Vinzenz Stepan

Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures

Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR‐based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis.

Graz Endocrine Causes of Hypertension (GECOH) study: a diagnostic accuracy study of aldosterone to active renin ratio in screening for primary aldosteronism

BackgroundPrimary aldosteronism (PA) affects approximately 5 to 10% of all patients with arterial hypertension and is associated with an excess rate of cardiovascular complications that can be significantly reduced by a targeted treatment. There exists a general consensus that the aldosterone to renin ratio should be used as a screening tool but valid data about the accuracy of the aldosterone to renin ratio in screening for PA are sparse. In the Graz endocrine causes of hypertension (GECOH) study we aim to prospectively evaluate diagnostic procedures for PA.Methods and designIn this single center, diagnostic accuracy study we will enrol 400 patients that are routinely referred to our tertiary care center for screening for endocrine hypertension. We will determine the aldosterone to active renin ratio (AARR) as a screening test. In addition, all study participants will have a second determination of the AARR and will undergo a saline infusion test (SIT) as a confirmatory test. PA will be diagnosed in patients with at least one AARR of ≥ 5.7 ng/dL/ng/L (including an aldosterone concentration of ≥ 9 ng/dL) who have an aldosterone level of ≥ 10 ng/dL after the saline infusion test. As a primary outcome we will calculate the receiver operating characteristic curve of the AARR in diagnosing PA. Secondary outcomes include the test characteristics of the saline infusion test involving a comparison with 24 hours urine aldosterone levels and the accuracy of the aldosterone to renin activity ratio in diagnosing PA. In addition we will evaluate whether the use of beta-blockers significantly alters the accuracy of the AARR and we will validate our laboratory methods for aldosterone and renin.ConclusionScreening for PA with subsequent targeted treatment is of great potential benefit for hypertensive patients. In the GECOH study we will evaluate a standardised procedure for screening and diagnosing of this disease.

Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid

Dobnig H et al. (Department of Internal Medicine, Karl Franzens University, Graz, Austria). Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid (Case report). J Intern Med 1996; 239: 365–9.

Pheochromocytoma in a 2.75‐year‐old‐girl with a germline von Hippel–Lindau mutation Q164R

Pheochromocytomas are rare tumors of the adrenal gland occurring sporadically or as part of familial cancer syndromes. Here we report on the case of a pheochromocytoma due to the germline missense mutation c.491A>G (Q164R) in exon 3 of the von Hippel–Lindau gene in a girl as young as 2.75 years. Extended analyses of her relatives showed that the mutation occurred de novo in the patients father who was subsequently diagnosed with bilateral pheochromocytomas and a retinal angioma. To the best of our knowledge, this is the youngest patient presenting with pheochromocytoma so far described in the literature. The same VHL mutation has been reported in a patient who developed a pheochromocytoma at the age of 10 years; therefore, for known VHL Q164R mutation carriers, we suggest screening for pheochromocytoma beginning at 2 years of age.

Aldosterone to Active Renin Ratio as Screening Test for Primary Aldosteronism: Reproducibility and Influence of Orthostasis and Salt Loading

Measurement of the aldosterone to active renin ratio (AARR) is the recommended screening test for primary aldosteronism (PA), but several sampling conditions impact on the AARR. We aimed to evaluate the reproducibility and the influence of orthostasis and salt loading on the AARR. The Graz Endocrine Causes of Hypertension (GECOH) study is a diagnostic accuracy study among hypertensive patients at a tertiary care centre in Graz, Austria. With a median interval of 4 weeks we determined the AARR under standardized sampling conditions twice in the sitting position, after 1h in the supine position, and after a salt infusion test (SIT). We identified 9 patients with PA and 151 patients with essential hypertension (EH). The Pearson correlation coefficient between both AARR measurements in the sitting position was 0.79 (p<0.001). In EH, recumbency was associated with a significant decrease of aldosterone and, to a lesser extent, of renin, thus lowering the AARR as compared to the sitting position (p<0.001 for all). In PA, recumbency had only minor effects, but it increased the rate of false negative AARR. SIT suppressed the AARR and its components in EH, whereas in PA only renin was slightly decreased. AARR has a good intra-individual reproducibility and decreases during recumbency. These results suggest that a single AARR determination in the sitting position is a reliable screening tool for PA.

von Hippel–Lindau disease: treatment of retinal haemangioblastomas by targeted therapy with systemic bevacizumab

Editor, W e read with interest the report by von Buelow and colleagues in this journal on the systemic treatment of a sporadic juxtapapillary retinal haemangioma with systemic bevacizumab (von Buelow et al. 2007). We present a similar case of a patient who underwent treatment with systemic bevacizumab for recurrent retinal haemangiomas associated with von Hippel–Lindau (VHL) disease. To our knowledge, this is the first report on the use of bevacizumab for this indication. VHL disease is an autosomaldominant inherited phacomatosis. Affected individuals develop retinal capillary haemangiomas (RCHs) and haemangioblastomas of the central nervous system, renal cell carcinomas, pheochromocytomas and other tumours (Singh et al. 2001). The underlying mechanism of VHL disease is a mutation of the VHL tumour suppressor gene, resulting in increased levels of the hypoxia inducible factor (HIF) and subsequently the over-expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-a (TGF-a) and erythropoietin. A 22-year-old woman was diagnosed with VHL disease in 1996 after she had noticed reduced visual acuity in her left eye caused by multiple RCHs in both eyes, which were treated with photocoagulation at another hospital. On her left eye she developed retinal detachment and finally, at the age of 29, after multiple surgeries (encircling band and vitrectomy), the left eye became blind and painful and finally had to be enucleated. Genetic testing confirmed VHL disease. She was first seen at our clinic in Graz at the age of 30, with best-corrected visual acuity (BCVA) in the right eye of 20 ⁄ 20. She continued to develop new RCHs, which were treated with lasercoagulation but showed only incomplete regression (Fig. 1A). Vision remained stable until 2007, when BCVA dropped to 20 ⁄ 30 because of a posterior vitreous detachment and vitreous bleeding. Ultrasonography (Cine-Scan S; Quantel Medical, Clermont-Ferrand France) showed circumscribed tractional retinal detachment and confirmed vitreous traction to the apex of the haemangiomas (Fig. 1B). The vitreous bleeding resolved spontaneously. However, BCVA did not improve and cystoid macular oedema (CMO) was diagnosed on optical coherence tomography (OCT) (Carl Zeiss Ophthalmic Systems Inc., Humphrey Division, Dublin, California, USA) (Fig. 1C) and flourescein angiography (FA) (Fig. 1D). CMO did not improve over the following 6 months and peripheral retinal haemangiomas progressed. The patient refused any surgery or invasive treatment, including intravitreal injections. Finally we decided to treat the patient with bevacizumab intravenously at a dose of 5 mg ⁄kg over 90 min every second week after informed consent was given. Treatment was tolerated well except for paraesthesia and petechial bleeding of nail beds, which presented after the first cycle. Before each therapy with bevacizumab the patient’s blood pressure and renal parameters were evaluated. After 2 months, BCVA improved to 20 ⁄25

The influence of vascular diathesis on the localization of inflammatory foci in renal allografts with a specific antigranulocyte antibody

Immunoscintigraphy with technetium-99m labelled BW 250/183, a murine monoclonal antibody specific for granulocytes, yielded a false-positive result in a patient suspected of having an abscess in his renal graft. To substantiate the presumption that diathesis and unspecific accumulation of the antibody may have caused this result, ten selected patients were investigated who presented with chronic vascular graft rejection but without signs of bacterial infection. Scintiscans were recorded 4 and 24 h after administration of99mTc-labelled BW 250/183. Graft-background ratios (GBRs) were calculated for each transplant. These were compared with the mean of physiological kidney-background ratios (KBRs) and with bone marrow-background ratios (BMBRs). After removal, the grafts were examined with pathological and immunohistological methods. Seven transplants demonstrated 4-h GBRs (mean: 3.9±1.1,P <0.001) significantly outside the range of normal KBRs while three were within the normal range (mean: 1.8±0.4). The relation between 4-h and 24-h GBRs varied. After 24 h five GBRs still remained increased (mean: 3.2±1.4,P <0.05). By contrast the BMBRs decreased uniformly by 18%±5%. After graft removal, histopathology demonstrated no dominant granulocyte accumulations but various degrees of chronic vascular and tubulo-interstitial rejection. Immunohistochemical studies did not indicate cross-reactivity of BW 250/183. Increased GBRs of longstanding renal allografts indicate the passage of the antibody through injured vascular walls rather than the presence of granulocyte accumulations. Therefore, variability of GBRs with time reflects changes in transitory concentrations of99mTc-labelled BW 250/183 in the tissues.

Genetic Components of Lactose Intolerance and Community Frequency

The fact that individuals heterozygous for primary adult lactose intolerance (LCT-13910) show intermediate BMDs is indeed interesting, and on this point, we fully agree with Büning et al. In our results, we explicitly mentioned an “increasing, but not significant gene-dose effect” in nonvertebral fractures and low BMD for heterozygous subjects. In fact, it has recently been shown that subjects heterozygous for the LCT-13910 polymorphism have reduced lactase activity compared with homozygous lactose-tolerant subjects. However, the ratio of lactase/sucrase activity in this study was significantly higher in LCT-13910 heterozygous subjects than in homozygous lactose-intolerant individuals. This remaining activity is possibly sufficient for clinically unremarkable lactose maldigestion, but nonetheless, may exert effects on bone metabolism and osteoporosis risk over a longer period. The observation of decreased BMD in LCT-13910 heterozygous subjects, therefore, rather additionally supports than contradicts our conclusion that adult-type hypolactasia is associated with osteoporosis. The aversion to dairy nutrients and a consequently decreased calcium supply together with intestinal calcium malabsorption may well be the first and most important cause of an individually decreased calcium balance and risk for osteoporosis in lactose-intolerant subjects. However, we have increasing evidence that some of the effects of the LCT-13910 polymorphisms on bone size and stature might not be calcium dependent alone, because they persist after correction for calciotropic parameters (JBJ van Meurs and AG Uitterlinden, personal communication, 2004). Thus, some of the regulatory aspects of the lactase phlorizin hydrolase (LPH) gene have to be assumed to be independent of a simple lactose intolerance effect per se. Furthermore, we have to consider several other environmental and genetic influences on calcium and lactose digestion that interfere with the LPH conditions, such as the vitamin D system. Our and other recent data show a strong influence of the vitamin D system on the severity and phenotypical consequence of lactose intolerance regarding bone, which will be further analyzed. We have to state clearly that primary adult lactose intolerance is a condition that affects about one-half of the world’s population. It has a severe impact on calcium supply and bone properties and should be kept in mind in every future human nutritional and pharmaceutical study in this field. The new possibility of an exact diagnostic tool for lactose intolerance using LCT-13910 genotyping will add further aspects to the discussion on consumption of dairy nutrients that is ongoing in the Journal, because the intake of diary nutrients is directly influenced by the genetic disposition to lactose intolerance, at least in adults. Further investigations, including interventional studies, will be necessary to fully explain the role of lactase activity and lactose intolerance for osteoporosis.

Hyperkalaemia and diarrhoea in a patient with surreptitious ingestion of potassium sparing diuretics

We report a patient who presented with the unusual combination of chronic diarrhoea and hyperkalaemia. The patient was admitted to our hospital after repeated negative evaluations elsewhere including exploratory laparotomy. The patient had a long history of diarrhoea with hypokalaemia which was documented on several occasions in the past. Several months before admission to our hospital for evaluation of diarrhoea the patient developed hyperkalaemia. Her daily stool output reached 1200 g and her serum potassium was as high as 6.0 mmol/l. Extensive evaluation revealed surreptitious ingestion of the diuretics triamterene, hydrochlorothiazide and spironolactone as the cause of hyperkalaemia and diarrhoea. In addition, she had melanosis coli which was interpreted to be the consequence of surreptitious ingestion of anthraquinone-containing laxatives in the past although no current laxative intake could be proven. We postulate that diarrhoea in our patient was mainly due to the decreased sodium absorption in the small intestine and colon caused by diuretics. Serum aldosterone levels were more than eight times the upper limit of normal. Increased aldosterone levels presumably arose secondary to volume contraction and sodium chloride depletion, but presumably were not able to affect renal and colonic electrolyte transport because of blockage of mineralocorticoid receptors by spironolactone. Thus, the unusual combination of diarrhoea and hyperkalaemia resulted.

Radiofrequenzablation von Schilddrüsenknoten: Good Clinical Practice Empfehlungen

J. Klin. Endokrinol. Stoffw. 2018 · 11:73–80 https://doi.org/10.1007/s41969-018-0043-6 Online publiziert: 21. September 2018