Inheritance of intrahepatic cholestasis of pregnancy in one kindred

Hirvioja M-L, Kivinen S. Inheritance of intrahepatic cholestasis of pregnancy in one kindred
Clin Genet 1993: 43: 315–317. © Munksgaard, 1993
We report three sisters with intrahepatic cholestasis of pregnancy (ICP) and the pedigree of the family, including six: generations. ICP was observed in five successive generations; most of the patients also had cholelithiasis. The uniform expression, the complete penetrance of the trait and the direct parent-to-child transmission support the Mendelian dominant mode of inheritance. Determination of HLA A, B and C haplotype was made in five ICP patients, without any findings of HLA type common to everyone. X-linked inheritance cannot be excluded in this study.     

Association of chest radiography findings with host-related genetic factors in patients with nephropathia epidemica

Different host genetic factors causes imbalance in the immune response. The purpose of this study was to establish whether pathological findings in chest radiography are related to the various host-related immunological factors in nephropathia epidemica (NE). Chest radiography findings, human leukocyte antigen (HLA) alleles B8, DR3, B27, genotypes of the genes of tumour necrosis factor alpha (TNFalpha), interleukin -1alpha (IL-1alpha), IL1beta and IL-1 receptor antagonist (IL1RA) were analysed in 114 patients with serologically confirmed acute NE. Both the presence and severity of abnormal NE-related chest radiography findings associated with the B8, DR3 and TNF2 alleles are known to form a frequent extended HLA haplotype in European populations. Pleural effusion showed the strongest association with these genetic factors. Pathological findings in chest radiography are related to host genetic factors in NE. Pleural effusion is a sign of increased capillary permeability, an important feature in NE. Host genetic factors may contribute to increased capillary permeability observed in NE patients.     

Increased long-term cardiovascular morbidity among patients treated with radioactive iodine for hyperthyroidism

Objective Previous studies suggest that hyperthyroid patients remain at increased risk of cardiovascular morbidity after restoring euthyroidism. The aim of this study was to compare the rate and causes of hospitalization of hyperthyroid patients treated with radioactive iodine (RAI) with those of an age‐ and gender‐matched reference population in a long‐term follow‐up study. Patients and measurements A population‐based cohort study with a median follow‐up time of 9 years was conducted among 2611 hyperthyroid patients treated with RAI between 1969 and 2002 in Tampere University Hospital, and among 2611 reference subjects. Information on hospitalizations was obtained from the nationwide Hospital Discharge Registry. New events were analysed as the main outcome, including only the first hospitalization due to a given indication. Results The rate of hospitalization due to cardiovascular disease (CVD) was higher among patients with hyperthyroidism than among the control population [637·1 vs. 476·4 per 10 000 person‐years, rate ratio (RR) 1·12, 95% confidence interval (CI) 1·03–1·21]. The risk remained elevated up to 35 years after the RAI treatment. Hospitalizations due to atrial fibrillation (RR 1·35), cerebrovascular disease (RR 1·31), diseases of other arteries and veins (RR 1·22), hypertension (RR 1·20) and heart failure (RR 1·48) were more frequent in the patients than controls, while no such difference was found for coronary artery disease. Hospitalizations due to cancer, infectious and gastrointestinal diseases, and fractures were also more common in patients than in controls. Conclusions Hyperthyroidism increases hospitalizations due to CVDs. The excess risk is sustained decades after treatment. Patients treated for hyperthyroidism constitute a high‐risk group for CVD and may benefit from preventive interventions.     

Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms

CYP1A2 is involved in the metabolism of several widely used drugs and endogenous compounds, and in the activation of procarcinogens. Both genetic and environmental factors influence the activity of this enzyme. The current knowledge regarding factors influencing the activity of CYP1A2 is summarized in this review. Substrates, inhibitors and inducers of CYP1A2 activity, as well as phenotyping probes, are discussed. The functional significance and clinical importance of CYP1A2 gene polymorphisms are reviewed and interethnic differences in the distribution of CYP1A2 variant alleles and haplotypes are summarized. Finally, future perspectives for the possible clinical applications of CYP1A2 genotyping are discussed.     

Clinical trial: gluten microchallenge with wheat-based starch hydrolysates in coeliac disease patients - a randomized, double-blind, placebo-controlled study to evaluate safety

Background Wheat‐based starch hydrolysates such as glucose syrups, dextrose and maltodextrins are found in more than 50% of European processed food. These products contain low amounts of residual gluten and it has been questioned whether they are safe for coeliac disease patients. Aim To investigate whether coeliac disease patients can safely consume wheat‐based starch hydrolysate products. Methods This randomized, double‐blind, placebo‐controlled, prospective follow‐up study involved 90 coeliac disease patients in remission randomized to consume glucose syrups, maltodextrins or placebo for 24 weeks. Small bowel mucosal morphology and inflammation, symptoms, coeliac serology and malabsorption laboratory data were evaluated at baseline and at the end of the study. Results Daily ingestion of wheat‐based starch hydrolysates, glucose syrups and maltodextrins, had no deleterious effect on small‐bowel mucosal villous architecture or inflammation in coeliac disease patients when compared to the placebo group. Neither were there any significant differences in gastrointestinal symptoms, serology or malabsorption parameters after 24 weeks. Conclusions Wheat‐based starch hydrolysates, glucose syrups and maltodextrins did not have harmful effect on coeliac disease patients. Coeliac patients can thus safely continue to consume these products.     

<Emphasis Type="Italic">CYP2C9</Emphasis> genetic variants and losartan oxidation in a Turkish population

Objective Cytochrome P₄₅₀ 2C9 (CYP2C9) is a polymorphic enzyme catalysing the metabolism of several important drugs. Losartan has recently been suggested as a selective probe for CYP2C9 metabolic activity. The aim of the study was to determine the activity of CYP2C9, using losartan as a probe drug, in relation to CYP2C9 genotype in healthy Turkish subjects.Methods A single oral dose of 25 mg losartan was given to 85 Turkish unrelated subjects. Concentrations of losartan and its carboxylic acid metabolite, E3174, were analysed by means of high-performance liquid chromatography in urine collected for 8 h. The CYP2C9 genotypes were determined in 85 subjects using polymerase chain reaction-based endonuclease digestion methods specific for CYP2C9*2 and *3. Losartan oxidation was also studied in vitro, using human CYP2C8 and CYP2C9 enzymes expressed in yeast.Results The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3 were 0.100 and 0.088, respectively. The urinary losartan/E3174 ratio was significantly higher in subjects with CYP2C9*1/*3 genotype (median 2.35, n=12) than in subjects with CYP2C9*1/*1 (0.71, n=58) and *1/*2 (0.85, n=10) genotypes (P<0.05). In contrast to CYP2C9, no E3174 was formed by CYP2C8 in vitro.Conclusion The urinary losartan to E3174 metabolic ratio after a 25-mg losartan dose was found to be a safe and useful phenotyping assay for CYP2C9 activity in vivo. CYP2C9*3 variant allele is a major determinant of the enzyme activity, and it decreases losartan metabolism significantly, while CYP2C9*2 allele has less impact on enzyme function.     

Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

Aims/hypothesis

This case–control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland.

Methods

Altogether, 1673 longitudinal stool samples from 129 case children who turned positive for multiple islet autoantibodies and 3108 stool samples from 282 matched control children were screened for the presence of enterovirus RNA using RT-PCR. Viral genotype was detected by sequencing.

Results

Case children had more enterovirus infections than control children (0.8 vs 0.6 infections per child). Time-dependent analysis indicated that this excess of infections occurred more than 1 year before the first detection of islet autoantibodies (6.3 vs 2.1 infections per 10 follow-up years). No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion. The most frequent enterovirus types included coxsackievirus A4 (28% of genotyped viruses), coxsackievirus A2 (14%) and coxsackievirus A16 (11%).

Conclusions/interpretation

The results suggest that enterovirus infections diagnosed by detecting viral RNA in stools are associated with the development of islet autoimmunity with a time lag of several months.