Inflammatory bowel disease in sub-Saharan Africa: a protocol of a prospective registry with a nested case-control study.

INTRODUCTION: The epidemiology of inflammatory bowel disease (IBD) in sub-Saharan Africa is poorly documented. We have started a registry to determine the burden, phenotype, risk factors, disease course and outcomes of IBD in Zimbabwe. METHODS AND ANALYSIS: A prospective observational registry with a nested case-control study has been established at a tertiary hospital in Harare, Zimbabwe. The registry is recruiting confirmed IBD cases from the hospital, and other facilities throughout Zimbabwe. Demographic and clinical data are obtained at baseline, 6 months and annually. Two age and sex-matched non-IBD controls per case are recruited-a sibling or second-degree relative, and a randomly selected individual from the same neighbourhood. Cases and controls are interviewed for potential risk factors of IBD, and dietary intake using a food frequency questionnaire. Stool is collected for 16S rRNA-based microbiota profiling, and along with germline DNA from peripheral blood, is being biobanked. The estimated sample size is 86 cases and 172 controls, and the overall registry is anticipated to run for at least 5 years. Descriptive statistics will be used to describe the demographic and phenotypic characteristics of IBD, and incidence and prevalence will be estimated for Harare. Risk factors for IBD will be analysed using conditional logistic regression. For microbial analysis, alpha diversity and beta diversity will be compared between cases and controls, and between IBD phenotypes. Mann-Whitney U tests for alpha diversity and Adonis (Permutational Multivariate Analysis of Variance) for beta diversity will be computed. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Parirenyatwa Hospital's and University of Zimbabwe's research ethics committee and the Medical Research Council of Zimbabwe. Findings will be discussed with patients, and the Zimbabwean Ministry of Health. Results will be presented at scientific meetings, published in peer reviewed journals, and on social media. TRIAL REGISTRATION NUMBER: NCT04178408.

Investigation on the hereditary basis of colorectal cancers in an African population with frequent early onset cases.

BACKGROUND: Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than 40 years, and hereditary factors may contribute. We investigated the frequency and patterns of inherited colorectal cancer among black Zimbabweans. METHODS: A population-based cross-sectional study of ninety individuals with a new diagnosis of colorectal cancer was carried out in Harare, Zimbabwe between November 2012 and December 2015. Phenotypic data was obtained using interviewer administered questionnaires, and reviewing clinical and pathology data. Cases were screened for mismatch repair deficiency by immunohistochemistry and/or microsatellite instability testing, and for MLH1, MSH2 and EPCAM deletions using multiplex ligation-dependent probe amplification. Next generation sequencing using a 16-gene panel was performed for cases with phenotypic features consistent with familial colorectal cancer. Variants were assessed for pathogenicity using the mean allele frequency, phenotypic features and searching online databases. RESULTS: Three Lynch syndrome cases were identified: MSH2 c.2634G>A pathogenic mutation, c.(1896+1_1897-1)_(*193_?)del , and one fulfilling the Amsterdam criteria, with MLH1 and PMS2 deficiency, but no identifiable pathogenic mutation. Two other cases had a strong family history of cancers, but the exact syndrome was not identified. The prevalence of Lynch syndrome was 3·3% (95% CI 0·7-9·4), and that of familial colorectal cancer was 5·6% (95% CI, 1·8-12·5). CONCLUSIONS: Identifying cases of inherited colorectal cancer in sub-Saharan Africa is feasible, and our findings can inform screening guidelines appropriate to this setting.

A case-control study of risk factors for colorectal cancer in an African population.

The interplay between hereditary and environmental factors in the causation of colorectal cancer in sub-Saharan Africa is poorly understood. We carried out a community based case-control study to identify the risk factors associated with colorectal cancer in Zimbabwe. We recruited 101 cases of colorectal cancer and 202 controls, matched for age, sex and domicile. Potential risk factors including family history, socioeconomic status, urbanization, diabetes mellitus and previous schistosomiasis were evaluated. Conditional logistic regression was used to estimate the odds ratios associated with the different factors. Cases were more likely to have a tertiary education (32.7 vs. 13.4%, P<0.001) and a higher income (18.8 vs. 6.9%, P=0.002). After multivariate analysis, diabetes mellitus [odds ratio (OR): 5.3; 95% confidence interval (CI): 1.4-19.9; P=0.012], previous urban domicile (OR: 2.8; 95% CI: 1.0-7.8; P=0.042), previous schistosomiasis (OR: 2.4; 95% CI: 1.4-4.2; P=0.001) and cancer in a first-degree relative (OR: 2.4; 95% CI: 1.2-4.8; P=0.018) were associated independently with colorectal cancer. Our findings suggest that family history, diabetes mellitus, previous schistosomiasis and approximation to a western lifestyle are the predominant associations with colorectal cancer in Africans. This offers opportunities for targeted prevention and hypothesis-driven research into the aetiology of colorectal cancer in this population.

Dietary patterns and colorectal cancer risk in Zimbabwe: A population based case-control study.

BACKGROUND: The rising incidence of colorectal cancer in sub-Saharan Africa may be partly caused by changing dietary patterns. We sought to establish the association between dietary patterns and colorectal cancer in Zimbabwe. METHODS: One hundred colorectal cancer cases and 200 community-based controls were recruited. Data were collected using a food frequency questionnaire, and dietary patterns derived by principal component analysis. Generalised linear and logistic regression models were used to assess the associations between dietary patterns, participant characteristics and colorectal cancer. RESULTS: Three main dietary patterns were identified: traditional African, urbanised and processed food. The traditional African diet appeared protective against colorectal cancer (Odds Ratio (OR) 0.35; 95% Confidence Interval (CI), 0.21 - 0.58), which had no association with the urban (OR 0.68; 95% CI, 0.43-1.08), or processed food (OR 0.91; 0.58-1.41) patterns. The traditional African diet was associated with rural domicile, (OR 1.26; 95% CI, 1.00-1.59), and a low income (OR1.48; 95% CI, 1.06-2.08). The urbanised diet was associated with urban domicile (OR 1.70; 95% CI, 1.38-2.10), secondary (OR 1.30; 95% CI, 1.07-1.59) or tertiary education (OR 1.48; 95% CI, 1.11-1.97), and monthly incomes of $201-500 (OR 1.30; 95% CI, 1.05-1.62), and the processed food pattern with tertiary education (OR 1.42; 95% CI, 1.05-1.92), and income >$1000/month (OR 1.48; 95% CI, 1.02-2.15). CONCLUSION: A shift away from protective, traditional African dietary patterns may partly explain the rising incidence of colorectal cancer in sub-Saharan Africa.

The shifting epidemiology of colorectal cancer in sub-Saharan Africa.

The perception that colorectal cancer is rare in sub-Saharan Africa is widely held; however, it is unclear whether this is due to poor epidemiological data or to lower disease rates. The quality of epidemiological data has somewhat improved, and there is an ongoing transition to western dietary and lifestyle practices associated with colorectal cancer. The impact of these changes on the incidence of colorectal cancer is not as evident as it is with other non-communicable diseases such as diabetes. In this Viewpoint, we discuss the epidemiology of colorectal cancer in sub-Saharan Africa. Colorectal cancer in this region frequently occurs at an early age, often with distinctive histological characteristics. We detail the crucial need for hypothesis-driven research on the risk factors for colorectal cancer in this population and identify key research gaps. Should colorectal cancer occur more frequently than assumed, then commensurate allocation of resources will be needed for diagnosis and treatment.

The incidence and histo-pathological characteristics of colorectal cancer in a population based cancer registry in Zimbabwe.

BACKGROUND: Data on colorectal cancer (CRC) in sub-Saharan Africa is mainly based on hospital series which suggest low incidence and frequent early onset cancers. This study characterises colorectal cancer in a population-based cancer registry in Zimbabwe. METHODS: Cases of CRC recorded by the Zimbabwe National Cancer Registry between 2003 and 2012 were analysed. Demographic and pathological characteristics were compared according to ethnicity and age. Trends in age standardised incidence rates (ASR) were determined. RESULTS: There were 886 and 216 cases of CRC among black Africans and Caucasians respectively, and 26% of the black Africans were younger than 40 years. Signet ring cell carcinomas were more common among black Africans compared to Caucasians (4% vs 1%, p=0.027). ASR increased by 1.9%/year and 3.9%/year among black African males and females respectively. CONCLUSION: CRC incidence is rising among black Africans and has unique demographic and pathological characteristics.

Retrospective study of colorectal cancer in Zimbabwe: colonoscopic and clinical correlates.

AIM: To compare differences in the frequency of colorectal cancer at colonoscopy in Zimbabwe according to ethnicity. METHODS: All lower gastrointestinal endoscopic procedures performed between January 2006 and December 2011 at a gastroenterology clinic in Harare, Zimbabwe were reviewed. The demographic characteristics, clinical indications, differences in bowel preparation and the endoscopic and histological diagnoses were compared between different ethnic groups with emphasis on colorectal cancer. The clinical and demographic characteristics and the endoscopic findings were compared using the student t-test and the χ2 test, while the clinical indications associated with a diagnosis of colorectal cancer were determined by logistic regression. RESULTS: All colonoscopies and sigmoidoscopies performed in 1236 Caucasians, 460 black Africans and 109 Asians were analysed. Colorectal cancer was diagnosed more frequently in the black African patients compared to Caucasians or Asians (10% vs 3%, 10% vs 2%, P<0.001). However, polyps were less common among black Africans (5%) compared to both Caucasians (8%) and Asians (9%) (P=0.03). Among patients with colorectal cancer, black Africans tended to be younger than Caucasians, who were over-represented in the oldest age category; 32 % vs 2% were less than 50 years and 41% vs 78% were older than 60 years (P<0.001). Anaemia and weight loss were associated with colorectal cancer in both black African [odds ratio (OR): 2.73 (95%CI: 1.33-5.61) and 3.09 (1.35-7.07)] and Caucasian patients [OR: 6.65 (95%CI: 2.93-15.09) and 3.47 (1.52-7.94)]. CONCLUSION: The likelihood of diagnosing colorectal cancer in patients referred for colonoscopy in Zimbabwe is at least as likely among black Africans as it is among Caucasians.

Serum ferritin concentrations in Africans with low dietary iron.

In the setting of high dietary, several studies have provided evidence for a strong effect of both high dietary iron and an unidentified genetic locus on iron stores in Africans. To investigate whether these effects are discernible in the setting of low dietary iron, serum ferritin concentrations were measured in 194 Zimbabwean men >30 years of age and 299 postmenopausal women who consumed a non-iron-fortified diet and who did not drink iron-rich traditional beer or other alcoholic beverages. Comparisons were made with non-alcohol drinking African-Americans studied in the third National Health and Nutritional Examination Survey (NHANES III) who consume an iron-fortified diet. As stratified by age and sex, serum ferritin concentrations were significantly lower in the 493 Zimbabweans studied than in 1,380 comparable African-Americans (P < 0.0005). Nevertheless, nine Zimbabwean subjects (1.8% of all cases) had modestly elevated serum ferritin concentrations not associated with evidence of inflammation or hepatic dysfunction. These data suggest that mild serum ferritin concentration elevations may occur among Zimbabweans not exposed to high dietary iron and that iron fortification of the diet may have substantial effects on serum ferritin concentration.

Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene.

The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C-->T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 microg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 microg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.

Rapid emergence of resistance to penicillin and trimethoprim-sulphamethoxazole in invasive Streptococcus pneumoniae in Zimbabwe.

Pneumococcal pneumonia and meningitis are common infectious disease problems in people who are HIV seropositive in southern Africa. For many years two inexpensive antibiotics, penicillin and trimethoprim-sulphamethoxazole (TMP-SMX) had been effective in treatment, but recently resistance to these agents has been reported from many parts of the world. This study was designed to determine the antimicrobial resistance patterns in invasive pneumococci from hospital patients in Harare, Zimbabwe. A total of 160 isolates of Streptococcus pneumoniae from blood cultures and CSF cultures were examined. The isolates came from adults and children in hospital in Harare between 1994 and 2000. The majority of isolates came from HIV positive adults (74%) and children (75%). Isolates of pneumococci with an MIC of 1.0 mg/l or more were first seen in 1997 and by 2000 they made up 35% of all isolates. Significantly more isolates from HIV seropositive patients (50%) showed reduced susceptibility to penicillin compared with isolates from HIV seronegative patients (16%), and high level resistance (MIC 1.0 mg/l or higher) was found in 16% isolates from HIV positive patients compared with 6% isolates from HIV seronegative patients. Resistance to TMP-SMX was common, with more than 50% isolates from HIV positive and HIV negative patients having reduced susceptibility to this antibiotic combination.

Iron status in black persons is not influenced by haptoglobin polymorphism.

Iron status in man is influenced by environmental and genetic factors. The molecular variation of haptoglobin is one of the genetic factors influencing iron status in Caucasians. Differences in iron metabolism between blacks and whites have been reported. We wanted to investigate the effect of haptoglobin polymorphism on iron status in blacks. We studied 300 African subjects who were apparently healthy with normal erythrocyte sedimentation rate and with no increase in dietary iron because of traditional beer consumption. We determined haptoglobin (Hp) phenotypes using starch gel electrophoresis and measured indirect iron status indices using standard methods. We compared iron status indices according to haptoglobin type. Ninety two individuals (31%) had Hp 1-1, 114 persons (38%) had Hp 2-1, 20 subjects (7%) had Hp 2-1(Modified) and 54 individuals (18%) had Hp 2-2 type. Haptoglobin was not detectable in 19 subjects and Hp 2-1(Johnson) was found in one subject. In both males and females, serum iron concentration, total iron binding capacity, transferrin saturation and ferritin concentration were not different with regard to Hp phenotype. These results suggest that haptoglobin phenotypic variation may not be a factor which influences iron status in black persons.

Cryptococcus neoformans meningoencephalitis in African children with acquired immunodeficiency syndrome.

BACKGROUND: The number of children with AIDS in Africa is high. Such children may be at risk for cryptococcal meningoencephalitis, but data are scarce regarding this disease in our population. METHODS: We examined records of HIV-infected children (< or =16 years) diagnosed with cryptococcal meningoencephalitis in Harare, Zimbabwe, between 1995 and 2000. To elucidate features unique to pediatric disease, the children were compared with adult patients with HIV-associated cryptococcal meningoencephalitis. RESULTS: Thirteen children presented to our institution with headache (85%), nuchal rigidity (69%), vomiting (46%), impaired mental status (38%), convulsions (38%) and focal neurologic signs (23%). The mean duration of symptoms before diagnosis was 9 days. Cerebrospinal fluid examination revealed normal white blood cell counts in 64%, protein value in 67% and glucose concentration in 57% of patients. Children were more likely than adults to have seizures (38% vs. 11%, P = 0.02) and normal cerebrospinal fluid protein (67% vs. 10%, P < 0.01). The in-hospital mortality was 43%. Convulsions (P = 0.05) and impaired mental status (P < 0.01) were associated with increased mortality CONCLUSIONS: Cryptococcal meningoencephalitis in African children presents acutely or subacutely, can have a fulminant picture and is consistent with progressive meningoencephalitis.

Effect of transferrin polymorphism on the metabolism of vitamin C in Zimbabwean adults.

BACKGROUND: Transferrin is the major iron binding protein in human plasma. In black persons, the transferrin CD phenotype has been associated with alterations in certain markers of iron status. OBJECTIVE: We studied vitamin C status in a Zimbabwean population according to transferrin phenotype because vitamin C metabolism is influenced by iron-driven oxidative stress. DESIGN: The study population consisted of 150 black African adults, 90 of whom were at risk of iron overload on the basis of high dietary iron content in the form of traditional beer. Transferrin phenotypes, indirect measures of iron status, and leukocyte ascorbic acid concentrations were determined. The in vitro rate of L-ascorbic acid depletion in sera from different transferrin phenotypes was investigated. RESULTS: The transferrin phenotype frequencies of transferrin CC and CD were 0.893 and 0.107, respectively. The iron status of transferrin CC and CD subjects was similar. After adjustment for traditional beer consumption, baseline leukocyte vitamin C concentrations were significantly higher in 16 transferrin CD subjects ( +/- SE: 2.10 +/- 0.34 and 2.61 +/- 0.28 fmol/leukocyte in men and women, respectively) than in 134 transferrin CC subjects ( +/- SE: 1.65 +/- 0.11 and 1.99 +/- 0.11 fmol/leukocyte in men and women, respectively; P = 0.024). Oral administration of ascorbic acid (2.0 g every 24 h for 48 h) led to slower rises in leukocyte vitamin C concentrations in subjects with the transferrin CD phenotype than in subjects with the transferrin CC phenotype (P = 0.028). After in vitro supplementation of serum with 570 micromol vitamin C/L, the rate of L-ascorbic acid depletion was significantly lower in subjects of a transferrin CD phenotype than in subjects with the transferrin CC phenotype. CONCLUSION: Transferrin polymorphism may affect vitamin C status in blacks.