[Clinical course and differential diagnosis of thrombotic microangiopathy]. / Klinik und Differenzialdiagnose der thrombotischen Mikroangiopathie.

BACKGROUND: Thrombotic microangiopathies are complex diseases, requiring early differential diagnosis and targeted intervention. OBJECTIVES: Presentation of clinical phenotype and diagnostic algorithm, discussion of underlying pathophysiology, clinical management and therapy. METHODS: Summary of current knowledge from literature and expert opinion. RESULTS: Our understanding of pathophysiology and therapeutic options have changed substantially in recent years. Early differential diagnosis and targeted therapy are of prognostic relevance. CONCLUSIONS: A better understanding of underlying pathophysiology, increased clinical awareness and novel therapeutic options allow for a better prognosis of patients with thrombotic microangiopathy.

The protective effect of human renal sinus fat on glomerular cells is reversed by the hepatokine fetuin-A.

Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of proinflammatory and upregulation of regenerative factors in cocultured EC and PO, indicating a protective influence of RFSC. However, fetuin-A inverted these benign effects of RSFC from an anti- to a proinflammatory status. RSF was quantified by magnetic resonance imaging and liver fat content by 1H-MR spectroscopy in 449 individuals at risk for type 2 diabetes. Impaired renal function was determined via urinary albumin/creatinine-ratio (uACR). RSF did not correlate with uACR in subjects without NAFLD (n = 212, p = 0.94), but correlated positively in subjects with NAFLD (n = 105, p = 0.0005). Estimated glomerular filtration rate (eGRF) was inversely correlated with RSF, suggesting lower eGFR for subjects with higher RSF (r = 0.24, p < 0.0001). In conclusion, our data suggest that in the presence of NAFLD elevated fetuin-A levels may impair renal function by RSF-induced proinflammatory signalling in glomerular cells.

[Endocrine abnormalities in a young patient with metastatic cancer - case 3/2013]. / Endokrine Veränderungen bei einem jungen Patienten mit metastasiertem Tumorleiden - Fall 3/2013.

HISTORY AND ADMISSION FINDINGS: We report on a 24-year-old male patient who presented with worsening of the general condition and abdominal pain. INVESTIGATIONS: On physical examination, gynecomastia was noted. Laboratory tests showed manifest hyperthyroidism. The beta-hCG levels were markedly increased. By ultrasound, the thyroid gland was hyperperfused without thyroid nodules. Several large echo mixed lesions were found in the liver. The testes appeared normal. DIAGNOSIS: In light of the typical laboratory findings, a non-seminomatous extragonadal germ cell tumor was diagnosed. Hyperthyroidism was most probably HCG induced. TREATMENT AND COURSE: Initially the patient was treated with thyreostatic drugs. After initiation of chemotherapy and a marked decrease in beta-hCG, thyreostatic therapy could be terminated. CONCLUSIONS: Germ cell tumors may cause an increase in beta-hCG concentration. By cross-reacting with the TSH-receptor this could induce hyperthyroidism. Germ cell tumors are therefore a rare differential diagnosis of hyperthyreoidism.

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions.

AIMS/HYPOTHESIS: Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. METHODS: Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. RESULTS: Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. CONCLUSIONS/INTERPRETATION: Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.

A polymorphism in the gene encoding AdipoR1 affects olfactory recognition.

Polymorphisms in the gene encoding adiponectin receptor 1 (AdipoR1) are associated with insulin resistance, fatty liver, increased risk for type 2 diabetes and cardiovascular disease. AdipoR1 is expressed in the central nervous system and in the olfactory mucosa of mice and humans. We therefore hypothesized that a common polymorphism in AdipoR1 might alter olfactory function. We investigated a group of 222 healthy subjects (male: n = 147, female: n = 75) for olfactory recognition, and genotyped them for the polymorphism rs6666089 in the human AdipoR1 gene. This polymorphism has been previously shown to be associated with insulin resistance. Olfactory recognition was tested using standardized sniffing sticks, and parameters of glucose metabolism and serum adiponectin levels were assessed. We found a significant olfactory impairment in carriers of the AdipoR1 polymorphism rs6666089 (olfactory recognition: GG: 89.4 ± 1.2%, GA: 86.9 ± 1.4%, AA: 77.2 ± 4.8%, additive model, P = 0.0004, adjusted for age). Adiponectin levels had no impact on olfactory recognition. Fasting plasma glucose, fasting plasma insulin, body mass index and HbA1c did not differ between the genotype groups. In conclusion, the presence of a genetic variation in AdipoR1 is associated with decreased olfactory recognition in healthy subjects. Adiponectin signalling may have an important role in olfactory function and regulation of appetite.

[Retroperitoneal masses: two case reports--Case 11/2009]. / Retroperitoneale Raumforderungen: Zwei Kasuistiken--Fall 11/2009.

HISTORY AND ADMISSION FINDINGS: A 35-year old patient (male, headaches, visual impairment, 170/100 mmHg, case 1) and a 61-year old patient (female, headaches, epistaxis, 230/110 mmHg, case 2) were investigated in our hospital. INVESTIGATIONS: Laboratory findings in case 1 verified acute renal failure (serum creatinine 23 mg/dl, urea 146 mg/dl, pH 7.19). Bilateral obstructive uropathy was seen in sonography, and CT showed periureteral, retroperitoneal masses (RPM). In case 2, the lab showed a marked hyperreninism with secondary hyperaldosteronism, and ultrasound revealed a lowered right renal resistance-index. The MRI showed a retroperitoneal mass with long-segmental compression of the right renal artery (no lymphomas). CT-guided biopsy revealed grade 2 adenocarcinoma. No metastases were seen in the PET-CT. DIAGNOSIS, TREATMENT AND COURSE: In case 1, Morbus Ormond with post-renal failure owing to obstructive uropathy was assumed. After drainage of obstructive uropathy, immunsuppressive therapy (glucocorticoids and azathioprine) was started, and renal function recovered completely in the patient who was free of complaints in the further clinical course. In case 2, cancer disease progressed to osteoblastic metastases under palliative chemotherapy. CONCLUSIONS: RPM generally cause symptoms at rather late stages of the underlying disease. A total of 75% of RPM are based on idiopathic retroperitoneal fibrosis (M. Ormond). Common causes of secondary RPM are drugs, neoplasms, infectious diseases and former therapies in the retroperitoneum (surgery, radiotherapy). Histological investigation is recommended for RPM with atypical location, clinical suspicion of underlying neoplastic or infectious diseases and lacking response to glucocorticoids. The standard therapy for M. Ormond includes glucocorticoids, tamoxifene or methotrexate (or combinations of glucocorticoids with either tamoxifene or methotrexate). In case of secondary RPM, therapy depends on the cause of RPM.

[Normokalaemic primary aldosteronism due to an aldosterone-producing adrenal adenoma--Case 06/2009]. / Normokaliämischer primärer Hyperaldosteronismus infolge eines Aldosteron-produzierenden Nebennierenadenoms--Fall 06/2009.

HISTORY AND ADMISSION FINDINGS: A 39-year-old patient presented with normokalaemic therapy refractory arterial hypertension despite of four antihypertensive drugs for further diagnostics. INVESTIGATIONS: Ultrasound displayed no evidence of renal artery stenosis. Furthermore, the kidneys were normal sized and morphologically without pathological findings. Renal function was normal. Free cortisol and catecholamine levels in a 24-hr-urine sample were within the normal range. Plasma renin activity was reduced and both the plasma aldosterone concentration and the aldosterone to renin ratio were elevated. A saline infusion test showed no suppression of the plasma aldosterone concentration, nor did an orthostatic testing show an increase. MRI revealed an adenoma of the right adrenal gland. DIAGNOSIS, TREATMENT AND COURSE: The results were consistent with primary aldosteronism due to an aldosterone-producing adenoma of the adrenal gland. The patient underwent laparoscopic adrenalectomy. The histological findings confirmed an adenoma of the adrenal gland. Three months later, blood pressure was normal under a single treatment regimen with an AT(1) receptor blocker. CONCLUSIONS: Screening for endocrine causes of hypertension is recommended in young patients, therapy refractory hypertension, and in hypokalaemic hypertension. Normokalaemia does not exclude primary aldosteronism as the underlying cause of hypertension.

The risk allele load accelerates the age-dependent decline in beta cell function.

AIMS/HYPOTHESIS: Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes' risk alleles on the age-dependent decline in insulin secretion. METHODS: The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles. All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating AUC(proinsulin)/AUC(insulin). RESULTS: The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants (p

[Hypercalcemic crisis due to primary hyperparathyroidism]. / Hyperkalzämische Krise infolge eines primären Hyperparathyreoidismus.

HISTORY AND ADMISSION FINDINGS: A 54-year-old female patient presented with increasing somnolence since two days. Furthermore, the patient reported left-sided mid-abdominal pain and obstipation for one week. Immediately prior to admission, the patient had returned from a 14-day beach holiday on the Azores. Physical examination of the somnolent patient revealed a sun-tanned skin, signs of exsiccosis, and tachycardia with 116 beats per minute. INVESTIGATIONS: Laboratory studies showed marked hypercalcemia due to primary hyperparathyroidism and acute renal failure. Neck ultrasonography revealed a hypoechogenic, 5.8 x 3.5 x 3.1 cm-measuring mass behind the lower pole of the right thyroid lobe. DIAGNOSIS, TREATMENT AND COURSE: Serum calcium levels significantly decreased after immediate rehydration, bisphosphonate administration, and continuous hemodialysis that was also indicated because of acute renal failure with anuria. After knowledge of increased parathormone levels the patient underwent rapidly resection of the parathyroid adenoma which was histologically confirmed. CONCLUSIONS: Hypercalcemic crisis is often associated with acute renal failure due to calcium-induced polyuria.

[Hypercalcaemic crisis and acute renal failure due to primary hyperparathyroidism]. / Hyperkalzämische Krise und akutes Nierenversagen infolge eines primären Hyperparathyreoidismus.

Hypercalcaemic crisis is a rare endocrine emergency. Often, an acute renal failure develops due to hypercalcaemia-induced polyuria. The molecular causes comprise stimulation of the calcium-sensing receptor in the ascending Henle loop and a reduced aquaporin expression in the collecting ducts. We report on a 54-year-old woman who was admitted for hypercalcaemic crisis and acute renal failure. Immediate rehydratation, bisphosphonate administration, and slow-extended daily dialysis (SLEDD) were initiated leading to a marked reduction of serum calcium. Endocrine work-up revealed primary hyperparathyroidism due to a parathyroid adenoma, which was treated by emergency surgery. Haemodialysis was continued in the first post-operative weeks for prolonged acute renal failure.