Trimethylaminuria. / Trimetylaminuri.

BACKGROUND: Trimethylaminuria is a rare disorder characterised by foul odour from bodily fluids and breath. The condition is caused by a homozygous mutation in the FMO3 (flavin monooxygenase 3) gene coding for the enzyme that converts TMA (trimethylamine) to trimethylamine N-oxide. The result is elevated levels of secreted trimethylamine, which has a strong odour. The condition is likely to affect mental, emotional and social health. The diagnosis is reached by testing of free TMA (trimethylamine) and percentage N-oxidation in urine samples or by genetic testing. CASE PRESENTATION: A man in his fifties had from childhood occasionally been told that his breath resembled rotten fish. He had searched for a diagnosis on the internet and was referred to testing for trimethylaminuria, and the diagnosis was confirmed. INTERPRETATION: Urine test samples with high levels of free TMA and subnormal percentage of trimethylamine N-oxide revealed the diagnosis of trimethylaminuria. There is no causal treatment. Patients are advised to avoid choline-rich foods and take hygienic measures.

Multisteroid LC-MS/MS assay for glucocorticoids and androgens, and its application in Addison's disease.

OBJECTIVE: Liquid chromatography-mass spectrometry (LC-MS/MS) offers superior analytical specificity compared to immunoassays, but is not available in many regions and hospital due to expensive instrumentation and tedious sample preparation. Thus, we developed an automated, high-throughput LC-MS/MS assay for simultaneous quantification of 10 endogenous and synthetic steroids targeting diseases of the hypothalamo-pituitary-adrenal-axis and gonads. METHODS: Deuterated internal standards were added to 85µl serum and processed by liquid-liquid-extraction. Cortisol, cortisone, prednisolone, prednisone, 11-deoxycortisol, dexamethasone, testosterone, androstenedione and progesterone were resolved by ultra-high pressure chromatography on a reversed-phase column in 6.1 minutes, and detected by triple-quadrupole MS. The method was used to assess steroid profiles in women with Addison's disease (AD, n=156) and blood donors (BD, n=102). RESULTS: Precisions ranged 4.5-10.1% RSD, accuracies 95-108%, and extraction recoveries 60-84%. The method was practically free of matrix effects and robust to individual differences in serum composition. Most postmenopausal AD women had extremely low androstenedione below 0.14 nmol/L and median testosterone 0.15 nmol/L [interquartile range 0.00-0.41], considerably lower than postmenopausal BD (1.28 nmol/L [0.96-1.64] and 0.65 nmol/L [0.56-1.10], respectively). AD women in fertile years had androstenedione 1.18 nmol/L [0.71-1.76] and testosterone 0.44 nmol/L [0.22-0.63], approximately half of levels found in BD of corresponding age. CONCLUSION: This LC-MS/MS assay provides highly sensitive and specific assessments of glucocorticoids and androgens with low sample volumes, and is suitable for endocrine laboratories and research. Its utility was demonstrated in a large cohort of women with AD, and the data suggest that women with AD are particularly androgen deficient after menopause.

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A-producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

[Primary adrenal failure--causes, diagnostics and therapy]. / Primaer binyrebarksvikt - årsaker, diagnostikk og behandling.

BACKGROUND AND METHODS: An overview of primary adrenal failure with emphasis on replacement therapy is presented. The article is based on a review of recent literature and authors' personal experience. RESULTS AND CONCLUSIONS: Addison's disease is usually caused by an autoimmune destruction of the adrenal cortex. It is relatively rare (prevalence 14 per 100,000 inhabitants), but often considered as a differential diagnosis when evaluating fatigue, tiredness and loss of weight. Addison's disease is treated by repletion of glucocorticoids and mineralocorticoids. The recommended starting dose is 25 mg cortisone acetate per day divided into three (12.5 + 6.25 + 6.25 mg) or two doses (12,5 mg x 2). Mineralocorticoid replacement is given as fludrocortisone 0.05 - 0.2 mg in one dose per day. Treatment with 20 - 50 mg dehydroepiandrosterone has been studied in adrenal failure, but the evidence for positive effects is weak, and it can not be recommended as standard treatment in primary adrenal failure.