Characteristics and outcome of surgically treated acromegaly patients attending an endocrinology clinic at a tertiary referral centre in Durban, South Africa over a period of 10 years

Background: The mode of presentation, clinical, radiologic and laboratory characteristics of patients with acromegaly and the outcome following various modalities of treatment are not well documented in South Africa.Aim: To evaluate treatment outcome and follow-up of patients with acromegaly over a period of 10 years.Methods: The study is a retrospective record review of patients with acromegaly attending Inkosi Albert Luthuli Central Hospital, Durban, 2003–2013.Results: The study included 27 patients (16 female and 11 male) with a mean age at diagnosis of 44.2 ± 14.0 years. The mean growth hormone (GH) at diagnosis was 51.8 ± 32.6 μg/l and mean IGF-1 956.8 ± 432.9 μg/l. In 25 patients (92.5%) pituitary macroadenoma was identified; microadenoma was present in 2 (7.4%) patients. Trans-sphenoidal surgery was employed in 26 (96.3%) as the initial therapy; only 1 patient was treated medically. Adjunctive medical therapy was used in 23 (88.5%) and radiotherapy in 6 (22.2%). After a mean follow-up of 4.4 ± 3.4 years, 9 (33.3%) subjects were cured (normal age-matched and gender-matched IGF-1 and random GH < 1.0 μg/l). No deaths were recorded and post-procedural hypopituitarism developed in 22 (84.6%) patients.Conclusions: Patients with acromegaly in KwaZulu-Natal present with advanced clinical features and large pituitary adenomata. The overall cure rate is lower than reported from developed countries.Keywords: acromegaly, diagnostic criteria, medical and radiotherapy, modes of treatment (surgery

Rickets mimicker: A report of two cases of primary hyperparathyroidism in adolescence

The presentation of primary hyperparathyroidism (PHPT) in most Western countries has evolved from the classic description of ‘stones, bones, and groans’ to becoming increasingly asymptomatic as a result of more frequent serum calcium screening. However, many developing countries are still reporting predominantly symptomatic PHPT with the classic complications of skeletal disease and nephrolithiasis still being quite common. Furthermore, the exact prevalence of PHPT in children is not known but it is thought to be uncommon and the clinical presentation and outcomes in this subgroup of patients are not well described in the literature. Two cases of PHPT occurring in adolescent boys are reported. Both cases initially presented with chronic bone pain involving the lower limbs and had a long delay before the diagnosis of PHPT was confirmed. They developed progressive deformities of the lower limbs, which resembled rickets clinically. Radiological features were also suggestive of rickets. However, biochemistry confirmed parathyroid hormone mediated hypercalcaemia in both cases and after parathyroid surgery a parathyroid adenoma was confirmed histologically as the aetiology of hypercalcaemia. Therefore, PHPT occurring in adolescence may have a clinical presentation almost identical to that of rickets. All patients presenting with skeletal deformities including a rickets phenotype must have serum calcium and phosphate levels measured as part of the diagnostic workup

Characteristics and outcome of patients with pheochromocytoma at a tertiary endocrinology clinic in Durban, South Africa over 14 years

Objectives: To evaluate the characteristics and outcomes of treatment of patients with pheochromocytoma at Inkosi Albert Luthuli Central Hospital (ILACH) in Durban, South Africa over 14 years.Design: Retrospective chart review.Setting and subjects: Patients with pheochromocytoma attending the endocrinology clinic at IALCH between 2012 and 2016 were studied.Outcome measures: Clinical, biochemical and radiological data were collected at presentation, on discharge, one year and five years after surgical intervention; tumour characteristics, histopathological features and surgical outcome were also assessed.Results: The analysis included 35 patients (mean age 33.2 ± 15.7 years; 60% female). Headache (68.6%), palpitation (60%) and sweating (57.6%) were the three most common presenting symptoms; hypertension was the predominant clinical finding (85.7%). Most pheochromocytomas were sporadic (82.9%), adrenal gland tumours (68.6%) and benign (77.1%); of eight patients with malignant tumours, two were familial. Adrenalectomy was undertaken in the majority (n = 34; 97.1%); 55.2% were large tumours. The use of adjunctive radiotherapy (n = 4; 11.4%) and chemotherapy (n = 1; 2.9%) was low. There was low overall mortality (5.7%), but 57.6% developed intraoperative hypotension. At one year postoperatively, 80% (n = 28) of patients were defined as cure, biochemically in 23 (82.1%) and with radiology in five (17.9%).Conclusions: Most patients presenting to IALCH had large intra-abdominal tumours with high cure rate, low mortality but a high rate of perioperative complications. Late presentation and large tumour size was a feature.Keywords: pheochromocytoma , South Africa, surgical outcom

Microvascular complications in South African patients with long duration diabetes mellitus

Objective. To determine the prevalence of microvascular complications in South African black and Indian patients with long-duration diabetes mellitus (DM).Design. A retrospective analysis was undertaken of clinical records of 219 OM patients (132 black, 87 Indian) with longduration OM (over 10 years) attending a diabetes clinic in Durban. Data recorded on each subject included demographic details (age, gender, ethnic group, type of diabetes, age of onset and duration of diabetes), presence of retinopathy, markers of nephropathy and biochemical variables. The prevalence of complications and the clinical and biochemical parameters were evaluated for type 1 and type 2 diabetes and for each ethnic group.Results. Of the 219 patients, 47 had type 1 OM (36 blacks, 11 Indians) and 172 were classified as type 2 OM (96 blacks, 76 Indians). The mean age of onset of OM wa later in blacks than Indians, both for type 1 (P < 0.05) and type 2 OM (P < 0.01). In patients with type 1 OM, the prevalence of retinopathy was 53.2% (blacks 55.6%, Indians 45.5%), persistent proteinuria was found in 23.4% (blacks 25%, Indians 18.2%) and hypertension in 34%. 0 ethnic difference was found except for the prevalence of hyperten ion which was higher in blacks than Indians (41.7% v. 9.1%, P < 0.5). Onset of retinopathy from time of diabetes diagno is occurred earlier in blacks than Indians (13.0 ± 4.6 yrs v. 18.0 ± 4.6 yrs, P < 0.05). For the type 2 DM group, retinopathy was found in 64.5% (black v. Indian 68.8 v. 59.2%) and per istent proteinuria in 25% (black v. Indian 30.2 v. 1 .4%). Hypertension wa observed in 68% and wa more prevalent in blacks (84.4 v. 47.,*%, P < 0.01) There was an earlier onset of retinopathy (P < 0,05) and hypertension (P < 0.01) from time of diabetes diagnosis in blacks than Indians. In the type 1 OM group retinopathy was a sociated with a ignificantly longer duration of diabetes (P < 0.05) and higher glycated haemoglobin (HbA1) (P < 0.05). For type 2 DM subjects there was a significant association between retinopathy and longer duration of diabetes (P < 0.05) and higher systolic blood pressure (P < 0.05).Conclusion. 1his study has shown that there is a high prevalence of microvascular complications in South African patients with long-duration diabetes mellitus

Characteristics of subjects with diabetes mellitus diagnosed before 35 years of age presenting to a tertiary diabetes clinic in Durban, South Africa, from 2003 to 2016

Background: Most patients diagnosed with diabetes mellitus < 35 years will have type 1 diabetes (T1D). The increase in youthonset type 2 diabetes  (T2D) parallels the obesity epidemic and in African subjects ketosis-prone type 2 diabetes (KPD) may occur in this age group.Objectives, setting and subjects: To evaluate the clinical, biochemical and immunologic characteristics of patients diagnosed with diabetes < 35 years presenting to a tertiary diabetes clinic in Durban, South Africa over 13  years.Design: A retrospective chart review of patients < 35 years diagnosed with diabetes was conducted. Data included clinical and laboratory variables, complications and follow-up status.Results: The study included 517 patients of whom 445 (86.1%) were  diagnosed with T1D, 27 (5.2%) with T2D, 27 with KPD (5.2%) and 18 (3.5%) with other forms of diabetes. Mean age of the total group was 28 ± 10 years. Subjects with T1D were younger at diagnosis with a lower BMI than both T2D and KPD. HbA1c was higher in subjects with T1D. Overall mortality was low (3.5%) and follow-up was poor in all groups.Conclusion: The majority of young people with diabetes in KwaZulu-Natal, South Africa, have T1D, with small numbers of other types. Glucose control is poor with a high loss to follow-up.Keywords: diabetes in youth, South Afric

Polygenic Prediction of Type 2 Diabetes in Africa.

OBJECTIVE: Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American, European, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans. RESEARCH DESIGN AND METHODS: Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS: The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American-derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19-4.03; P = 2.79 × 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS: African American-derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D

Genetic loci implicated in meta-analysis of body shape in Africans.

BACKGROUND AND AIMS: Obesity is one of the leading causes of non-communicable diseases (NCD). Thus, NCD risk varies in obese individuals based on the location of their fat depots; while subcutaneous adiposity is protective, visceral adiposity increases NCD risk. Although, previously anthropometric traits have been used to quantify body shape in low-income settings, there is no consensus on how it should be assessed. Hence, there is a growing interest to evaluate body shape derived from the principal component analysis (PCA) of anthropometric traits; however, this is yet to be explored in individuals of African ancestry whose body shape is different from those of Europeans. We set out to capture body shape in its multidimensional structure and examine the association between genetic variants and body shape in individuals of African ancestry. METHOD AND RESULTS: We performed a genome-wide association study (GWAS) for body shape derived from PCA analysis of anthropometric traits in the Ugandan General Population Cohort (GPC, n = 6407) and the South African Zulu Cohort (SZC, n = 2595), followed by a GWAS meta-analysis to assess the genetic variants associated with body shape. We identified variants in FGF12, GRM8, TLX1NB and TRAP1 to be associated with body shape. These genes were different from the genes been associated with BMI, height, weight, WC and waist-hip ration in continental Africans. Notably, we also observed that a standard deviation change in body shape was associated with an increase in blood pressure and blood lipids. CONCLUSION: Variants associated with body shape, as a composite variable might be different for those of individual anthropometric traits. Larger studies are required to further explore these phenomena

Genome-wide association study of type 2 diabetes in Africa

Abstract: Aims/hypothesis: Genome-wide association studies (GWAS) for type 2 diabetes have uncovered >400 risk loci, primarily in populations of European and Asian ancestry. Here, we aimed to discover additional type 2 diabetes risk loci (including African-specific variants) and fine-map association signals by performing genetic analysis in African populations. Methods: We conducted two type 2 diabetes genome-wide association studies in 4347 Africans from South Africa, Nigeria, Ghana and Kenya and meta-analysed both studies together. Likely causal variants were identified using fine-mapping approaches. Results: The most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10−13). Fine-mapping of the TCF7L2 locus suggested one type 2 diabetes association signal shared between Europeans and Africans (indexed by rs7903146) and a distinct African-specific signal (indexed by rs17746147). We also detected one novel signal, rs73284431, near AGMO (p = 5.2 × 10−9, minor allele frequency [MAF] = 0.095; monomorphic in most non-African populations), distinct from previously reported signals in the region. In analyses focused on 100 published type 2 diabetes risk loci, we identified 21 with shared causal variants in African and non-African populations. Conclusions/interpretation: These results demonstrate the value of performing GWAS in Africans, provide a resource to larger consortia for further discovery and fine-mapping and indicate that additional large-scale efforts in Africa are warranted to gain further insight in to the genetic architecture of type 2 diabetes

ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

Abstract: Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10−9). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations