[Prevention and multimodal therapy of hyperthyroidism]. / Prävention und multimodale Therapie der Hyperthyreose.

Subclinical and overt hyperthyroidism have been associated with various negative clinical outcomes as for example an increased risk of atrial fibrillation or increased cardiovascular mortality, especially in old age. In order to avoid hyperthyroidism it is strongly recommended not to start any iodine containing drug therapy or to avoid application of contrast agents unless the patient presents with an unremarkable clinical course. TSH suppressive therapy for the treatment of endemic goiter or differentiated low risk thyroid carcinoma is unnecessary, since it favours the development of subclinical hyperthyroidism. Overt hyperthyroidism is treated with antithyroid drugs and/or radioiodine therapy or surgery according to the underlying disease (toxic nodular goiter, Graves' disease).

Association between serum ferritin and the insulin resistance syndrome in a representative population.

OBJECTIVE: Unexplained hepatic iron overload with increased serum ferritin (SF) values has been associated with the insulin resistance syndrome (IRS), defined by the presence of one or more of the following criteria: increased body mass index (BMI), diabetes, hyperlipidemia or hypertension. However, as yet the association between IRS and SF in a representative population has not been investigated. METHODS: The study subjects participated in a nationwide epidemiological survey on metabolic disorders in the adult German population. The 1200 probands included in this study are representative of the German population. To eliminate major causes of secondary iron overload, 114 (9.5%) subjects with excessive alcohol consumption and 16 (1.5%) subjects with serological evidence for hepatitis B or C were excluded. For all remaining 1070 probands, complete clinical data of SF, HbA1c, known diabetes, BMI, cholesterol, high-density lipoprotein-cholesterol and blood pressure were available. RESULTS: SF values were significantly increased in men and women with high BMI (> 25 kg/m2), increased cholesterol (> 200 mg/dl), and increased systolic (> 160 mmHg) blood pressure, in women with diabetes, and in men with increased diastolic (> 95 mmHg) blood pressure. Furthermore, there was a significant correlation between the number of IRS criteria and SF. CONCLUSIONS: This study shows a significant correlation between SF and the presence of IRS criteria in a large representative population. Interestingly, the severity of the IRS seems to be associated with increased SF levels suggesting a causal connection. Further studies are required to investigate the pathophysiological mechanism and consequences of increased SF levels in patients with IRS.

[Postalimentary hypoglycaemia in post-gastrectomy late dumping syndrome]. / Postalimentäre Hypoglykämien bei Spätdumping-Syndrom.

HISTORY AND CLINICAL FINDINGS: A 48-year-old patient had been suffering from postalimentary hypoglycemias for several months, occurring regularly 2 hours after a meal. 5 years before, repeated fundaplications as well as a selective proximal vagotomy due to reflux oesophagitis had been performed. INVESTIGATIONS: Physical examination revealed no pathological findings. The diurnal blood sugar profile with hourly capillary glucose measurement showed a physiological fasting glucose homeostasis and two-hour postprandial decrease of blood glucose down to 20 mg/dl. The oral glucose tolerance test revealed a noticeable insulin secretion with a pathologically increased insulin/glucose index. Scintigraphy demonstrated an initially delayed, then accelerated gastric emptying as a consequence of the selective proximal vagotomy. DIAGNOSIS, TREATMENT AND COURSE: A postalimentary hypoglycemia by hypersecretion of insulin in the context of a post-gastrectomy late dumping syndrome was diagnosed. A surgical pyloroplasty was not effective. In addition to the modification of eating habits, treatment with subcutaneous applied octreotide (Sandostatin), a somatostatin-analogue, was initiated. CONCLUSIONS: Postalimentary hypoglycemia can be assigned to late dumping syndrome in most cases already by ascribed history taking. The correct diagnosis can be achieved by an oral glucose tolerance test with measurement of insulin secretion and gastric emptying scintigraphy. Beside other therapeutical options the treatment with octreotide is a promising alternative with manageable side effects.

[Newly diagnosed diabetes mellitus--what to look out for]. / Neu entdeckter Diabetes mellitus in der Praxis: Wie geht's jetzt weiter?

Screening for diabetes makes good sense in particular in patients with overweight, hypertension or dyslipidemia. For type 2 diabetes is often not recognized until sequelae have put in an appearance. Consideration must be given to the possible presence of neuropathy, micro- and macroangiopathy and cardiovascular and cerebral disease. The primary therapy recommendations for type 2 diabetics comprise diet, weight loss and increased exercise. Depending on the success of these measures and the patient's constitution, medication with biguanides, sulfonylureas, glinides, glitazones alpha-glucosidase inhibitors or, where indicated, insulin, is then applied.

Definition and characterization of relative hypo- and hyperleptinemia in a large Caucasian population.

The adipocyte-derived hormone, leptin, has been implicated in the regulation of appetite, weight gain and glucose homeostasis as well as in liver fibrogenesis, hematopoiesis and immune function. No previous reports have clearly defined pathologically elevated or decreased serum leptin levels for Caucasian adults. The aim of this study was to define and characterize subjects with relative hyper- and hypoleptinemia in a large population-based German cohort. Percentiles of leptin levels by body mass index (BMI) were calculated from 4971 adult Germans, and the participants with leptin levels above the 95th and below the 5th percentile were defined as relatively hyperleptinemic and relatively hypoleptinemic, respectively, for their BMI. These participants were compared with the intermediate group with respect to anthropometric and clinical data and parameters of glucose and iron metabolism, lipid status, renal, adrenal and reproductive function. Relatively hyperleptinemic participants (HL) showed higher insulin, c-peptide, and total cholesterol levels than the hypoleptinemic subjects; in males, ferritin levels were higher and testosterone levels lower in the HL group. In conclusion, we report the first percentile curves for serum leptin by BMI in a large Caucasian population. Relatively low leptin values may be associated with a lower metabolic risk than relatively high serum leptin values.

Orofacial granulomatosis as initial manifestation of Crohn's disease: a report of two cases.

Patients with Crohn's disease generally present with chronic diarrhoea and/or abdominal pain. However, it may be the extraintestinal manifestations as orofacial granulomatosis (OFG)--a rare syndrome with chronic swelling of the lips and the lower half of the face combined with oral ulcerations and hyperplastic gingivitis--that urge patients to seek medical advice. We report two rare cases in which swelling of the lips and cheeks were the initial symptoms that finally led to the diagnosis of Crohn's disease.

The Pro115Gln polymorphism within the PPAR gamma2 gene has no epidemiological impact on morbid obesity.

The peroxisome-proliferator-activated receptor gamma2 (PPAR gamma2) is a transcriptional key regulator of adipocyte differentiation. PPAR gamma2 can be inactivated by phosphorylation of a serine residue at position 114. A point mutation leading to an amino acid exchange at position 115 (Pro115Gln) was shown to preclude serine phosphorylation and to consecutively accelerate adipocyte differentiation emphasizing the pathophysiological relevance of this mutation. So far, four markedly obese heterozygote carriers of the Pro115Gln mutation (body mass index 37.9-47.3 kgxm (-2)) have been identified in a circumscribed study population. In order to evaluate the epidemiological relevance of the Pro115Gln mutation in morbid obesity we screened the DNA of all subjects with a body mass index greater than 35 kgxm (-2) who had participated in a nationwide German epidemiological field survey. There was no homozygote or heterozygote carrier of the Pro115Gln polymorphism among them. We conclude that the Pro115Gln polymorphism within the PPAR gamma2 gene has no relevant epidemiological impact on morbid obesity in Germany. It needs further investigation whether this polymorphism might play a role in related metabolic disorders.

Intracellular depletion of insulin by oleate is due to an inhibited synthesis and not to an increased secretion.

In the polyclonal rat pancreatic beta-cell line INS-1, immunoreactive insulin (IRI, insulin and its precursors) and C-peptide (surrogate marker for mature insulin) were quantified after a 1-h incubation at 16.7 mM glucose with or without oleate. Oleate caused a 20% decrease (P

Successful treatment of erectile dysfunction and infertility by venesection in a patient with primary haemochromatosis.

A 36-year-old patient with primary haemochromatosis presented with erectile dysfunction. Laboratory findings revealed reduced levels of luteinizing hormone (0.4 IU/l; normal range 2-12 IU/l), follicle-stimulating hormone (0.1 IU/l; normal range 1-12 IU/l) and testosterone (0.49 microg/l; normal range 2-8.1 microg/l). We made the diagnosis of secondary hypogonadism due to haemochromatosis, which is generally supposed to be irreversible. Due to consequent venesection therapy, levels of ferritin and transferrin saturation could be normalized, and levels of luteinizing hormone and follicle-stimulating hormone increased to normal ranges. Also, testosterone levels became normal and remained so without any androgen substitution. The patient subsequently regained erectile function and potency. This case underlines the fact that a hypogonadotrophic hypogonadism caused by iron overload can be reversed by a consequent venesection therapy.

Frequency and significance of Pro12Ala and Pro115Gln polymorphism in gene for peroxisome proliferation-activated receptor-gamma regarding metabolic parameters in a Caucasian cohort.

Peroxisome proliferation-activated receptor-gamma2 (PPARgamma2) is exclusively expressed in adipose tissue and belongs to the transcriptional regulators of adipocyte differentiation. Recently, two missense single-point mutations have been described in the PPARgamma2 gene: Pro12Ala and Pro115Gln. It was our aim to determine the frequency of these polymorphisms in a Caucasian cohort and to investigate their possible role in the pathogenesis of obesity, type 2 diabetes, and related metabolic disorders. The genotypes of 359 subjects (149 males, 210 females) with varying degrees of obesity and with or without type 2 diabetes were determined. Subsequent to genomic polymerase chain reaction amplification, the HpaII restriction fragment length polymorphism (RFLP) analysis and the HindII RFLP analysis were used for genotyping the Pro12Ala and Pro115Gln polymorphism, respectively. For the Pro115Gln polymorphism, all 359 subjects showed wild-type sequence, emphasizing the very rare occurrence of the mutated allele. For the Pro12Ala polymorphism, 276 subjects (76.9%) were homozygous for the wild-type allele, 80 (22.3%) were heterozygous, and only 3 (0.8%) were homozygous for the mutated allele. Genotype frequency was calculated to be 0.88 for the wild-type allele and 0.012 for the mutated allele. No significant differences were found in age; gender; body mass index; total cholesterol; low-density, high-density, and very low density lipoproteins; triglycerides; Lp(a); uric acid; and diabetes manifestation by comparing the different genotypes. Therefore, a major role of these polymorphisms in the pathogenesis of obesity and diabetes can be excluded.

GG-genotype in the promotor region of uncoupling-protein-1 gene is associated with lower level of dehydroepiandrosterone in type 2 diabetes.

The A-->G (-3826) point mutation within the distal region of the uncoupling-protein-1 (UCP-1) promoter is possibly involved in the development of obesity, diabetes and related disorders. DHEAS has been found to stimulate expression of UCP-1-mRNA. The aim of our study was to evaluate the prevalence of the three UCP-1 genotypes in type 2 diabetic patients out of a population based sample. Possible associations of A-->G mutation with serum levels of DHEAS and with obesity, diabetes and retinopathy were examined. - In 549 diabetic patients (312 males and 237 females) out of a population-based sample UCP-1 genotype was determined by genomic PCR and Bcl-I-RFLP analysis. Serum levels of DHEAS were measured by ELISA. - Genotype frequencies were: GG genotype, 4.4% (n= 24); AG genotype 37.3% (n=205) and AA genotype 58.3% (n= 320). The genotype groups were comparable with respect to sex, BMI, HbA1c, systolic blood pressure (BP), retinopathy and also to serum levels of C-peptide, leptin and cortisol. Serum levels of DHEAS were lowest in GG-genotype as compared to AG and AA (GG: 1.8+/-1.5 micromol/l, AG: 2.2+/-1.8 micromol/l, AA: 2.6+/-2.1 micromol/l; AA vs AG, AA vs GG: p<0.05). In a multiple linear regression analysis, which controlled for age, C-peptide, cholesterol, systolic BP, BMI, and HbA1c DHEAS was significantly negatively correlated with levels of cholesterol and positively with systolic BP only in females (p<0.05). - Allelic frequency for G in diabetic subjects was 0.23 which was similar as compared to a non-diabetic population examined by us in an earlier study. GG-genotype was associated with low levels of DHEAS in diabetic patients but not with retinopathy. We suggest a role for UCP-1 polymorphism in the pathogenesis of obesity and arteriosclerosis. This hypothesis, however, needs further investigation.

Prevalence of markers of hepatitis B in the adult German population.

The prevalence of hepatitis B virus markers was investigated in 5305 individuals considered to be representative for the adult German population. After adjustment of the data according to the age and sex distribution in the whole German population an anti-HBc prevalence of 8.71% (95% confidence interval, 7.94-9.48%) and an HBsAg carrier rate of 0.62% (95% confidence interval, 0.40-0.84%) were calculated. Anti-HBc prevalence increased with age from 4.12% in the youngest group to 15.66% in the 61-70-year-old. The percentage of HBsAg carriers showed a maximum of 1.12% in the 41-50-year-old individuals and decreased significantly in the older age groups. 1.40% (95% confidence interval, 1.08-1.72%) of individuals had anti-HBc only. There was a trend to higher rates of this pattern in males than in females; a significantly higher percentage of persons with anti-HBc only was found in anti-HBc-positive individuals below 31 years than in older individuals. Five participants with anti-HBc only (7.7%, or about 0.1% of the whole population) showed HBV-DNA despite the absence of HBsAg. 3.1% of anti-HBc positive individuals where also positive for anti-HCV, that was significantly higher than the percentage of anti-HCV-positives among persons without any HBV marker (0.46%). This study provides a comprehensive picture of the current hepatitis B situation in Germany, showing new data especially on the distribution of HBsAg in the general population and on the subgroup of individuals with anti-HBc only.

Mutation analysis of the human adipocyte-specific apM-1 gene.

BACKGROUND: The aim of this study was to analyse the human adipocyte-specific apM-1 gene for sequence variations. METHODS: Sequence analysis was performed in 344 randomly chosen blood samples using a capillary sequencer. RESULTS: Whereas no mutations were detected in intronic regions and in 2.7 kb of the promoter, two sequence variations were found within the coding sequence of apM-1. For both mutations, a polymerase chain reaction-(PCR) based restriction fragment length polymorphism (RFLP) analysis was developed, which provided a rapid screening method. A conservative T --> G transition at nucleotide + 45 within exon-2 [Gly15Gly] was detected with an allelic frequency of 0.9 for the wild-type allele and 0.1 for the mutated allele. In addition, a missense point mutation at nucleotide + 331 within exon-3 [Tyr111His] was detected with an allelic frequency of 0.97 for the wild-type allele and 0.03 for the mutated allele. This mutation replaces a tyrosine by an histidine within the carboxyterminal globular domain of apM-1. Concerning the Gly15Gly polymorphism, the TT genotype was found in 275 subjects (79.9%), the TG genotype in 67 subjects (19.5%) and the GG genotype in 2 subjects (0.6%): one with maturity onset diabetes of young age (MODY-diabetes) and one with Lipoatrophic Diabetes Syndrome (LPDS). Concerning the Tyr111His polymorphism, the TT genotype was found in 328 subjects (95.4%), the TC genotype in 15 subjects (4.3%) and the CC genotype in 1 subject (0.3%). CONCLUSION: The existence of two yet unknown mutations within the apM-1 gene was demonstrated and RFLP analysis was established for rapid screening. Well defined cohorts of patients are necessary to determine the putative role of apM-1 gene mutations in the pathogenesis of metabolic disorders.

Elevated levels of leptin and insulin but not of TNF alpha are associated with hypertension in type 2 diabetic males.

Leptin and TNF alpha are thought to influence blood pressure. Therefore, the aim of our study was to investigate leptin and TNF alpha levels and their association with blood pressure, sex steroids, insulin, creatinine and lipids in type 2 diabetic patients. In 424 type 2 diabetic patients (79 hypertensive females [+Hf], 79 normotensive females [-Hf]; 133 hypertensive males [+Hm], 133 normotensive males [-Hm]) matched for sex, age and BMI serum leptin levels were measured by RIA and TNF alpha, insulin, estradiol, progesterone by ELISA as well as free testosterone by RIA. Leptin levels were comparable in +Hf and -Hf (16.5 +/- 1.0 microg/l vs 16.3 +/- 1.0 microg/l) but higher in +Hm as compared to -Hm (8.3 +/- 0.47 microg/l vs 6.5 +/- 0.34 microg/l; p<0.05). In addition, in comparison to -Hm serum levels of insulin (190 +/- 10 pmol/l vs 161 +/- 11 pmol/l; p< 0.005) and also of creatinine (118.6 +/- 3.6 micromol/l vs 101.7 +/- 2.3; p< 0.0001) were higher in +Hm. Pearson's Correlation coefficient revealed a positive correlation between levels of leptin and diastolic blood pressure (p<0.05) and also between leptin and insulin (p<0.001) in males, however, only before correction for BMI. No correlation between leptin and creatinine was found in males and females. Levels of TNF alpha were comparable in all subgroups. No correlation between levels of TNF alpha and serum leptin levels, blood pressure and insulin was found. In females TNF alpha was positively correlated with creatinine (p<0.001) and in males positively with progesterone (p<0.001). Taken together, higher serum leptin levels were found in hypertensive type 2 diabetic males as compared to normotensives, which may be related to the BMI and higher levels of insulin. These findings are accompanied by a trend to lower levels of free testosterone in hypertensive type 2 diabetic males. TNF alpha levels were comparable in female and male hypertensive and normotensive type 2 diabetic subjects.

[Diabetic retinopathy and associated risk factors in type-1 and type-2 diabetics in the Upper Palatinate]. / Diabetische Retinopathie und assoziierte Risikofaktoren bei Typ 1- und Typ 2-Diabetikern in der Oberpfalz.

BACKGROUND AND OBJECTIVE: Diabetic retinopathy is the main cause of blindness in industrial countries. This study was undertaken to determine the prevalence of diabetic retinopathy and risk indicators among volunteers in a rural district in Bavaria, Germany. PATIENTS AND METHODS: Using a mobile survey unit, we investigated 627 diabetic volunteers (275 women, 352 men, mean age 64.5 +/- 12.5 yr) in 23 cities and villages. One retinal Polaroid photo was taken per eye, using a non-mydriatic camera (Canon CR4-45 NM). RESULTS: In 60 subjects (9.6%) retinal photographs were not assessable. Among the remaining 567 patients (76 type-1 diabetes, HbA1c 7.3 +/- 1.2% and 491 type-2 diabetes, HbA1c 7.7 +/- 1.5%) in 72.3% no retinopathy was found (57.9% type-1 diabetes/74.5% type-2 diabetes). Non-proliferative retinopathy was diagnosed in 22% (38.2%/19.6) and proliferative retinopathy in 5.6% (3.9%/5.9%). Photocoagulation scars were present in 6.1% (11.7%/5.3%) and macular oedema in 11.8% (14.1%/11.6%). In 6.1% (5.3%/6.6%) of patients visual acuity was less than 0.1 in at least one eye. The degree of retinopathy was found to be related to the duration of diabetes mellitus, age at onset, glycaemic control (HbA1c), blood pressure and symptoms of neuropathy. CONCLUSIONS: The prevalence of retinopathy of 22.0% in the study group was found to be low for non-proliferative diabetic retinopathy, perhaps due to the methods used and/or good or acceptable glycaemic control measured as HbA1c.