Biomedical subjects
C Q Edwards
Publications and source records attributed to C Q Edwards.
Iron overload in Africa. Interaction between a gene and dietary iron content.
BACKGROUND AND METHODS: In contrast to hemochromatosis, which in white populations is inherited through a gene linked to the HLA locus, iron overload in sub-Saharan Africa is believed to result solely from increased dietary iron derived from traditional home-brewed beer. To examine the hypothesis that African iron overload also involves a genetic factor, we used likelihood analysis to test for an interaction between a gene (the hypothesized iron-loading locus) and an environmental factor (increased dietary iron) that determines transferrin saturation and unsaturated iron-binding capacity. We studied 236 members of 36 African families chosen because they contained index subjects with iron overload. Linkage to the HLA region was tested with use of lod scores. RESULTS: In the index subjects, increased iron was present in both hepatocytes and cells of the mononuclear-phagocyte system. Among family members with increased dietary iron due to the consumption of traditional beer, transferrin saturation in serum was distributed bimodally, with 56 normal values (less than 60 percent saturation) and 44 elevated values; the mean serum ferritin concentration was five times higher in the subjects with elevated transferrin saturation (P less than 0.005). The pedigree analysis provided evidence of both a genetic effect (P less than 0.005) and an effect of increased dietary iron (P less than 0.005) on transferrin saturation and unsaturated iron-binding capacity. In the most likely model, increased dietary iron raised the mean transferrin saturation from 30 to 81 percent and lowered the mean unsaturated iron-binding capacity from 38 to 13 mumol per liter in subjects heterozygous for the iron-loading locus. The hypothesis of tight linkage to HLA was rejected. CONCLUSIONS: Iron overload in Africa may be caused by an interaction between the amount of dietary iron and a gene distinct from any HLA-linked gene.
Disorders of excess iron.
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Comparison of stainable liver iron between symptomatic and asymptomatic hemochromatosis homozygotes and their homozygous relatives.
The authors compared the amount of hepatic parenchymal cell stainable iron in 159 hemochromatosis homozygotes. They were separated into four groups. Group 1: 59 symptomatic hemochromatosis probands with hemochromatosis (mean age 49 years) who were identified because of symptoms and signs of iron overload. Group 2: 38 asymptomatic probands with hemochromatosis (mean age 29 years) identified during population screening studies or during routine health maintenance evaluation. Group 3: 47 homozygous relatives (mean age 43 years) of Group 1 probands. Group 4: 15 homozygous relatives (mean age 30 years) of Group 2 probands. The symptomatic probands (Group 1) were 20 years older and had much more stainable hepatic iron (p less than 0.0001) than the asymptomatic probands (Group 2). The homozygous relatives (Group 3) of the symptomatic probands also were older and had much more stainable hepatic iron than the homozygous relatives (Group 4) of asymptomatic probands (p less than 0.0002). The results of this study suggest that population screening studies can result in early identification of individuals with hemochromatosis before massive hepatic iron overload occurs and before symptoms of iron overload develop.
Coincidental hemochromatosis and viral hepatitis.
A 35-year-old woman presented with liver failure, hepatic iron overload, and secondary amenorrhea due to hypogonadotropic hypogonadism. She had chronic inflammatory hepatitis which was considered to be due to post-transfusional viral hepatitis. Her hepatic iron overload was considered to be due to hemochromatosis. Her premature menopause was thought to be due to the severity of her liver disease, but her iron overload also could have contributed to gonadotrophin deficiency. She underwent liver transplantation and 5 months later, she experienced return of menstrual function. The distinction between hepatitis as a cause of iron loading, hemochromatosis as a cause of hepatic inflammation, the small influence of alcohol on increased iron stores, and other features of her history, physical examination, and laboratory evaluation are discussed.
Southern blood club symposium: an update on selected aspects of hemochromatosis.
Genetic epidemiology studies have indicated that hereditary hemochromatosis (HH) occurs in caucasians with a frequency of 3 to 13 per thousand. Clinical recognition however occurs far less frequently. The disparity is best resolved by defining HH as homozygosity for the HLA-linked hemochromatosis allele, regardless of the total body iron burden. Variability of clinical expression is explained in part by physiologic iron loss in women but variability in males may be due to environmental factors, gene-gene interactions or polymorphisms in mutated hemochromatosis alleles. Although clinical variability is great, the laboratory phenotype of HH is fairly constant and is marked by elevation of the transferrin saturation. The elevated transferrin saturation occurs early in life, before organ iron loading occurs and can be used as a screening tool to detect HH before organ damage occurs. Cloning and characterizing the HH gene, which is located within 1 centimorgan of the HLA-A locus should resolve some of the issues concerning clinical variability.
HLA-linked hemochromatosis alleles in sporadic porphyria cutanea tarda.
We tested the hypothesis that the hepatic siderosis that characterizes sporadic porphyria cutanea tarda is due to the presence of HLA-linked hemochromatosis alleles. We studied 21 probands with sporadic porphyria cutanea tarda and 135 of their relatives by determining HLA haplotypes and measuring transferrin saturation and serum ferritin concentration. Liver biopsies were performed in all probands and in relatives when appropriate. Seventeen pedigrees were available and were studied by both likelihood analysis and by a gene counting method. We estimated that 10 of the 17 probands with available living relatives possessed at least one hemochromatosis allele. Thirteen of the 21 probands (62%) possessed at least one HLA-A3 alloantigen. Eighteen of 69 relatives who shared an HLA haplotype with a proband (26%) had an elevation of transferrin saturation or serum ferritin concentration. Only one first-degree relative not sharing an HLA haplotype with a proband had an elevated transferrin saturation or serum ferritin concentration. These findings indicate that HLA-linked hemochromatosis alleles are far more common in patients with sporadic porphyria cutanea tarda than in individuals in the general population and may be responsible for the hepatic siderosis associated with most cases of sporadic porphyria cutanea tarda.
Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes.
We studied 43 haemochromatosis homozygotes and seven normal individuals to test the hypothesis that there is an almost continuous relative deficiency of apotransferrin in treated and untreated homozygotes. Transferrin saturation was measured at 2-h intervals for 24 h while all subjects ate their usual diet. Subjects with haemochromatosis were separated into four groups based on sex and whether or not they had been iron-depleted. Nineteen treated and 11 untreated male homozygotes had mean transferrin saturation values of 70 and 81%, respectively. Five treated and eight untreated female homozygotes had mean transferrin saturation values of 71 and 69%. Normal subjects had mean transferrin saturation values of 29% (3 males) and 21% (4 females). These data demonstrate continuously high transferrin saturation values, greater than 69% in most treated and untreated male and female homozygotes, resulting in hepatic iron accumulation of non-transferrin-bound iron from the portal circulation.
Prevalence of hemochromatosis among 11,065 presumably healthy blood donors.
There is evidence that iron loading and organ damage can be prevented in patients with hemochromatosis if prophylactic phlebotomy is employed early in the disease--findings emphasizing the importance of early detection before clinical signs occur. This study was designed to determine the efficacy of transferrin saturation as a screening tool for hemochromatosis and to assess the frequency of homozygosity for the HLA-linked hemochromatosis gene in a healthy population. We screened 11,065 presumably healthy blood donors (5840 men and 5225 women). Donors with transferrin saturations of 62 percent or more after an overnight fast were considered potential homozygotes and were asked to undergo liver biopsy and pedigree analysis. The frequency of values for transferrin saturation of 62 or higher in men was 0.008 and in women 0.003. Thirty-eight persons with values higher than 62 were studied in detail; 35 underwent liver biopsy. Liver iron stores ranged from normal to markedly increased. Twelve siblings with an identical HLA match to a proband underwent liver biopsy, and 11 had increased liver iron stores. According to likelihood analysis of the pedigrees, 26 of the 38 probands were homozygotes, and 12 were heterozygotes. The estimated frequency of homozygosity was based on the data in men, because the threshold value of 62 for the transferrin saturation identified only half as many female homozygotes as expected. The frequency of homozygosity was 0.0045, corresponding to a gene frequency of 0.067. The value of population screening is demonstrated in these studies by the detection of homozygotes before clinical manifestations of hemochromatosis occur.
Increased frequency of HLA-A3 in subjects with sporadic porphyria cutanea tarda.
The HLA-A3 alloantigen, usually associated with the hemochromatosis gene, was detected in 12 of 18 patients (67%) with sporadic porphyria cutanea tarda but in only 23 per cent of 328 normal subjects (p = 0.0006). This difference remained significant after correcting for the number of HLA-A locus antigens tested (p = 0.025). These results suggest that an HLA-linked hemochromatosis allele is present and may account for the iron abnormalities in many patients with sporadic porphyria cutanea tarda.
Sporadic porphyria cutanea tarda in individuals with HLA-linked hemochromatosis allele(s). Preliminary report.
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Screening for hemochromatosis in healthy blood donors. Preliminary results.
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A self-controlled study of the effect of continuous subcutaneous insulin infusion on diabetic neuropathy.
Ten patients with poorly controlled type I diabetes mellitus and a documented complication of their disease were observed during 6 months of conventional diabetic management followed by 6 months of insulin infusion pump treatment and home blood glucose monitoring. Median nerve conduction velocity (NCV) was inversely correlated with the glycosylated hemoglobin (HbA1c) level at entry into the study (r = 0.71; P less than 0.05). The mean HbA1c value at the end of the conventional treatment period was 14.3% and fell to 10.1% by completion of the pump treatment period (P less than 0.0001). The median NCV was significantly greater at the completion of the infusion treatment period than it was at the end of the conventional management portion of the study. However, the rate of increase in NCV during the infusion period was not greater than the rate established during the prior treatment period. In addition, change in HbA1c levels during the pump treatment period did not correlate with change in conduction velocity for any of the nerves studies. These results from a self-controlled study of continuous subcutaneous insulin infusion indicate that improved blood glucose control without normalization of metabolic parameters is not sufficient to reverse the functional deterioration of large, fast-conducting nerve fibers that occurs in type I diabetes.
Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A.
We studied a family with HLA-linked hereditary hemochromatosis in which an informative recombination occurred within the HLA region. The father, an obligate heterozygote for hereditary hemochromatosis, had HLA haplotypes A2,B13 and A11,B27. The mother, also an obligate heterozygote, had HLA haplotypes A29,B44 and A2,B7. Three haplotypes were found among three homozygous affected offspring. Two affected siblings were HLA-identical with haplotypes A2,B13 and A29,B44. The proband had HLA haplotypes A2,B13 and A2,B44, the latter a recombinant haplotype inherited from her mother. Since the maternal hemochromatosis allele was linked to the A29,B44 haplotype, and since the proband has hemochromatosis, the maternal hemochromatosis allele was transmitted to the proband with the B44 antigen. This is the first known example of recombination in an individual with HLA-linked hemochromatosis in whom the hemochromatosis allele appeared to segregate with the HLA-B antigen instead of the -A antigen. The possibility of either a double reciprocal recombination event or a gene conversion event cannot be excluded. Combined with earlier observations of segregation of the hemochromatosis allele with the A locus in HLA recombinants, the findings in this pedigree map the hemochromatosis locus between the HLA-B and HLA-A loci rather than outside the HLA region.
Heterozygosity for HLA-linked hemochromatosis as a likely cause of the hepatic siderosis associated with sporadic porphyria cutanea tarda.
Subnormal activity of hepatic uroporphyrinogen decarboxylase is responsible for the derangement of porphyrin biosynthesis in both sporadic and familial porphyria cutanea tarda, but the enzymatic defect is not clinically expressed in the absence of hepatic siderosis. The pedigree study described here offers support for the hypothesis that a single allele for HLA-linked hereditary hemochromatosis is responsible for the hepatic siderosis in sporadic porphyria cutanea tarda. A two-locus causation model for sporadic porphyria cutanea tarda might explain both the observed incidence of overt cases and the rarity of multiple affected individuals within a pedigree.
Effect of insulin infusion pump use on diabetic retinopathy.
Ten patients with insulin-dependent diabetes mellitus (IDDM) had fundus photographs and fluorescein angiograms obtained before and after a control period characterized by conventional insulin injections and a test period characterized by continuous subcutaneous insulin infusion (CSII). The mean glycosylated hemoglobin value at the end of the control period was 14.3% +/- 3.8% and decreased to 10.1% +/- 3.3% at the end of the test period. During the control period, none of the patients' eyes changed more than one grade in a modified Early Treatment Diabetic Retinopathy Study classification. All seven eyes without retinopathy at the start of the control period were still without retinopathy at its completion. One eye improved three grades during the test period, but four eyes, including two without retinopathy when CSII was initiated, progressed one grade. The data suggest that metabolic control that is improved but not normalized by CSII neither reverses retinopathy in IDDM nor prevents its development.
Thermostable erythrocyte rosette-forming lymphocytes in hereditary hemochromatosis. I. Identification in peripheral blood.
Although the immunoregulatory role of iron has been demonstrated in vitro, evidence for a similar role in vivo is controversial. We have, therefore, studied certain functional and structural properties of lymphocytes in hereditary (idiopathic) hemochromatosis (HH), a disease characterized by iron overload. T- and B-lymphocyte percentages in peripheral blood, serum immunoglobulin levels, and proliferative responses of peripheral blood mononuclear cells (PBM) to lectins were comparable with those of controls. Furthermore, HH serum with elevated iron concentrations did not significantly alter proliferative responses of normal lymphocytes to mitogens. In contrast to those normal findings was the identification of a subset of T lymphocytes in HH that formed rosettes with sheep red blood cells (SRC) at 37 degrees C in abnormally high numbers. Those lymphocytes that formed thermostable erythrocyte rosettes (TE-R) were not immature thymocytes, activated T lymphocytes, or an artifact of passive attachment of anti-SRC antibodies to the HH lymphocyte surface. Their presence did not correlate with a concentration of iron in the serum, the length of treatment, or the presence of the HLA antigen, A3. We conclude that the cellular expression of HH may be detected not as an immunological abnormality, but rather as an abnormality in receptor expression.
The inheritance of high density lipoprotein cholesterol and apolipoproteins A-I and A-II.
A large pedigree was ascertained through cases of early myocardial infarction. High density lipoprotein cholesterol and apolipoproteins A-I and A-II were measured on family members. Likelihood analysis, using the polygenic/major gene mixed model, provided no evidence that major loci play a role in determining the levels of any of the three measurements. Heritability estimates, assuming polygenic inheritance, were 0.59 and 0.26 for HDL-C level and A-II level, respectively. No evidence of genetic transmission of A-I level was found.