Daniela Lapa

Altered intestinal absorption of L-thyroxine caused by coffee.

OBJECTIVE To report eight case histories, and in vivo and in vitro studies showing coffees potential to impair thyroxine (T4) intestinal absorption. DESIGN Of eight women with inappropriately high or nonsuppressed thyroid-stimulating hormone (TSH) when T4 was swallowed with coffee/espresso, six consented to the evaluation of their T4 intestinal absorption. This in vivo test was also administered to nine volunteers. In three separate tests, two 100 microg T4 tablets were swallowed with coffee, water, or water followed, 60 minutes later, by coffee. Serum T4 was assayed over the 4-hour period of the test. Two patients and two volunteers also agreed on having tested the intestinal absorption of T4 swallowed with solubilized dietary fibers. In the in vitro studies, classical recovery tests on known concentrations of T4 were performed in the presence of saline, coffee, or known T4 sequestrants (dietary fibers, aluminium hydroxide, and sucralfate). MAIN OUTCOME For the in vivo test, average and peak incremental rise of serum T4 (AIRST4 and PIRST4), time of maximal incremental rise of serum T4 (TMIRST4), and area under the curve (AUC) were determined. In patients and volunteers, the four outcome measures were similar in the water and water + coffee tests. In patients and volunteers, compared to water, coffee lowered AIRST4 (by 36% and 29%), PIRST4 (by 30% and 19%), and AUC (by 36% and 27%) and delayed TMIRST4 (by 38 and 43 minutes); bran was a superior interferer. In the in vitro studies, coffee was weaker than known T4 sequestrants. CONCLUSION Coffee should be added to the list of interferers of T4 intestinal absorption, and T4 to the list of compounds whose absorption is affected by coffee.

Thyroxine binding to members and non-members of the serine protease inhibitor family

Partition of T4 to plasma proteins is classically attributed only to TBGC ≈70%), transthyretin (≈15%) and albumin (≈10%), based on zone electrophoresis. Since TBG migration spans the α1 and α2 regions, and since HDL, which have α1 migration, transport ≈4% of circulating T4, other α-globulins could bind T4 and “contaminate” the TBG area. Hence, we determined the association of [125I]T4 to TBG and, for comparison, to transthyretin and albumin. Sera from 50 normolipidemic individuals were equilibrated with [125I] T4 and analyzed by both zone electrophoresis and radioimmunoprecipitation with specific antisera. Transthyretin-T4 or albumin-T4 bindings as assessed by the two methods agreed, while TBG-T4 did not, because other α-globulins carrying T4 with low affinity co-migrated with TBG. Some, but not all, of these α-globulins belong to the same superfamily of TBG and also bind steroid hormones.

A patient with stress-related onset and exacerbations of Graves disease.

Background An 18-year-old, nonsmoking woman presented to her general practitioner with a 1-week history of weakness, fatigue, palpitations, nervousness, tremors, insomnia, heat intolerance, and sudden enlargement of a thyroid goiter that had been detected 2 years earlier. The patients symptoms had started shortly after she experienced emotional stress. Diagnostic work-up disclosed an avid radioactive iodine uptake by the goiter. On ultrasound examination, the thyroid gland was enlarged with a diffusely hypoechogenic structure and intense vascularization.Investigations Thyroid scintigraphy with 131I; ultrasonography of the thyroid gland; and measurements of serum free T3, free T4, TSH levels and thyroid autoantibodies, including autoantibodies against thyroglobulin (TgAb), thyroperoxidase (TPOAb) and TSH receptor (TRAb).Diagnosis Graves disease, with stress-related onset and subsequent stress-related exacerbations.Management The patient was treated with methimazole to normalize levels of thyroid hormone and thyroid autoantibodies, and with bromazepam to help her cope with stress. The daily dose of methimazole was kept low during pregnancy. Over the 4 year period when the patient was taking methimazole, exacerbations of hyperthyroidism occurred twice: during her first pregnancy and 9 months after her first delivery. On all three occasions, symptoms were preceded by stressful life events. Further exacerbations were avoided by starting bromazepam treatment soon after the patient experienced stressful events.

Abnormalities of GH secretion in a young girl with Floating-Harbor syndrome

We present a 9.1-year-old girl of Calabrian (Italy) ancestry, with clinical features (cranio- facial dysmorphism, short stature with delayed bone age and speech delay) suggesting the diagnosis of Floating-Harbor syndrome (FHS). Physical examination showed: height 113.9 cm (−2.9 SD), with a parent’s target of 156.2 cm (+1.0 SD), weight 20.7 kg, BMI 16.0 (−0.04 SD), and many phenotypic abnormalities: long eyelashes, large bulbous nose with broad nasal bridge, short philtrum, moderately broad mouth, tooth folding and malocclusion, posteriorly rotated ears, low posterior hair line, short neck, clinodactyly of the 5th finger and hyperextensible finger joints. Diffused hyperpigmentation and hypertrichosis with sporadic pubic terminal hairs, but neither clitoromegaly nor other signs of hyperandrogenism and/or precocious puberty, were observed (T1, P1). Carpal bone evaluation showed a delayed bone age (TW2: 5–5/10, −3.6 yr) and the statural age/bone age ratio was 1.1. Other dysmorphic syndromes were excluded on the basis of clinical evidence, also evaluated by a computer-assisted search (P.O.S.S.U.M. version 3.5, 1992). Analysis of chromosome 22 by the FISH method, using specific probes Cos29 and Tuple1, excluded microdeletions in the region 22q11.2, typical of Velo-cardio-facial syndrome. In this case, we report the impairment of serum GH responsiveness (GH baseline values: 0.2–1.9 ng/ml) to the administration of oral 150 μg clonidine [peak 4.7 ng/ml, normal values (nv)>10 ng/ml] and oral 4 mg dexamethasone (8.1 ng/ml, nv>10 ng/ml). Moreover, the evaluation of spontaneous 24-h GH secretion (Carmeda AB, Stockholm, Sweden) showed low mean GH levels (1.75 ng/ml, nv>3.0 ng/ml), with a maximum sleep-related peak of 2.8 ng/ml. Serum IGF-1 values were in the low-normal range (80–176 ng/ml, nv 133–626 ng/ml). While in FHS the cranio-facial features minimize with advancement of age, the impairment of growth velocity is permanent and results in severe dwarfism. In our case, treatment with recombinant GH (0.10 U/kg/day), administered by a needle-free device, induced a dramatic increase of growth velocity, increasing the height from −2.8 to −1.9 SD after 18 months, thus indirectly confirming a role of GH deficiency in the pathogenesis of FHS dwarfism.

Re-evaluation of the thyroxine binding to human plasma lipoproteins using three techniques.

Using gel filtration chromatography (GFC), we found that human VLDL, LDL and HDL transport ≈0.03, 0.2 and 3% of plasma T4. As T4 could dissociate from carriers during GFC, we evaluated [125I]T4 transport to lipoproteins (Lp) in 50 normolipidemic and euthyroid subjects by GFC and 2 independent methods: zone electrophoresis (ZE) and radioimmunoprecipitation (RIP). At GFC, VLDL+LDL transported less T4 (≈0.3%) than either ZE (≈1.3%) or RIP (≈1.5–2.0%). In contrast, GFC values for the HDL (≈3%) were close to the RIP values (≈3.5%), but lower than ZE (≈8.5%) because of partial co-migration with TBG. In conclusion, GFC underestimates T4 binding to VLDL and LDL, which, indeed, is of the same magnitude as binding of some steroid hormones to CBG and SHBG. Hence, the anti-atherosclerotic effects of T4 resulting from binding to the LDL should be greater than anticipated based on GFC data.

Certain HLA alleles are associated with stress-triggered Graves’ disease and influence its course

There are no studies on HLA analysis in patients in whom Graves’ disease (GD) hyperthyroidism has been preceded by ≥1 stressful event. The aim of the present study was to identify predisposing or protecting HLA alleles and their effects on the course of GD in this subset of patients. We performed serological HLA typing in 58 Caucasian patients with stress-related GD and in 130 matched healthy controls (HC). We also performed genomic HLA typing in 20/58 patients and in all HC. Five HLA alleles and three loci were more frequent in patients compared to HC: B8, Cw7, C*07, C*17, DR3, DR4, DRB1*04, and DQ2. In contrast, B14 was less frequent in patients than in HC. Depending on outcome after ATD withdrawal (remission, exacerbation on-ATD, relapse off-ATD), in patients, some alleles/loci were over-represented, while others were under-represented. Age, FT3, and FT4 fold increase over the upper normal limit at onset were different depending on the allele/locus carried. In GD patients with stress-triggered hyperthyroidism, HLA typing may be helpful in predicting the outcome of the disease after ATD withdrawal.

Germline mutation of von Hippel-Lindau (VHL) gene 695 G>A (R161Q) in a patient with a peculiar phenotype with type 2C VHL syndrome.

Abstract:  Von Hippel–Lindau (VHL) disease is an autosomal dominant familial neoplastic disorder with an estimated birth incidence of approximately 1:36000 live. VHL has intrafamilial variability expression and it is characterized by the predisposition to develop hemangioblastomas of the central nervous system and retina, pheochromocytomas, clear‐cell renal carcinoma, adenomas, and carcinomas of the pancreas, paragangliomas, renal and pancreatic cysts, papillary cystadenomas of the epididymis and, rarely, cystadenomas of the endolymphatic sac tumor and broad ligament. We describe a Sicilian girl with type 2C VHL who showed the apparently de novo mutation R161Q in association with an extra‐axial supratentorial frontal meningioma, which can be included as a characteristic sign in VHL.