. Clinically detectable permanent signs of polyneuropathy were observed only in some cases with most severe and prolonged acute attack.

[Social problems of porphyria]. / Problemy spoleczno--socjalne w porfirii.

Late consequences of the attacks of acute porphyrias were studied. Among 312 patients who were investigated the motor disability (neuropathy) was found in 9 patients, psychoneurological changes in 1 case and drug abuse in 7 subjects. In the group of 200 patients in remission (chosen at random) 72 persons (36%) received a disability pension. The existence of problems in change of the profession when it was necessary for health-reasons was marked. It was find that Dolargan (Pethidine) is too often applied to the patients in remission. It was made the warning that drug dependence will arise very easy in patients with porphyria.

[[35 Years of effort to improve the diagnosis of porphyria]. / 35 lat staran o lepsze rozpoznawanie porfirii.

World history of porphyria is given in brief. The activities of Porphyria Center during period of 25 years have shown how difficult it was to introduce diagnostic measures for this rare and very little known group of diseases. The obstacles encountered during the popularization of the knowledge of porphyria were: minimal information on porphyria, very seldom seen in Poland, therefore rather negative approach of the doctors to these patients,--almost never porphyria was seen in differential diagnostics of abdominal pains or polyneuropathies, herefore diagnosis, if made, was very late, often just before death. From the other side insufficient support for doctors was given by laboratories because of the lack of simple diagnostic tests. Along the 35 years of the work in the Institute of Haematology and Transfusiology the situation was steadily improving but slowly due to technical and economical difficulties. The Center was organized, now well equipped and able to diagnose and differentiate all types of porphyrias. A computerised basis of the collected material consist of 383 families (6000 persons registered). Among them there are nearly 600 acute (who have passed one or more attacks of porphyria) and about 1000 latent cases of porphyria. The mortality which was 52% in the first collected group of patients (1960-1970) has fallen to less than 10% concerning very severe and late diagnosed attacks. In 1996-1998 there were only two deaths during attacks of porphyria in Poland.

[Acute intermittent porphyria in the practice of an intensive care specialist]. / Ostraia peremezhaiushchaiasia porfiriia v praktike vracha-reanimatologa.

Acute intermittent porphyria (AIP) is a hereditary disease caused by disordered haem biosynthesis and characterized by paroxysmal exacerbations. It usually manifests in adult women. Provoking factors are pregnancy, alcohol, and "porphyrogenic" drugs. Grave attacks of AIP require urgent hospitalization in intensive care wards, rapid purposeful diagnosis and adequate therapy, determining the prognosis. The number of drugs should be minimized and drugs with a known porphyrogenic effect absolutely ruled out. A 35-year-old patient with the first episode of AIP is described; the disease eventuated in death after 2 months.

Net survival after exposure to polychlorinated biphenyls and dioxins: the Yusho study.

BACKGROUND: Net survival is an important measure of the overall outcome of disease management. This net survival is the most appropriate for international comparisons of disease impact between countries or time periods with different patterns of all-cause mortality because it is not influenced by other causes of death. However, little information is available on net survival among Yusho patients, who were accidentally exposed to PCBs and other dioxin-related compounds. METHODS: We estimated the net survival of 1664 Yusho patients (860 males, 804 females) as Yusho cohort subjects using the unbiased Pohar-Perme method. RESULTS: Among males, 1-, 5-, 10-, and 15-year net survival were 99.5% (95% confidence interval (CI): 97.9, 99.9), 99.1% (CI: 95.0, 99.9), 97.4% (CI: 86.5, 99.5), and 97.4% (CI: 84.2, 99.6), respectively. Among females, net survival remained almost constant. 1-, 5-, 10-, and 15-year net survival were generally higher in females than in males. CONCLUSIONS: This study provides the first unbiased estimations of net survival among Yusho patients. We confirmed that older male Yusho patients have experienced a significant decrease in net survival. Our results suggest that the excess hazard of PCBs and dioxins must be taken into account when evaluating unbiased estimates of net survival.

Yusho: 43 years later.

The aim of the present study is to describe recent issues with Yusho disease in Japan, describe the state of dioxin accumulation and the intake of dioxin via food in Japan, and introduce the Japan Environment and Children's Study. Yusho disease manifested in western Japan in 1968. The causes of Yusho are believed to be dioxin-related compounds, mainly polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs), via the ingestion of rice oil produced in February 1968. As of March 31, 2011, there were 1961 registered Yusho cases, but of these 539 are deceased. A retrospective cohort study on registered Yusho cases reported that the standardized mortality ratios (SMRs) for the major causes of death were not significantly elevated, with the exception of all-cancer (SMR=1.26; 95% confidence interval [CI]: 1.03-1.53) and lung cancer mortality (SMR=1.56; 95% CI: 1.03-2.27) in males. The results of the Yusho mortality study show that the SMR for liver cancer in males tends to decrease over time. In 2011, the Ministry of the Environment of Japan reported that the average concentration of dioxins in the blood (2002-2010) of the Japanese people was 19 pg-TEQ/g-fat, demonstrating a range of 0.10-130 pg-TEQ/g-fat, and that the average dioxin intake from food (2002-2010) was 0.82 pg-TEQ/kg-body weight/day, demonstrating a range of 0.031-6.2 pg-TEQ/kg-body weight/day according to 2006 WHO TEFs. The Japan Environment and Children's Study Project was launched in 2011 and is supported by the Ministry of the Environment of Japan. In this project, 100,000 mother and child pairs will be recruited over 3 years from designated study areas. Follow-up examinations will be carried out from pregnancy until the children are 13 years of age (a so-called birth-cohort study). This project will be implemented by the National Center at the National Institute for Environmental Studies and is supported by the Medical Support Center at the National Center for Child Health and Development. Field operations will be performed at 15 designated regional centers nationwide.

Relative survival after exposure to polychlorinated biphenyls and dioxins: a follow-up of Japanese patients affected in the Yusho incident.

OBJECTIVES: Little information is available on conditional survival among Yusho patients, who were accidentally exposed to PCBs and other dioxin-related compounds. In this study, we estimated relative survival among Yusho patients to quantify time trends in excess mortality compared to the general population. METHODS: A total of 1664 Yusho patients (860 males, and 804 females) were analyzed as Yusho cohort subjects. Relative survival ratio (RSR) was calculated as a measure of patient survival. RESULTS: Overall, 1-, 5-, 10-, and 15-year RSRs were 1.00 (95% confidence interval (CI): 0.99, 1.00), 1.00 (95% CI: 0.99, 1.01), 0.99 (95% CI: 0.98, 1.00), and 0.99 (95% CI: 0.98, 1.01), respectively. We did not observe meaningful increases or decreases in RSRs in either sex, which remained the same in all age groups for 1-, 5-, 10-, and 15-year RSRs. CONCLUSIONS: This study provides quantitative evidence that Yusho patients have no significant difference in relative survival compared with the general Japanese population. Our results suggest that PCBs and dioxin exposure confers no excess mortality. This information may be important for both the clinical management of and patient coping with Yusho disease.

Acute non-cancer mortality excess after polychlorinated biphenyls and polychlorinated dibenzofurans mixed exposure from contaminated rice oil: Yusho.

In Japan in 1968, rice-oil contaminated by polychlorinated biphenyls and polychlorinated dibenzofurans caused severe food poisoning, termed "Yusho" (oil disease). Several previous studies attempted to evaluate the effects targeting officially-certified Yusho patients. However, these studies have several limitations such as the left-truncated nature of the registry or residual confounding arising from the referent population selection. We thus conducted an area-based standardized mortality ratios (SMRs) study using vital statistics. A severely affected area (Tamanoura area) was adopted as the exposure group, with a reference population from Nagasaki prefecture in Kyushu, which included the Tamanoura. A large number of residents in Tamanoura were exposed to the rice-oil (28% of all the certified cases as of 2009). We estimated SMRs of non-cancer and cancer diseases for the years 1968-2002. Shortly after the exposure, SMRs of all causes, diabetes mellitus, cardiovascular disease, pneumonia/bronchitis, and bronchus/lung cancer were elevated. In particular, SMRs of heart disease were 1.97 [95% confidence intervals (CI): 1.09-3.56] in 1968, 2.05 (95% CI: 1.16-3.60) in 1969, and 1.89 (95% CI: 1.05-3.41) in 1975. However, we did not observe clear increase in SMRs more than 10 years after the exposure. This study provides further evidence in Yusho, especially on acute effects on non-cancer mortality.

Chester porphyria: a clinical study of a new form of acute porphyria.

Acute porphyria afflicts a large kindred in Chester that stems from a marriage in 1896 that has produced 200 descendants; this is the largest porphyric kindred to be identified in the United Kingdom. Six members aged 51 or under died from the condition over the past eight years. The diagnosis of porphyria was overlooked in some as the symptoms may mimic those of other acute illnesses, so that incomplete or incorrect death certificates have been issued. Psychosis, hypertension, and renal complications are particularly common. The porphyric members of the kindred show a previously undescribed hereditary disorder in which the characteristic enzymatic defects of acute intermittent porphyria and variegate porphyria coexist in the same subject. Acute porphyria is poorly understood by hospital and general practitioners, and this has caused anxiety in the kindred. A register of the kindred has been established, and families at risk should be offered biochemical screening, education, and genetic counselling.

Porfiria aguda: reporte de caso y revisión de tema / Porfiria aguda. reporte de caso e revisão de tema / Acute porphyria: case report and review

Las porfirias agudas comprenden un grupo de desórdenes genéticos en la síntesis del grupo heme que pueden comprometer la vida del paciente y cuyas manifestaciones son similares a las de otras condiciones médicas. La falta de reconocimiento clínico y la demora en el diagnóstico retarda en ocasiones el inicio del tratamiento específico, incrementando así la morbimortalidad. El diagnóstico se puede confirmar rápidamente demostrando niveles elevados de porfirinas totales en sangre y en orina y de porfobilinógeno y de ácido delta-aminolevulínico en la orina. La terapia con hemina intravenosa iniciada tan pronto como sea posible es el tratamiento más efectivo y los factores desencadenantes se deben identificar y minimizar al máximo. Un diagnóstico temprano y un completo y adecuado tratamiento mejoran el pronóstico y previenen el desarrollo de complicaciones. En este reporte de caso se muestran las manifestaciones clínicas típicas de una porfiria aguda en una mujer joven a la que se le hizo un rápido diagnóstico, pero que falleció sin recibir tratamiento por la falta de disponibilidad del medicamento en el país...

The acute porphyries include a group of genetic disorders in the heme biosynthesis, that cause neurovisceral manifestations that mimic many medical conditions, psychiatric illnesses and sometimes, it even compromises the patients life. The lack of clinical recognition and delay in diagnosis, often retard the specific treatment and follow an increase in the morbimortality. The diagnosis can be quickly confirmed when demonstrating levels markedly high of porphobylinogen, and delta-aminolevulínic acid in urine and total porphyirines in blood and urine. The therapy with intravenous Hemine started as soon as possible is the most effective treatment. The trigger factors should be identified and minimized. An early diagnosis and appropriate treatment thoroughly improves its prognosis and prevents the development of further complications. In this case report we show the typical manifestations of acute porphyria in a young woman, in which case the diagnosis was not delayed, the problem was the attainment of the specific treatment which was not available in Colombia and the patient died without treatment...

As porfiarias agudas compreendem um grupo de desordens genéticas na síntese do grupo heme que podem comprometer a vida do paciente e cujas manifestações são similares às de outras condições médicas. A falta de reconhecimento clínico e a demora no diagnóstico retarda em ocasiões o início do tratamento específico, incrementando assim a morbi mortalidade. O diagnostico se pode confirmar rapidamente demonstrando níveis elevados de porfirinas totais em sangue e na urina e de porfobilinógeno e de ácido aminolevulínico na urina. A terapia com hemina intravenosa iniciada tão cedo como seja possível é o tratamento mais efetivo e os fatores desencadeantes se devem identificar e minimizar ao máximo. Um diagnóstico cedo e um completo e adequado tratamento melhoram o prognóstico e prevem o desenvolvimento de complicações. Neste reporte de caso mostram-se as manifestações clínicas típicas de uma porfiria aguda numa mulher jovem à que se lhe fez um rápido diagnóstico, mas que faleceu sem receber tratamento pela falta de disponibilidade do medicamento no país...