Downloaded from British Journal of Nutrition (1999), 81, 427–434 427 https://www.cambridge.org/core Review article Iron overload in Sub-Saharan Africa: to what extent is it a public health problem? . IP address: 170.106.35.229 Alexander R. P. Walker1* and Isidor Segal2 1Human Biochemistry Research Unit, Department of Tropical Diseases, School of Pathology of the University of the Witwatersrand, and the South African Institute for Medical Research, Johannesburg, South Africa 2Gastroenterology Unit, Department of Medicine, Baragwanath Hospital and the University of the Witwatersrand, , on Johannesburg 2000, South Africa 26 Sep 2021 at 20:14:55 (Received 6 October 1997 – Revised 19 October 1998 – Accepted 7 January 1999) Excessive deposition of Fe in the organs and tissues of Sub-Saharan Africans was first described , subject to the Cambridge Core terms of use, available at in South Africa in 1929. Fe overload, or siderosis, was initially attributed to infections and to metallic poisoning (Cu, Sn, Zn), and then to malnutrition. In 1953 it was hypothesized that it was due primarily to excessive Fe intake derived from foods and drinks prepared in Fe vessels. Recently, in 1992 it was advanced that a gene distinct from any HLA-linked locus may also play a role. As to sequelae, in early research on series of hospital patients, the condition was linked to scurvy, osteoporosis, diabetes, cirrhosis, and latterly, to hepatocellular cancer and tuberculosis. Accordingly, many have concluded that Fe overload is responsible for considerable morbidity and mortality, that adventitious Fe intake should be reduced, and that phlebotomy be recom- mended for those severely affected. However, there are numerous limitations in the evidence. There are also problems in interpretation, since levels of Fe in the serum are affected additionally by a variety of factors: infection, inflammation, certain cancers and alcohol intake. These considerations complicate attempts to assess to what extent the associations described denote causation, and whether Fe overload has significant ramifications for ill in the general African population. While the adverse sequelae of overload may be less of significance than many believe, the precise pathogenicity of the phenomenon will remain uncertain until further investigations, including prospective studies, are undertaken. https://www.cambridge.org/core/terms Iron overload: Africa: Cirrhosis: Hepatocellular carcinoma ‘The first key to wisdom is assiduous and frequent public health problem. It is proposed, first to describe the questioning . For by doubting we come to inquiry, and by condition, then discuss its causation, its pathogenicity, inquiry we arrive at truth.’ Peter Abelard, 12th Century complicating factors, and subsequently, the need for further research. Fe overload in Africans in South Africa was first described . https://doi.org/10.1017/S000711459900077X by Strachan (1929). It is now believed that it results primarily from excessive intake of dietary Fe in a highly Iron overload in Sub-Saharan Africans bioavailable form (Walker & Arvidsson, 1953; Bothwell Early observations et al. 1964). Recently, it has been put forward that the overload in part may be genetically determined, and accord- As mentioned, Fe overload in Africans in South Africa was ingly is the result of the combined effects of environmental first described by Strachan (1929) in Johannesburg, in a and host factors (Gordeuk et al. 1992; Moyo et al. 1998). thesis entitled ‘Haemosiderosis and haemochromatosis in However, numerous questions remain unanswered. South African natives with a comment on the aetiology of In the present contribution, the aim is to seek to learn haemochromatosis’. The dissertation was based on a of the extent to which Fe overload in Africans presents a necropsy study of 876 individuals from several parts of Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. * Corresponding author: Dr A. R. P. Walker, fax +27 11 489 9001, email [email protected] Downloaded from 428 A. R. P. Walker and I. Segal https://www.cambridge.org/core southern and central Africa, who died in Johannesburg indicated that extremely high concentrations of Fe were between 1925 and 1928. Strachan concluded that ‘haemo- common; thus 15 % of bodies had concentrations exceeding chromatosis’ is a not uncommon disease in regional groups 10 g Fe/kg DM, i.e. about thirty times the proportion of African natives. In his view, the chief incriminating normally present. However, there appeared to be no clear- factor appeared to be the diet. The development of the cut correlation between Fe concentration, and ash and Ca complete picture of bronzed diabetes depended on the concentrations, reckoned on either percentage or volume degree of deposition of the pigment and of its rate of basis. It was therefore concluded that severe siderosis in deposition. He noted that in mild cases pigmentation alone vertebral bodies is not necessarily associated with low . IP address: may occur (as seen in younger Africans), but in slightly mineral density. more severe cases, cirrhosis may develop. Strachan con- In a study made on a random group of 100 African sidered Cu, Sn, or Zn, to be the probable aetiological factor. patients with diabetes, seven showed moderate siderosis Later, Gillman & Gillman (1947, 1951) also in South together with portal fibrosis (Seftel et al. 1961). 170.106.35.229 Africa, maintained that malnutrition and pellagra cause hepatic damage, with deposition of haemosiderin in the Later clinical and pathological observations liver cells (cytosiderosis); later, this is followed by the excretion of Fe in the bile, with consequent reabsorption Investigations have been made on series of patients and , on and widespread Fe deposition (siderosis). However, controls from a number of hospitals in Northern Province 26 Sep 2021 at 20:14:55 Higginson et al. (1953) from their post-mortem findings, and Mpumulanga, South Africa (Friedman et al. 1990). noted Fe deposition to be widespread in the reticulo- Levels of serum ferritin indicated diverse degrees of Fe endothelial system from the beginning, and the need for overload. In one group of patients, the majority of liver division into two stages was doubted. It was considered biopsies undertaken revealed heavy siderosis, associated unwise to isolate changes in the liver from those occurring with varying degrees of hepatic damage, namely fibrosis, in the rest of the body. It was argued that were Fe cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B , subject to the Cambridge Core terms of use, available at deposition a feature of pellagra, an approximately similar virus (HBV) infection rate was found to be high, approxi- histologic picture would be expected in all cases of acute mately 70 % in both patients and controls in the same pellagra on admission to hospital, if the metabolic community. In terms of responsibility for HCC, the com- processes involved were similar in each. This was not plexity of the situation is such that as many as 80 % of cases reported by Gillman & Gillman (1951), nor was it the have been attributed to chronic HBV infection (Zhou et al. experience of Higginson et al. (1953). The latter noted 1987; Kew, 1995). The possible interaction of HBV with that liver biopsies from patients suffering from many hepatitis C virus (HCV) remains uncertain (Kew, 1994). different diseases showed the same range of histological According to this author, additional risk factors may include pattern of Fe deposition. aflatoxin, alcohol consumption and smoking. For example, In the study just mentioned (Higginson et al. 1953), an in 50 % of a large series of patients with HCC studied examination was made of forty-four necropsies of Africans at Baragwanath Hospital, Soweto, Johannesburg, South who represented cases of Fe overload of varying severity. Africa, a high consumption of alcohol was implicated Deposition of the element was found in the liver, spleen, (Paterson et al. 1985). heart, kidney and pancreas. Whereas normal Fe concentra- As regards Fe overload being a risk factor for HCC, a tions in liver and spleen averaged 0⋅7 and 1⋅4 g/kg respec- number of reports have provided potentially supportive https://www.cambridge.org/core/terms tively, they averaged 8 and 22 g/kg in the presence of data. At Baragwanath Hospital, in a study of tumour moderate siderosis, and 30 and 43 g/kg with severe side- morphology conducted on ninety patients of rural and rosis. Maximal concentrations of Fe in the liver and spleen urban origins, Fe content was graded in liver tissue; the were 55 and 105 g/kg DM respectively. Corresponding prevalence of severe hepatic Fe overload was 33⋅2% concentrations in haemochromatosis have been reported as (Paterson et al. 1985). This proportion was much higher 36 and 6 g/kg DM (Sheldon, 1935). From this small series of than the proportion with Fe overload (liver Fe concentration necropsies undertaken in Africans it was concluded that $ 10 g/kg DM), namely, 24⋅6 %, found in a necropsy series there was no constant correlation between the degree of of Africans dying from all causes at the same institution fibrosis and the amount of Fe pigment in the liver. Cases of (MacPhail et al. 1979). In a recent rural-based study made in . severe Fe deposition were seen without cirrhosis and vice Eastern Province, South Africa, 203 biopsy specimens of https://doi.org/10.1017/S000711459900077X versa. Later studies, however, undertaken in the 1960s, liver tissue from 246 African