Genetics of autoimmune thyroid disease in the Lebanese population.

This study aims to investigate the association of human leukocyte antigen (HLA) class II genes and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with autoimmune thyroid diseases in the Lebanese population. A total of 128 patients with autoimmune thyroid disease (55 with Graves' disease (GD) and 73 with Hashimoto's thyroiditis (HT)) were typed for HLA DQA1 (0301 and 0501) and DQB1 (0201, 0302, and 0303) and for 49A/G CTLA-4 using PCR-based sequence-specific priming methods. A total of 186 matched controls were typed for the same alleles and compared to the diseased population. Results showed no significant differences in HLA DQB1*0201 or DQB1*0301 allelic frequencies or CTLA-4 polymorphisms between patients and controls. For GD, there was a weak association with HLA DQB1*0302 [34.6% (19 of 55) vs. 21.5% (40 of 186), P = 0.048, odds ratio (OR) = 1.926, confidence interval (CI) = 0.999-3.715] and HLA DQB1*0302-DQA1*0501 haplotype [56.36% (31 of 55) vs. 40.8% (76 of 186), P = 0.042, OR = 1.870, CI = 1.018-3.433]. For HT, the frequencies of DQB1*0302-DQA1*0501 haplotype [28.8% (21of 73) vs. 14.5% (27 of 186), P = 0.008, OR = 2.378, CI = 1.241-4.558] and DQB1*0302-DQA1*0301 haplotype [60.2% (44 of 73) vs. 38.7% (72 of 186), P = 0.002, OR = 2.402, CI = 1.381-4.180] were significantly higher in patients. On the other hand, weak association was found between HT and DQA1*0301 allele [32.9% (24 of 73) vs. 20.9% (39 of 186), P = 0.044, OR = 1.846, CI = 1.011-3.373]. Findings show that DQB1*0302-DQA1*0501 and DQB1*0302-DQA1*0301 haplotypes may play a role in the pathogenesis of HT in the Lebanese population. For the 49A/G CTLA-4 polymorphism, no significant difference was found between patients and controls.

Serum uric acid in relation with the metabolic syndrome components and adiponectin levels in Lebanese University students.

BACKGROUND: The relation between serum uric acid (SUA) and metabolic syndrome (MetS) parameters has never been studied in a young Middle-Eastern population. In addition, the relation between SUA and adiponectin was poorly studied. METHODS: We looked at the relation between SUA, and both adiponectin and MetS components in 381 randomly selected Lebanese university students (201 males and 180 females). RESULTS: SUA was positively correlated with body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), fasting blood glucose (FPG), triglycerides, total and LDL-cholesterol, and homeostasis model assessment (HOMA) index (p<0.001 for all variables, p<0.01 for FPG) and inversely correlated with HDL-cholesterol and adiponectin (p<0.001 for both variables). In men, SUA was positively correlated with BMI, WC, SBP, DBP, FPG, triglycerides, total and LDL-cholesterol, and HOMA index and inversely correlated with adiponectin (p<0.001 for all variables, p<0.05 for adiponectin); these correlations persisted after BMI adjustment, for WC, FPG, triglycerides, total-cholesterol, LDL-cholesterol, and HOMA index. In women, SUA was positively correlated with total and LDL-cholesterol (p<0.001), independently of BMI. In a multiple regression analysis, SUA was independently associated with WC, triglycerides, total cholesterol, HDLcholesterol and adiponectin in the overall population while, in men, it was associated with triglycerides, total-cholesterol, and WC. CONCLUSION: Our results suggest, in young adults, a gender difference in the relation between SUA and both adiponectin and MetS parameters. In addition, we observed in both genders a strong relation of SUA with total cholesterol. Further studies are needed in larger populations in order to elucidate these findings.

Predictors of intra-operative parathyroid hormone decline in subjects operated for primary hyperparathyroidism by minimally invasive parathyroidectomy.

BACKGROUND: The predictors of intra-operative PTH (IOPTH) decline during minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism have been but poorly studied. MATERIALS AND METHODS: This retrospective study included 108 patients who underwent MIP for a single adenoma. Serum calcium and phosphorus were measured before surgery and 1 day post-operatively. IOPTH was measured before (intra-operative preincision or PTHt0) and 10 min after removal of the adenoma (PTHt10). The Modification of Diet in Renal Disease (MDRD) equation was used to estimate the glomerular filtration rate. The weight of the adenoma was assessed in all the subjects. RESULTS: The sex ratio female/male was 5.37 with a mean age of 57.3 yr. The mean pre- and postoperative values were for calcium 2.80 and 2.19 mmol/l, respectively (p<0.0001) and for phosphorus 0.90 and 1.16 mmol/l, respectively (p<0.0001). The PTH dropped from a mean value of 184.8 to 50.8 pg/ml 10 min after adenoma resection with a mean drop of 69.7%. Thirteen patients (12%) did not achieve a PTH fall of more than 50%. In a bivariate analysis, age, an MDRD<60 ml/min and weight of adenoma were inversely associated with IOPTH fall (p=0.009, p=0.004, and p<0.001, respectively) while gender, body mass index, hypertension, diabetes, pre-operative phosphorus and calcium had no significant effects. In the multivariate analysis, age, weight of adenoma, and MDRD were still independent negative predictors of the IOPTH fall (p=0.01, p=0.018, and p<0.001, respectively). CONCLUSION: Our results suggest that during MIP the presence of a parathyroid adenoma with a high weight, in an elderly subject or in a subject with altered renal function, will result in a lesser degree of IOPTH fall.

[Spasmodic laughter syncope. An unusual complication of pseudobulbar palsy]. / Syncope du rire spasmodique. Une complication inhabituelle du syndrome pseudobulbaire.

INTRODUCTION: Spasmodic laughter is a classical sign of pseudobulbar palsy, but it has never been reported, to our knowledge, to provoke syncope. CASE REPORT: A 63-year-old hypertensive and diabetic man with peripheral neuropathy and lacunar pseudobulbar palsy presented with three episodes of spasmodic laughter which had induced syncope. No new episode was observed after the beginning of low dose bisoprolol. DISCUSSION: Sustained or spasmodic laughter is accompanied by repetitive bursts of forced expiration, corresponding to short repetitive Valsalva maneuvers. Laughter-induced syncope is considered as one of the many Valsalva-type/vagally mediated syncopal attacks leading to rapid fall in blood pressure without compensatory tachycardia. The presence of autonomic diabetic neuropathy may also contribute to these attacks.

Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population.

Wolfram syndrome (WFS) is a rare hereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). WFS seems to be a heterogeneous disease that has not yet been fully characterized in terms of clinical features and pathophysiological mechanisms because the number of patients in most series was small. In this study we describe 31 Lebanese WFS patients belonging to 17 families; this, to our knowledge, is the largest number of patients reported in one series so far. Criteria for diagnosis of WFS were the presence of insulin-dependent diabetes mellitus and optic atrophy unexplained by any other disease. Central diabetes insipidus was found in 87% of the patients, and sensorineural deafness confirmed by audiograms was present in 64.5%. Other less frequent features included neurological and psychiatric abnormalities, urodynamic abnormalities, limited joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotropic hypogonadism in males, and diabetic microvascular disease. New features, not reported in previous descriptions, such as heart malformations and anterior pituitary dysfunction, were recognized in some of the patients and participated in the morbidity and mortality of the disease. Genetic analysis revealed WFS1 gene mutations in three families (23.5%), whereas no abnormalities were detected in mitochondrial DNA. In conclusion, WFS is a devastating disease for the patients and their families. More information about WFS will lead to a better understanding of this disease and hopefully to improvement in means of its prevention and treatment.

Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy post-menopausal women.

In vitro studies have shown that 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] decreases cytokine production by monocytes and lymphocytes. In addition, intravenous or oral pulse calcitriol treatment suppresses interleukin 6 (IL6) and interleukin1beta (IL1beta) in hemodialysis patients. We studied the effect of a daily 12-week course of 1000 mg calcium and 800 U cholecalciferol on circulating 25 hydroxyvitamin D [25(OH)D], PTH, cytokines, osteoprotegerin (OPG), C-reactive protein (CRP), bone markers, lipid parameters and insulin levels in 47 healthy post-menopausal women. Thirty-nine women completed the study. A significant increase in 25(OH)D and a significant decrease in PTH were observed (p=0.0043 and p<0.0001, respectively). In addition, alkaline phosphatase, osteocalcin and, to a lesser extent, urinary free deoxypiridinoline (DPD) decreased significantly (p<0.0001, p=0.0002 and p=0.026, respectively). No change in circulating IL6, tumor necrosis factor alpha (TNFalpha), CRP, OPG, triglycerides, LDL- and HDL-cholesterol, and insulin levels was observed. Correlation studies in the 47 women enrolled in the study revealed inverse significant correlations between OPG on one side and body mass index, LDL-cholesterol, IL6, CRP and insulin levels on the other (p=0.002, p=0.002, p=0.004, p=0.023 and p=0.0001). Also, IL6 was significantly correlated with insulin levels (p=0.0005). In a multivariate model, both insulin and LDL-cholesterol were independently associated with OPG, while only insulin was independently associated with IL6. Our results showed no effect of a short-term calcium-vitamin D treatment on circulating cytokines, CRP, insulin levels and lipid parameters. This could be related to the low circulating cytokine concentrations in healthy subjects or to the short duration of treatment. The interesting association we found between OPG and some cardiovascular risk markers deserves further investigation.

Host and environmental factors defining the epidemiology of type 1 diabetes mellitus in a group of Lebanese children and young adults.

The effect of a number of host and environmental factors on the onset of type 1 diabetes mellitus (DM1) in a group of Lebanese children and young adults was studied. Results showed that DM1 in a group of 253 patients presented no gender preference and that the age of onset was similar in both genders. The overall body mass index reflected good metabolic control. HbA1c had a mean value of 8.98%, suggesting poor glucose control. Family history of DM1 and type 2 diabetes mellitus as well as consanguinity in patients' families were not different from those reported in the literature. Finally, onset of DM1 showed seasonal variation, peaking during winter months. DM1 showed a higher prevalence of onset among children born first and a decreased incidence as birth order increased. This study provides valuable data for the diagnosis, control and prevention of DM1 in children.

Type-2 diabetes family history delays the onset of type-1 diabetes.

Type-1 diabetes (T1D) is an autoimmune disease leading to insulin deficiency. Its occurrence is influenced by genetic and environmental factors. The human leukocyte antigen (HLA) region on chromosome 6 accounts for 45% of the genetic susceptibility for the disease, mainly the HLA-DQB1*0201 and HLA-DQB1*0302 alleles. Among the environmental factors involved, early exposure to cow's milk seems to be a trigger. In this study, we investigated the occurrence of T1D in 253 Lebanese Caucasian patients, in relation to HLA-DQB1*0201, HLA-DQB1*0302, HLA-DQB1*0602, gender, and early exposure to cow's milk, as well as to family history of T1D and type-2 diabetes (T2D). Our genetic analysis results show that in the patients studied, 77% and 40% were positive for BQ1*0201 and BQ1*0302, respectively. As for BQ1*0602, only 0.8% of patients were positive for this T1D protective allele, compared with 24% among the controls. Furthermore, our results did not show any gender preference of the disease or any effects of early intake of cow's milk on the age at onset of T1D. When family history of T2D or T1D was studied, our results show a novel finding whereby an immediate family history of T2D, but not T1D, delays the age at onset of T1D.

Malignant struma ovarii: an unusual presentation.

Malignant struma ovarii is a rare disease; only a few cases are well documented in the literature. Thus, the overall prognosis and modalities of treatment are still somewhat controversial. In this article, the authors report a case of malignant struma ovarii discovered 4 years after ovariectomy after metastasis to the lungs and bones. Review of the pathology of the ovarian struma did not reveal the classic criteria of malignancy, there were, however, many features considered to be atypical and thus suspicious. The patient was treated by total thyroidectomy followed by repetitive doses of 131I. However, because of difficulties in increasing the level of endogenous thyrotropin (TSH) because of functional thyroid metastases in such an advanced disease, recombinant human thyrotropin (rhTSH; Thyrogen, thyrotropin alpha, Genzyme Corporation, Cambridge, MA) was used before administration of radioiodine. With this therapeutic protocol, the patient is still clinically stable 2 years after diagnosis.

[Hypovitaminosis D: a major worldwide public health problem]. / L'hypovitaminose D, problème mondial majeur de santé publique.

PHYSIOLOGY: Vitamin D increases intestinal absorption of calcium favoring the microenvironment necessary for bone mineralization. In addition, vitamin D prevents hypocalcemia via its osteoclastic action. Severe hypovitaminosis leads to rickets in children and its equivalent in adults, osteomalacia. Mild to moderate hypovitaminosis D causes secondary hyperparathyroidism increasing the risk of fracture, particularly femoral neck fracture. Vitamin D would also have an antiinflammatory and anticancer effect. WORLDWIDE: Hypovitaminosis D is frequently observed in Europe in the elderly, particularly in the institutionalized population, but is also seen in otherwise healthy younger adults. An estimated 40% of the young European population has some degree of hypovitaminosis D. Surprisingly, it is more frequent in sunny Mediterranean countries than in certain northern countries such as Norway. The lower incidence observed in the United States is probably related to the vitamin D supplementation of the American diet. Hypovitaminosis D in Africa and the Middle-East is also an important problem, being considered to be one of the 5 most prevalent childhood diseases in developing countries. ENVIRONMENTAL FACTORS: The limited quantity of vitamin D in food and multiple environmental factors contribute to hypovitaminosis D. These factors include insufficient sun exposure and urban lifestyle with a high degree of pollution. In addition, cutaneous photosynthesis of vitamin D is limited by hyperpigmentation in black people, wearing traditional veils that limit sun exposure, and use of sun lotions, further contributing to vitamin D deficiency. CONCLUSIONS AND RECOMMENDATIONS: The very high prevalence of hypovitaminosis D in the world, and particularly in Europe, Africa and the Middle-East, points to the need for public health measures in these countries. While waiting for these measures to be implemented, vitamin D supplementation (for example in tablet form) should be encouraged in order to meet minimum requirements. Finally, the beneficial effect of moderate sun exposure on cutaneous vitamin D synthesis (and psychological well-being) must not be overlooked.

Mutational analysis in Lebanese patients with congenital adrenal hyperplasia due to a deficit in 21-hydroxylase.

Molecular defects in the gene encoding steroid 21-hydroxylase (CYP21) result in impairment of adrenal steroid synthesis in patients affected with autosomal-recessive congenital adrenal hyperplasias (CAH). In this study, we report on the molecular screening of six point mutations, large deletions, gene conversion events and duplications in 25 unrelated Lebanese families affected by CAH due to steroid 21-hydroxylase. The methods used (PCR-digestion and southern blot) allowed the detection of 96% of the disease chromosomes. In classical forms, the most frequent mutation was the splice site mutation in intron 2 accounting for 39% of the disease alleles. Gene conversion events accounted for 14% of the alleles, but no large deletions were found. In nonclassical forms, the V281L mutation in exon 7 represent 86% of the tested alleles. Genotype-phenotype correlations were as expected: Delta 8nt, Q318X and gene conversion correspond to SW forms, whereas the intron 2 splice site mutation may give either SW or SV forms; the V281L mutation was responsible for nonclassical forms. The spectrum of mutations underlines the genetic diversity of the Lebanese population. No correlation could be drawn out between mutations and some specific religious communities, except for the Delta 8nt mutation, which is present only in the Christian Maronite group. Molecular study of the CYP21 gene might constitute a good support for clinicians, especially in consanguineous families, for whom we could provide genetic counselling.

Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers.

Hypovitaminosis D is associated with poor dietary intake and inadequate sunshine exposure. It is common worldwide, particularly in European elderly people. Information about vitamin D status in young adult populations from the Middle East is scarce. Furthermore, the relationship between hypovitaminosis D and some lifestyle factors such as style of clothing and dwelling location is not well defined. We assessed vitamin D intake and measured serum calcium, phosphorus, albumin, alkaline phosphatase, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary-free deoxypyridinoline (DPD) in 316 Lebanese volunteers (99 men and 217 women) aged 30-50 years; 156 were recruited from rural areas and 160 from urban areas. Fifty-one women from each area were veiled. The average daily vitamin D intake was 100.3 +/- 67.9 IU and was found to be higher in men compared with women, in urban subjects compared with rural ones and in nonveiled women compared with veiled ones. The mean level of 25(OH)D was 9.71 +/- 7.07 ng/ml. Hypovitaminosis D [25(OH)D < 12 ng/ml] affected 72.8% of our population. It was more common in women than in men (83.9% vs. 48.5%). Severe hypovitaminosis D [25(OH)D < 5 ng/ml] was observed in 30.7% of our subjects and was more prevalent in women (41.5%), particularly in the veiled ones (61.8%). 25(OH)D levels were the lowest in veiled women, and in women living in rural areas. Rural men had the highest 25(OH)D levels despite their very low vitamin D intake. In a multivariate model, inadequate vitamin D intake, urban dwelling, veil wearing, and high parity in women were independent predictors of hypovitaminosis D. 25(OH)D was related inversely to PTH and free DPD whereas osteocalcin achieved only a weak positive correlation with 25(OH)D. In the absence of information regarding time spent outdoors, our results show that hypovitaminosis D is common among young Lebanese people and is related mostly to low vitamin D intake. This should emphasize the need for more vitamin D in our population.

[Endocrinologic recovery after treatment of an intrasellar aneurysm]. / Récupération endocrinienne après cure d'un anévrisme intrasellaire.

OBJECTIVE: Cavernous intrasellar aneurysms are rare, but may be clinically mistaken for an hypophyseal tumor, thus the need for a preoperative diagnosis. CLINICAL PRESENTATION: We report on a 60-year-old woman suffering from retroorbital headache, diplopia and decreased visual acuity, along with hyperprolactinemia and both gonadotropic and thyreotropic deficencies. Computed tomography revealed a sellar mass with superior extension, but MR raised the possibility of a cavernous aneurysm, that was confirmed by arteriography, avoiding a disastrous transsphenoidal surgery. DISCUSSION: Intracavernous aneurysms are known having a benign course, but serious meningeal hemorrhage can occur in 1.4% of cases and carotid-cavernous fistulae in 8% of patients, warranting treatment. Medial development is rare and may be responsible for endocrinologic manifestations. Neurosurgical approach remains hazardous, and endovascular occlusion represents the method of choice. CONCLUSION: Intracavernous aneurysm must be taken into consideration in the differential diagnosis of pituitary masses because it has a completely different management.

[A rare manifestation of hypothyroidism: intestinal obstruction. Report of 2 cases and review of the literature]. / Manifestation rare de l'hypothyroïdie: l'occlusion intestinale. Rapport de deux cas et revue de la littérature.

Gastrointestinal manifestations of hypothyroidism are unfrequent. They consist particularly in hypomotility, intestinal atony, and pseudoobstruction. A high index of suspicion must exist, especially in elder subjects, in order to avoid unnecessary and even harmful investigation and intervention. We are reporting two cases of intestinal occlusion due to hypothyroidism with review of the literature.

[Blood and leukocyte glutathione and glutathione S-transferase: relationship to cholesterolemia in healthy volunteers]. / Glutathion et glutathion S-transférase sanguins et leucocytaires: relation avec la cholestérolémie chez des volontaires sains.

Hypercholesterolemia increases the oxidation of low density lipoprotein (LDL) which subsequently leads to atherogenesis. The oxidized LDL are also known to increase in vitro macrophage synthesis of glutathione. The purpose of this study was to investigate the relationship between lipid parameters and the glutathione system (glutathione, glutathione S-transferase) in total blood and within leukocytes. The glutathione and glutathione S-transferase were evaluated by spectrophotometric methods in sixty-two healthy volunteers (32 women, 30 men, mean age 39.9 +/- 7.7). No correlation was found between the level of blood cholesterol and the values of the blood glutathione system. However, a positive correlation between the values of glutathione and glutathione S-transferase in leukocytes and the blood cholesterol level was only found in women (r = 0.55 and r = 0.50 respectively, p < 0.01). We also found in men a positive correlation between body mass index and glutathione S-transferase in total blood and within leukocytes (r = 0.38, p < 0.05, r = 0.5, p < 0.01 respectively). No correlation was found between age, smoking and the values of the glutathione system. Our results suggest that the glutathione system in leukocytes is related to blood cholesterol levels. The fact that this positive correlation was only observed in women points to a possible role of estrogens in the regulation of the glutathione system which merits to be further studied.

[Extrapontine myelinolysis: treatment with TRH]. / Myélinolyse extra-pontine: traitement par T.R.H.

Central pontine and extra-pontine myelinolysis are a well known complication of hyponatremia. Other causes may be present. We report a case of head injury in a 13 year-old girl, who recovered well after surgery for extra-dural hematoma, but presented endocrinological disorders with hyperglycemia followed by a severe hyponatremia. Despite the correction of these metabolic disorders, the patient became comatose, and MRI, on T2 weighted image, showed hyperintense signals in the basal ganglia consistent with extra-pontine myelinolysis. The patient's state remained unchanged for six weeks. Since S. Konno and H. Wakui published cases of myelinolysis who dramatically improved after TRH treatment, the patient was given 0.6 mg i.v daily of TRH for six weeks. Improvement began within a few days, and continued until complete recovery.

[Laparoscopic adrenalectomy for pheochromocytoma. Case report and review of the literature]. / Surrénalectomie coelioscopique pour phéochromocytome. Rapport d'un cas et revue de la littérature.

Laparoscopic surgery has a wide application in general surgery. Since the first laparoscopic adrenalectomy, this approach has quickly been adopted, and increasing numbers are being reported. The small size of the adrenal gland, the benign nature of most adrenal tumors and the difficulty in reaching the organ via open means make resection of this gland particularly amenable to the laparoscopic approach. The potential benefits of this mini-invasive surgery include decreased operation blood loss, reduced narcotics requirements, shorter hospital stay and recovery time and minimize the parietal trauma. We report herein the first Lebanese case of laparoscopic adrenalectomy for pheochromocytoma with review of the literature.