The present investigation evaluated the serum transferrin receptor concentration in subjects with nontransfusional iron overload who were identified in two separate studies on the basis of a serum ferritin level above 400 micrograms/L. Subjects with preclinical hereditary hemochromatosis were evaluated in the first study and those with the African form of iron overload in the second. In the first study, hereditary hemochromatosis was identified in 14 white men on the basis of a persistent elevation in transferrin saturation above 55%. The serum receptor concentration was elevated above the upper cut-off of 8.5 mg/L in two of the subjects, but the mean receptor of 6.1 +/- 1.4 mg/L (mean +/- 2 SE) did not differ significantly from the normal mean for this assay of 5.6 +/- 0.3 mg/L. In the same study, 60 control subjects with secondary iron overload were identified on the basis of a serum ferritin persistently above 400 micrograms/L, with a normal serum C-reactive protein concentration but with a transferrin saturation < 55%. Three of these subjects had an elevated serum receptor concentration but the mean value of 5.5 +/- 0.4 mg/L did not differ from normals nor from subjects with hemochromatosis. In the second study, 49 black Africans with iron overload were divided into those with or without an elevated transferrin saturation. The mean serum receptor concentration of 5.0 +/- 0.8 mg/L and 4.5 +/- 0.4 mg/L, respectively, did not differ statistically. It was concluded that there is no evidence of generalized dysregulation of the transferrin receptor in hemochromatosis or African siderosis.

The findings in the cord blood sample of an infant from a treated hemochromatotic mother of a raised transferrin saturation (88%) and a raised ferritin concentration (250.2 micrograms/L) together with elevated maternal values (66% and 91.6 micrograms/L, respectively) yet a normal total placental iron content (26.9 mg) suggested that in common with gastrointestinal mucosal cells and reticuloendothelial cells in hemochromatosis, the placental cell may exhibit an abnormality of iron storage and transport.

The mechanism of severe mitral regurgitation (MR) due to active rheumatic carditis is ill defined. This study involved 73 patients, aged 7 to 27 years (mean 13), with severe MR and active rheumatic carditis who were subjected to surgery. Sixty-one were studied retrospectively (group 1) and 12 prospectively (group 2). Active rheumatic carditis was diagnosed according to the modified Jones' criteria, morphologic appearances of the heart at operation and histology of the valve. All patients had preoperative 2-dimensional echocardiographic and intraoperative assessment of the mitral valve apparatus. The presence of mitral valve prolapse—defined as failure of leaflet edge coaptation resulting in systolic displacement of the free edge of the involved leaflet toward the left atrium—was determined in all patients. Mitral anular diameter and maximal systolic chordal length were measured at 2-dimensional echocardiography in group 2 patients and compared to values obtained from matched control subjects. Anular and chordal dimensions in 6 of the group 2 patients were correlated with precise measurements obtained at surgery. Mitral valve prolapse involving the anterior leaflet was detected on echocardiography and confirmed at surgery in 69 patients (94%). Mitral anular dilatation was observed at operation in 70 patients (96%). Maximal anular diameter was significantly greater (p < 0.0001) than in matched control subjects (37 ± 4 vs 23 ± 2 mm). The mean anular dimension measured at surgery (36 ± 3 mm) was similar to that obtained by echocardiography and individual values using the 2 methods correlated well (r = 0.93). Chordal elongation was observed in 66 patients at operation (90%). Maximal systolic chordal length was significantly greater (p < 0.01) than that in matched control subjects (23 ± 4 vs 17 ± 1 mm), individual values for chordal length at operation correlated well (r = 0.99) with 2-dimensional echocardiographic measurements. Severe MR in active rheumatic carditis is due to a combination of mitral anular dilatation, chordal elongation and prolapse of the anterior leaflet.

In 1873 Kussmaul1 reported the observation that, in 2 patients with constrictive pericarditis, the expected inspiratory collapse of neck veins was replaced by increased inspiratory distension. The association of Kussmaul's sign, as it subsequently became called, with constrictive pericarditis is now widely accepted. At the same time it is also recognized that it is not specific to this pathology and can be observed in congestive heart failure,2–4 restrictive cardiomyopathy,5 right ventricular infarction6 and acute cor pulmonale.7 As stressed by Spodick,8 it is not a feature of pericardial tamponade and is of value in distinguishing tamponade from pericardial constriction. In spite of its clinical value and wide use, the underlying mechanism is poorly understood.9 We report our observations based on 6 patients with chronic constrictive pericarditis in an attempt to clarify the mechanism of this sign.

Certain metabolic pathways of iron were studied in macrophages (cultured human monocytes) obtained from normal and hemochromatotic subjects. The relative abilities of the hydrophobic ferrous chelator 2,2' bipyridine and the hydrophilic ferric chelators desferrioxamine (DFO) and diethylenetriaminepenta-acetic acid (DTPA) to release iron from normal and hemochromatotic macrophages which had previously been loaded with diferric transferrin were tested but there were no differences between the two groups. The relative affinity of the macrophages for diferric transferrin was next studied. Although the hemochromatic macrophages had a somewhat lower affinity for diferric transferrin iron than normal macrophages (Kd 4.7 x 10(-8) M vs. 3.0 x 10(-8)M) the difference did not reach statistical significance (t = 2.01013; P less than 0.07). In a further experiment there was no evidence that apotransferrin was directly involved in the release of iron from hemochromatotic macrophages. A clue to the nature of postendocytotic trans-membrane transport of iron was provided by the finding that it was inhibited by the hydrophobic ferrous chelator 2,2' bipyridine. However, the degree of inhibition was similar in both normal and hemochromatotic macrophages. In summary, none of the metabolic processes examined in the present study was abnormal in cultured human blood monocytes from hemochromatotic subjects.

Coronary arteriovenous fistula (CAVF) may occasionally be complicated by bacterial endocarditis. The actual anatomical site of infection has not been clearly defined. A 13-year-old boy with a CAVF and Streptococcus viridans bacteraemia is described. The origin of the fistulous tract and a vegetation in close proximity to the distal drainage site into the right ventricle was demonstrated by Doppler two-dimensional echocardiography.

Annals of the New York Academy of SciencesVolume 526, Issue 1 p. 328-330 Idiopathic Hemochromatosis in an Afrikaner Population T. E. Meyer, T. E. Meyer MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorR. D. Baynes, R. D. Baynes MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorT. H. Bothwell, T. H. Bothwell MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorD. Ballot, D. Ballot MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorT. Jenkins, T. Jenkins MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorP. L. Jooste, P. L. Jooste MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorE. D. Du Toit, E. D. Du Toit MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorP. Jacobs, P. Jacobs MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this author T. E. Meyer, T. E. Meyer MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorR. D. Baynes, R. D. Baynes MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorT. H. Bothwell, T. H. Bothwell MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorD. Ballot, D. Ballot MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorT. Jenkins, T. Jenkins MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorP. L. Jooste, P. L. Jooste MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorE. D. Du Toit, E. D. Du Toit MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this authorP. Jacobs, P. Jacobs MRC Iron and Red Cell Metabolism Unit Department of Medicine University of the Witwatersrand Johannesburg, South AfricaSearch for more papers by this author First published: June 1988 https://doi.org/10.1111/j.1749-6632.1988.tb55517.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume526, Issue1Hemochromatosis: Proceedings of the First International ConferenceJune 1988Pages 328-330 RelatedInformation

A simple, robust, inexpensive and reasonably accurate screening test, which involves colorimetric assessment of the unsaturated iron-binding capacity, was used to detect significant degrees of iron overload in a field setting. It was used in a survey of 152 men aged over 40 years who had previously been identified as having serum ferritin values above 400 micrograms/l and who were therefore potentially homozygous carriers of the HLA-linked iron-loading gene responsible for the clinical disorder idiopathic haemochromatosis (IHC). Such individuals almost always have a raised transferrin saturation and the screening test was compared with a standard method of measurement. The screening test accurately identified 7 out of 10 subjects with transferrin saturations above 62%. It also accurately identified 137 out of 142 subjects with saturation below 62%. There were 5 false-positive results; in all these subjects saturations were at the upper limit of normal or marginally raised. The test thus had a sensitivity of 77%, a specificity of 97%, an accuracy of 95% and a positive predictive accuracy of 67%. The test successfully identified a subgroup of subjects with serum ferritin values above 400 micrograms/l who appeared to have more severe degrees of iron overload. The screening test, which requires only 200 microliter serum and costs only 6.2 c, should not only be of potential value in identifying subjects at risk of developing the clinical manifestations of IHC but may prove even more useful in defining the prevalence of significant iron overload in the rural black population of South Africa.

A previous study conducted on a group of Afrikaans-speaking subjects in the south-western Cape indicated a high frequency (0.115) of the HLA-linked iron-loading gene which causes idiopathic haemochromatosis. The results of phenotypic and genotypic studies on the first degree relatives of identified homozygotes and heterozygotes are now reported. There was considerable heterogeneity of phenotypic expression in the group of heterozygotes, with overlap between the homozygous and heterozygous subjects. The heterozygous relatives of heterozygous index cases, who had been identified on the basis of a serum ferritin concentration greater than 400 micrograms/l, appeared to have more frequent and more marked abnormalities of iron measurements than the heterozygote relatives of homozygous index cases (serum ferritin value greater than 400 micrograms/l, percentage transferrin saturation greater than 60). This suggests that the screening test was identifying a group of more significantly affected heterozygotes, with biochemical abnormalities that overlapped with the identified homozygotes. The index cases were followed up over a period of 5 years and during this time the 7 subjects diagnosed as heterozygotes showed a progressive increase in serum ferritin concentrations, which suggests some iron accumulation. Individual pedigrees included instances of gene recombination within the major histocompatibility complex, and of probable false-positive genotype assignment. The overall results confirm a high frequency of the gene in this particular community.

HLA typing for the A and B loci was carried out in conjunction with measurements of iron status on 38 of the first-degree relatives of 8 patients suffering from idiopathic haemochromatosis (IHC). Seven of the 8 probands had the A3 allele, 2 in the homozygous form. Seven had the B7 allele and in 5 it was present with the A3 allele on the same chromosome. Six family members were diagnosed as homozygous for the HLA-linked iron-loading gene on the basis of genotype assessment, while 27 were assessed as being heterozygous. Five of the 6 homozygous subjects had developed significant iron overload. In contrast, disturbances of iron metabolism in the heterozygotes were mild and present in only 33%. Pseudodominant inheritance of IHC was noted in one family, presumably as the result of a homozygous/heterozygous mating. A pilot epidemiological survey was carried out on 222 Afrikaans-speaking men in an attempt to find affected individuals using the serum ferritin concentration as the screening test. One homozygous subject was identified (genotype A3, B7/A3, B7) and further family studies confirmed the presence of the HLA-linked iron-loading gene. These preliminary results suggest a disease frequency of about 4-5/1,000 in the Afrikaner population.

The serum ferritin concentration was used as a screening test to identify the presence of iron overload in 599 Afrikaans subjects (300 males and 299 females) living in the South Western Cape, South Africa. Seventeen of the males with concentrations greater than 400 micrograms/l were reevaluated three and five years later. Serum ferritin concentrations were measured again and further diagnostic procedures were carried out. These included an assessment of alcohol intake and measurements of serum gamma glutamyltransferase, the percentage saturation of transferrin, and HLA-A,-B,-C, and -DR loci typing on the subjects as well as their families. Liver biopsies were performed on some affected subjects. Of the original 16 index subjects, four were diagnosed as homozygous for the HLA linked iron loading gene which is responsible for the clinical disease idiopathic haemochromatosis. Six appeared to be heterozygotes, three were heterozygotes who were also abusing alcohol, and two did not fit into any of the diagnostic groups. The calculated gene frequency was 0.082, with an expected heterozygote frequency of 0.148. The fact that no females were identified in the study suggested that the diagnostic criteria for homozygosity (serum ferritin greater than 400 micrograms/l and % saturation greater than 60%) were set too high. The data were therefore recalculated for the 300 males; when this was done the gene frequency was 0.115 and the heterozygote frequency 0.024. Two subjects were diagnosed as homozygotes in the study of family members and 37 as heterozygotes (33 definite and four probable). Both the homozygotes and nine of the heterozygotes showed mild to moderate disturbances of iron metabolism. There was considerable overlap between the phenotype expression in these nine heterozygotes and the homozygotes, probably as a result of setting the threshold for the serum ferritin concentrations at the relatively high value of 400 microgram/ml. By doing this a small subset of heterozygotes with biochemical abnormalities was identified. The results of the present pilot study suggest a high frequency of the HLA linked iron loading gene in the Afrikaner population of South Western Cape.

Serum ferritin and hepatic enzyme concentrations were measured in 30 alcoholic subjects. Both the serum ferritin and gamma-glutamyltranspeptidase (GGT) values were raised in 23 subjects and a significant correlation was noted between the two measurements (r = 0,51; P less than 0,01). There was, however, no correlation between the initial serum ferritin concentration and the serum alanine transaminase and serum aspartate transaminase concentrations. The serum ferritin and GGT levels were followed serially during a period of abstinence in 9 subjects; values fell in parallel in all of them. The data indicate that a serum ferritin level above 300 micrograms/l is very unlikely to be the result of alcohol-induced liver damage if the serum GGT value is less than 50 U/l. The combined measurement of serum ferritin and GGT values should therefore prove useful in epidemiological studies concerned with defining the prevalence in different population groups of the HLA-linked iron-loading gene that leads to the clinical disorder of idiopathic haemochromatosis.