Refik Tanakol

Sunlight exposure and vitamin D deficiency in Turkish women.

Vitamin D is an essential steroid involved in bone metabolism, cell growth, differentiation, and regulation of the minerals in the body. The main sources of this vital vitamin are adequate diet and photosynthesis in the skin. The aim of this study was to investigate the efficiency of vitamin D synthesis in 48 premenopausal women (14–44 years) in relation to three different types of dressing in summer. Women in the first group (Group I) dressed in a style which exposed the usual areas of the skin to sunlight; women in the second group (Group II wore traditional clothing with the skin of the hands and face uncovered, while the third group (Group III) dressed in traditional Islamic style, covering the whole body including hands and face. Serum 25OHD levels of Group I, Group II, and Group III were 56±41.3 nmol/l, 31.9±24.4 nmol/l, 9±5.7 nmol/l, respectively (Group I vs Group Ill, p<0.001; Group II vs Group III, p<0,03; Group I vs Group II, p>0.05). Vitamin D levels were low in 44 percent of the Group I and 60% of the Group II, which suggested that sun exposure of skin areas of hands and face may partially provide vitamin D synthesis, but may not be enough to eliminate vitamin D deficiency. All the patients in group III had vitamin D levels below normal. This study emphasizes the necessity of vitamin D fortification of food even in a sunny country where some people may not be exposed to sunlight because of inappropriate clothing or an indoor-life.

Two novel GALNT3 mutations in familial tumoral calcinosis.

Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin‐like glycosyltransferase GalNAc transferase‐3 (GALNT3) and the phosphaturic hormone fibroblast growth factor‐23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low‐normal serum concentrations of intact biologically active FGF23 and high levels of C‐terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.

Effects of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women in short term

OBJECTIVE Fibroblast growth factor 23 (FGF23), a phosphatonin, inhibits renal phosphate reabsorption and suppresses 1-α hydroxylase activity. Calcitriol stimulates FGF23 synthesis in bone. We aimed to determine the effect of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women and to compare the FGF23 concentrations of vitamin D-deficient patients with healthy subjects and patients with genetically determined hypophosphatemic rachitis. DESIGN AND METHODS The study group was composed of vitamin D-deficient females (n=18, mean age 29.1 ± 9.9 years), vitamin D-sufficient healthy females (control group; n=19, mean age 28.5 ± 5.2 years), and patients with genetically determined hypophosphatemic rachitis (n=13, mean age 26.5 ± 15.1 years). The groups were compared for serum FGF23, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), calcium, phosphate, bone turnover markers, intact parathyroid hormone (PTH), and urinary excretion of calcium and phosphate. The vitamin D-deficient group was re-evaluated after a standard treatment regimen. RESULTS Serum FGF23 concentrations were significantly lower in vitamin D-deficient patients than in vitamin D-sufficient women and hypophosphatemic rachitis group. Serum FGF23 and phosphate concentrations further decreased significantly during replacement of vitamin D (P<0.05). A significant negative correlation was evident between FGF23 and PTH before vitamin D replacement in the patients (r=-0.469, P<0.05). CONCLUSION Decreased FGF23 concentrations, which further decline during vitamin D replacement therapy, may have favorable action on bone mineralization by counterregulatory effect on phosphate homeostasis. Lower 1,25(OH)2D concentrations at baseline and hypophosphatemia during treatment may have dominating effects on FGF23 concentrations in vitamin D deficiency, leading to decreased FGF23 concentrations at baseline and during replacement therapy.

Vitamin D receptor alleles, bone mineral density and turnover in postmenopausal osteoporotic and healthy women.

Objective: Vitamin D receptor (VDR) gene polymorphisms and bone metabolic markers were investigated as potential genetic markers for osteoporosis in postmenopausal Turkish women. The relationship between their VDR gene polymorphisms and bone states was determined. Materials and Methods: Restriction fragment length polymorphisms at the VDR gene locus (i.e., for BsmI, ApaI, and TaqI) was investigated in 75 postmenopausal osteoporotic (53.16 ± 1.31 years) and 66 healthy (52.62 ± 1.69 years) Turkish women and the genotypes were related to bone mineral density (BMD) at femoral neck (FN), lumbar spine (L1–4), trochanter, Ward’s triangle (Ward’s) and metabolic parameters of bone turnover. Results: In osteoporotic women, TaqI genotype-related differences of the VDR gene were found to be significant at all BMD sites; TT genotype had higher L1–4 BMD values than Tt and tt (p < 0.05); tt genotype had significantly lower BMD at FN (p < 0.05), trochanter (p < 0.01), and Ward’s (p < 0.05) compared to TT genotype. The tt genotype was found to be associated with higher (p < 0.05) serum osteocalcin levels compared to Tt and TT genotypes in the osteoporotic women, whereas no such association was found for the healthy women. Conclusion: Our data showed an association between VDR TaqI genotype and BMD at the FN, L1–4, trochanter and Ward’s triangle in nonobese postmenopausal osteoporotic women. Thus the VDR gene Taql polymorphism modulates differences in BMD in the postmenopausal osteoporotic women.

Cyproheptadine treatment in Cushing’s disease

Cyproheptadine, a nonselective 5-hydroxytryptamine receptor blocking agent, reduces ACTH and ß-endorphin secretion from the ACTH-producing tumors. A 35-year-old female suffering from Cushing’s disease due to microadenoma of the pituitary gland has been followed since the age of 15. Subtotal adrenalectomy followed by total adrenalectomy, pituitary irradiation, and transsphenoidal hypophysectomy, combined with second radiotherapy of the pituitary, were unsuccessful in achieving remission of the disease. Remission was achieved with cyproheptadine up to a dosage of 24 mg/day. Every attempt to discontinue cyproheptadine treatment was accompanied by recurrence of the disease. This is the first case of Cushing’s disease in which cyproheptadine treatment has been the only efficacious therapy for a period of 11 yr. Cyproheptadine may be an alternative long-term therapy for Cushing’s disease when other methods of treatment fail.

Lymphocytic panhypophysitis in a young man with involvement of the cavernous sinus and clivus

Lymphocytic hypophysitis is an unusual inflammatory lesion that is caused by autoimmune destruction of the pituitary gland. We report a case of 42-year-old man who presented with a 6-month history of severe headache, blurred vision in the right eye, hearing loss, polyuria, polydipsia, and impotence. Medical history showed that he and his mother had osteopetrosis. The results of the physical examination and laboratory tests showed that secondary hypothyroidism, hypogonadism, and hypocortisolism had developed. Central diabetes insipidus was diagnosed by water deprivation test. MRI of the sella showed pituitary enlargement with symmetrical suprasellar expansion, compression of the chiasma, thickened infundibulum, and involvement of both bilateral cavernous sinuses and clivus. Hormonal substitution with hydrocortisone, levothyroxine, and DDAVP resulted in rapid improvement of all symptoms and signs. Transsphenoidal biopsy was diagnostic of lymphocytic hypophysitis. In spite of extensive literature reviewing, we have not been aware of any case of lymphocytic hypophysitis with clivus involvement. The present case represents a variant of lymphocytic hypophysitis which has progressed to involve bilateral cavernous sinuses and the clivus.

Interleukin-6-producing pheochromocytoma presenting with fever of unknown origin

Pheochromocytoma usually presents with typical signsand symptoms, such as headache, sweating, and palpita-tions due to excessive catecholamine release. Few publica-tions have reported that these tumors are capable ofsecreting a variety of bioactive neuropeptides and hormonesother than catecholamines, resulting in unusual clinicalmanifestations.

Acute renal failure associated with nonfulminant hepatitis A virus infection.

Hepatitis A is usually a mild self-limiting infection of the liver. Nonfulminant acute renal failure very rarely complicates type A viral hepatitis. An unusual case, a 32-year-old female with serologically proven acute hepatitis A infection, was complicated by acute renal failure and the patient in this study is the first case associated with Cushings disease. She recovered, and the laboratory tests returned normal one month after initial hospitalization. Although the mechanism responsible for renal failure in acute hepatitis A virus infection is still uncertain, possible causes are discussed with the review of literature.

Polymorphisms at the Ligand Binding Site of the Vitamin D Receptor Gene and Osteomalacia

Vitamin D receptor (VDR) gene polymorphisms have been suggested as possible determinants of bone mineral density (BMD) and calcium metabolism. In this study, our aim was to determine whether there is an association between VDR gene polymorphism and osteomalacia or not. We determined ApaI and TaqI polymorphisms in the vitamin D receptor gene in 24 patients with osteomalacia and 25 age-matched healthy controls. Serum calcium, phosphorus, ALP, PTH, 25OHD levels were also examined. We used PCR and RFLP methods to test for an association between osteomalacia and polymorphisms within, intron 8 and exon 9 of the VDR gene. When the control and patients were compared for their ApaI and TaqI genotypes there was no relationship between VDR gene allelic polymorphisms and osteomalacia. Whereas a nearly significant difference for A allele was found in the allellic distribution of the patients (p = 0.08). Also no association between biochemical data and VDR gene polymorphisms was observed.

Lack of association between vitamin D receptor gene polymorphism (BsmI) and osteomalacia

Vitamin D receptor (VDR) gene polymorphism has been reported to be a determinant of bone formation and intestinal calcium absorption. We carried out this study to assess the role of VDR gene polymorphism in the pathogenesis of osteomalacia. We investigated BsmI polymorphisms in the gene encoding the 1,25 dihydroxyvitamin D receptor in 38 patients with osteomalacia and 31 healthy controls, along with examination of serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25 hydroxyvitamin D levels. VDR allelic variants were: BB, 31.6%; Bb, 44.7%; and bb, 23.7% in the osteomalacia patients and BB, 19.4%; Bb, 61.3%; and bb, 19.4% in the controls. Although heterozygotes (Bb) were more frequent than other genotypes in both groups, the BB genotype was found to be more prevalent in osteomalacia than in controls. There was no statistical relationship between VDR genotype and osteomalacia. It is concluded that, in this small group of patients, there was no relationship between VDR allelic polymorphisms and osteomalacia.