Ali S. Alzahrani

Epidemiology, Clinical and Complications Profile of Diabetes in Saudi Arabia: A Review

Diabetes mellitus is emerging as a major public health probelm in Saudi Arabia in parallel with the worldwide diabetes pandemic, which is having a particular impact upon the Middle East and the third world. This pandemic has accompanied the adoption of a modern lifestyle and the abandonment of a traditional lifestyle, with a resultant increase in rates of obesity and other chronic non-communicable diseases. The indigenous Saudi population seems to have a special genetic predisposition to develop type 2 diabetes, which is further amplified by a rise in obesity rates, a high rate of consanguinity and the presence of other variables of the insulin resistance syndrome. We highlight the epidemiology, clinical and complications profiles of diabetes in Saudi people. Diabetes is well studied in Saudi Arabia; however, there seems to be little research in the area of education and health care delivery. This is of paramount importance to offset the perceived impact on health care delivery services, to lessen chronic diabetes complications, and to reduce the expected morbidity and mortality from diabetes.

Long-term course and predictive factors of elevated serum thyroglobulin and negative diagnostic radioiodine whole body scan in differentiated thyroid cancer

Following the initial management, some patients with differentiated thyroid cancer (DTC) develop a state of high thyroglobulin (Tg) and negative diagnostic radioactive iodine (RAI) whole body scan (DxWBS). The predisposing factors and outcome of this condition are unclear. In this study, our objectives were to determine the predictive factors for the development of high Tg and negative DxWBS (Tg+/scan-) and to study the long-term course of the disease in patients with this condition. Methods: We, retrospectively, reviewed the medical records of a cohort of 105 non-selected DTC patients (26 males and 79 females; median age 37.7 yr, range 7–72). None of these patients had positive Tg antibodies or distant metastases. All Tg levels were obtained off thyroid hormone therapy. At the first follow-up visit after RAI ablation (13±7.6 months), patients were classified into those with low Tg (<2 ng/ml off L-T4) and negative DxWBS (control group) and those with high Tg (≥2 ng/ ml off L-T4) and negative DxWBS (Tg+/scan-group). Using univariate and multivariate logistic regression analyses, we evaluated a number of parameters (see results) for their association with the development of Tg+/scan-. In addition, the long-term course of the disease in Tg+/scan-group was analyzed. Results: In univariate analysis, the following factors were found to be significantly associated with Tg+/scan-: perithyroidal tumor extension (p=0.025), soft tissue invasion (p=0.001), cervical lymph node metastases (p=0.014) and Tg level before RAI ablation (p=0.015). In multivariate analysis, only soft tissue invasion remained significantly associated with Tg+/scan-[p 0.001, odds ratio, 15.6 (95% CI, 2.96–82.06)]. Age, sex, duration of goiter before surgery, pressure symptoms, tumor size, tumor multifocality, lymph nodedissection at initial surgery, tumor-node-metastasis (TNM) stage, and RAI ablative dose were not associated with Tg+/ scan-. In 53 patients with Tg+/scan-, 42 cases were followed without any therapeutic intervention; over a median follow-up of 71.6 months (range, 13–144.7), 31 cases had a spontaneous remission and 11 cases continued to have a persistent disease (Tg ≥2 ng/ml, negative DxWBS, and no palpable disease or distant metastases); Tg declined from 9.32±9.91 ng/ml at first visit after RAI ablation to 1.59±5.39 ng/ml at last visit (p<0.0001). In the other 11 cases of Tg+/scan-group, one or more therapeutic interventions (RAI, surgery, or external radiotherapy) were undertaken. Over a median follow-up of 98.4 months (range, 6–147), Tg decreased from 110.2±147.5 to 23.5±41.2 ng/ml (p 0.026); 4 cases achieved remission, 5 cases continued to have persistent disease, and 2 cases had progression of their disease, which led to their death. Conclusion: Soft tissue invasion on original surgery strongly predicts the development of Tg+/scan- in DTC patients. The long-term course of the disease is mostly favorable especially when the Tg level is only modestly elevated.

Impact of cervical lymph node dissection on serum TG and the course of disease in TG-positive, radioactive iodine whole body scan-negative recurrent/persistent papillary thyroid cancer.

In the management of papillary thyroid cancer (PTC), surgery is indicated for locoregional recurrent/persistent disease. In this study, we examined the effect of such surgery on serum TG and the course of the disease in 21 patients with PTC (mean age 38.5 yr), who after the initial surgery and radioactive iodine (RAI) ablation developed high TG (>10 ng/ml) and negative 123I whole body scan (DxWBS). All patients had neck persistent/recurrent PTC that was confirmed by ultrasound-guided fine needle aspiration. Prior to neck re-exploration, radiological studies (chest X-rays, CT scan of the chest, and fluoro-18-deoxyglucose positron emission tomography [FDG-PET]) showed no evidence of distant metastases. TG autoantibodies were negative in 19 patients. Second surgery consisted of unilateral (13 patients) or bilateral (8 patients) modified neck dissection. The mean±SE TG prior to neck re-exploration was 184.8±79.0 ng/ml and declined after surgery to 127.5±59.0 ng/ml (p=0.25). The corresponding TSH values were 150.6±23.0 and 143.4±20.0 mU/l, respectively (p=0.34). After a mean follow-up of 20.7±3 months, TG increased to 168±68.0 ng/ml. This increase, however, was NS (p=0.67). The corresponding TSH values were 143.4±20.0 and 132.0±22.0 mU/l (p=0.27). Following second surgery, only 4 patients achieved remission, the other 17 patients received one or more of the following therapies; RAI (10 patients), third surgery (5 patients), and/or external radiation (7 patients). Thirteen patients continued to have persistent disease and 4 patients showed progressive course of their disease (distant metastases or grossly palpable neck disease). In conclusion, second surgery for recurrent/persistent PTC leads to remission in only a minority of cases but the course of the disease tends to be stable in most cases.

Aberrant BRAF splicing as an alternative mechanism for oncogenic B-Raf activation in thyroid carcinoma†

Activating BRAF mutations have recently been reported in 28–83% of papillary thyroid carcinomas (PTCs). However, it is not known whether aberrant BRAF splicing occurs in thyroid carcinoma. To investigate aberrant BRAF splicing and its association with BRAF mutation in thyroid tumours, we studied aberrant BRAF splicing and BRAF mutation from 68 thyroid tumours. BRAFV600E mutation was detected in 20 of 43 PTCs and all three anaplastic thyroid carcinomas (ATCs). There is a higher frequency of BRAF mutation in PTC patients with stage III and IV tumours compared with stage I and II. Novel BRAF splicing variants were detected in 12 PTCs, three follicular variants of PTC (FVPTCs), and one ATC, as well as in two thyroid carcinoma cell lines, ARO and NPA. These variants did not have the N‐terminal auto‐inhibitory domain of wild‐type B‐Raf, resulting in an in‐frame truncated protein that contained only the C‐terminal kinase domain and caused constitutive activation of B‐Raf. These variants were significantly associated with advanced disease stage and BRAFV600E mutation (p < 0.001, Fisher exact test). Furthermore, expression of these variants in NIH3T3 and CHO cells could activate the MAP kinase signalling pathway, transform them in vitro, and induce tumours in nude mice. These data suggest that BRAF splicing variants may function as an alternative mechanism for oncogenic B‐Raf activation. Combination of the BRAFV600E mutation and its splicing variants may contribute towards disease progression to poorly differentiated thyroid carcinoma. Copyright

A Novel G102E Mutation of CYP27B1 in a Large Family with Vitamin D-Dependent Rickets Type 1

CONTEXT Mutations in the CYP27B1 gene, which encodes vitamin D 1alpha-hydroxylase, are the genetic basis for vitamin D-dependent rickets type 1 (VDDR-I). OBJECTIVE The aim of this study was to investigate the CYP27B1 mutation in a large family with VDDR-I and characterize the genotype-phenotype correlation. PATIENTS AND METHODS The index patient was a 23-yr-old female who had a progressive form of rickets and growth retardation since the age of 9 months. Laboratory data showed hypocalcemia, low urine calcium, hypophosphatemia, high serum alkaline phosphatase, elevated PTH, and low serum 1,25-dihydroxyvitamin D(3). Her parents were healthy first-degree cousins, and two of her 12 siblings were affected with similar but milder rickets. Three other siblings were asymptomatic but had biochemical evidence of the disease. The entire coding region of the CYP27B1 gene was sequenced, and the mutation was characterized by functional studies. RESULTS We found a novel biallelic c.305G>A sequence variation at codon 102, changing amino acid from glycine to glutamic acid (G102E) in the patient and five affected siblings, whereas a monoallelic c.305G>A variation was present in the mother and five nonaffected siblings. This variation was not present in 100 population controls. Expression of this mutant in CHO cells revealed an 80% reduction in the 1alpha-hydroxylase activity as compared to wild-type activity. CONCLUSIONS A novel mutation in the CYP27B1 gene was found in patients with VDDR-I. This mutation resulted in a significant reduction in 1alpha-hydroxylase activity. The residual enzymatic activity may account for the mild phenotype presentation in some affected members.

The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing’s disease

Despite the high resolution of magnetic resonance imaging (MRI) of the pituitary gland, up to 40% of cases of Cushing’s disease (CD) have normal MRI. Fused images of positron emission tomography and computed tomography (PET-CT) may have a potential diagnostic role in CD in general and in such cases in particular. Objective of this study is to explore the diagnostic potential of PET-CT for localization of adrenocorticotropin-secreting pituitary adenomas in CD. PET-CT was performed in 12 cases with de novo (7 cases) or persistent CD (5 cases) that were proven to have CD on biochemical, radiological and/or histopathological findings. These cases had a definite CD confirmed on histopathological and immunostaining examination of the subsequent transphenoidal surgical specimens (10 cases) and/or bilateral inferior petrosal sinus sampling (IPSS, 4 cases). PET-CT was positive in 7 of the 12 cases of CD (58%) showing a focal area of uptake in the pituitary gland. In these seven cases, MRI was positive in six (85.7%) but negative in one case (14.3%). In the other five cases with negative PET-CT, MRI was positive in two and negative in three cases. Of four cases with negative MRI, PET-CT was positive in one case (25%). We conclude that PET-CT is positive in around 60% of the cases of CD. Although the majority of cases with positive PET-CT had positive MRI, PET-CT may detect some cases with negative MRI and thus provides important diagnostic information. If these findings are confirmed in larger studies, PET-CT might become an important diagnostic technique, especially when the more invasive and technically demanding procedure of IPSS is not available or inconclusive.

Concomitant RAS, RET/PTC, or BRAF Mutations in Advanced Stage of Papillary Thyroid Carcinoma

BACKGROUND RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC. METHODS We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR-sequencing of tumor cDNA. RESULTS BRAF(V600E) was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRAS(Q61R) in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRAS(S65N) was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF(V600E) and KRAS, or BRAF(V600E) and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; p<0.01). CONCLUSIONS Our data show that concomitant mutations are a frequent event in advanced PTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRAS(S65N) can constitutively activate the MAPK pathway.

Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations.

Vitamin D-dependent rickets type 1 (VDDR-I) is caused by mutation in CYP27B1. The glycine residue at codon 102 is not conserved between human (G102) and rodent (S102). G102E mutation results in 80% reduction in its enzymatic activity but PolyPhen predicts benign change. It is not known whether G102S has any damaging effect on 1α-hydroxylase activity. We investigated the effect of CYP27B1G102S on its enzymatic activity and compared mutation prediction accuracy for all known CYP27B1 mutations among three free online protein prediction programs: PolyPhen, PolyPhen-2, and PSIPRED. G102S has no damaging effect on 1α-hydroxylase activity. G102D retained 30% enzymatic activity. All three programs correctly predicted damaging change for G102D. PolyPhen predicted benign change for G102S, whereas PolyPhen-2 and PSIPRED indicated possible damaging effect. Among 24 reported damaging mutations, PSIPRED, PolyPhen-2, and PolyPhen achieved 100%, 91.7% (22/24), and 75% (18/24) accuracy rate, respectively. The residues of incorrectly predicted mutations were not conserved. We conclude that G102D resulted in a significant reduction in 1α-hydroxylase activity, whereas G102S did not. PSIPRED and PolyPhen-2 are superior to PolyPhen in predicting damaging mutations.

Glucocorticoids Do Not Protect Against The Lethal Effects Of Experimental Heatstroke In Baboons

The mortality and neurological morbidity in heatstroke have been attributed to the hosts inflammatory responses to heat stress, suggesting that anti-inflammatory therapy may improve outcome. We tested the hypothesis that a high dose of dexamethasone protects baboons against the lethal effects of heatstroke. Ten anesthetized baboons (Papio hamadryas) were assigned randomly to dexamethasone (n = 5) or control group (n = 5). Dexamethasone (2 mg/kg i.v.) was administered in four divided doses every 6 h starting immediately before heat stress and continuing during cooling. All animals were heat-stressed in a prewarmed neonatal incubator at 44°C to 47°C until systolic blood pressure fell less than 90 mmHg and then cooled passively at the ambient temperature. Mortality and neurological morbidity were noted, and biochemical markers of tissue injury/organ dysfunction were determined. Circulating interleukin (IL) 6 and complement components (C3 and C4) were measured sequentially. All heat-stressed animals had systemic inflammation indicated by increased plasma IL-6 and decreased C3 and C4 levels. Dexamethasone attenuated the complement system activation and maintained a higher plasma concentration of IL-6, with a significant augmentation of arterial blood pressure. Dexamethasone did not prevent the occurrence of severe heatstroke but unexpectedly aggravated significantly the tissue injury and multiorgan system dysfunction. Two animals (40%) in the control group and one in the steroid group survived (P > 0.05). Dexamethasone failed to protect the baboons from the lethal effects of heatstroke. These results do not support clinical testing of corticosteroids as beneficial in preventive or therapeutic strategies for the treatment of heatstroke in humans.

Repeated Remissions of Cushing's Disease Due to Recurrent Infarctions of an ACTH-Producing Pituitary Macroadenoma

Infarction of prolactin-secreting or growth hormone-secreting pituitary adenomas is not unusual. However, Infarction of ACTH-secreting adenomas has rarely been reported. Cyclical course of Cushings syndrome alternating with adrenal insufficiency due to recurrent infarction of an ACTH-secreting pituitary adenoma has not been reported. We report here a 20-year-old lady who presented with florid signs of Cushings syndrome but was found to have adrenal insufficiency on biochemical evaluation. Magnetic resonance imaging (MRI) of the pituitary gland showed that she had infarction of an ACTH-secreting macroadenoma. Over the next 6 years, her disease ran a cyclical course characterized by periods of hypercortisolism alternating with adrenal insufficiency due to repeated episodes of infarctions of the ACTH-secreting pituitary macroadenoma with corresponding changes in the pituitary adenoma on serial MRIs. The case alerts clinicians to this possibility when a patient presents with clinical picture of Cushings syndrome but has adrenal insufficiency on biochemical testing. It also suggests that silent or subclinical infarction of pituitary adenomas is not uncommon and is probably under diagnosed.