Biomedical subjects
Publications and source records attributed to Paul C Adams.
Hemochromatosis is a common genetic disease with a wide range of clinical expression: from no symptoms to cirrhosis of the liver. The discovery of the gene has led to a genetic blood test useful in the diagnosis of hemochromatosis. Treatment by phlebotomy is simple and efficient and can prevent the development of cirrhosis, leading to a normal life expectancy.
Haemochromatosis continues to be considered an uncommon disease despite large scale population screening studies demonstrating a high prevalence of C282Y homozygotes of approximately 1 in 200. Since many of the C282Y homozygotes that are discovered through screening are asymptomatic, or have non-specific symptoms commonly found in the ageing population, the attribution of any symptoms to haemochromatosis has become increasingly difficult. The demonstration of significant liver disease in family members is a strong reminder of the vital importance of pedigree studies when a typical haemochromatosis patient is identified.
Heme oxygenase (HO) isozymes, HO-1 and HO-2, catalyze the conversion of heme to iron, carbon monoxide, and biliverdin. The present study was aimed at elucidating the role of the HO system in iron accumulation and oxidative stress in the liver. We have also studied the regulation of an iron exporter, ferroportin-1 (FPN-1), as an adaptive response mechanism to increased iron levels. Sprague-Dawley rats were treated with HO inducer hemin or HO inhibitor tin-protoporphyrin IX (SnPPIX) for 1 month. A portion of liver tissues was subjected to RT-PCR for HO-1, HO-2, and FPN-1 gene expression as well as an HO activity assay. Paraffin-embedded tissues were stained for iron with Prussian blue. Hepatic iron concentration was measured by High Resolution-Inductively Coupled Plasma-Mass Spectrometry. 8-hydroxy-2'-deoxyguanosine (8-OHdG) stain, a sensitive and specific marker of oxidative DNA damage, was performed to assess oxidative stress. Hemin treatment led to augmented HO expression and activity in association with increased iron accumulation and oxidative stress. FPN-1 expression was also found to be upregulated. SnPPIX treatment reduced HO activity, intracellular iron levels, and oxidative stress as compared to controls. Our data provides evidence of increased HO activity as an important pro-oxidant mechanism leading to iron accumulation in the liver.
The present study was designed to investigate hemochromatosis patients' suitability as blood donors as well as their perceptions and experience with the current public donation system. Participants were gathered from a list of current hemochromatosis patients (n=120) and members of the Canadian Hemochromatosis Society (n=1000). Of the 1120 surveys mailed out to these groups, 801 surveys were returned completed. The sample respondents had a mean age of 57.44 years (SD=12.73; range 19 to 87 years), and 57% were men. It was found that 20% (160) of the respondents have donated blood since their diagnosis; however, only 12% of the respondents indicated that they use voluntary blood donation as a means of maintaining their iron levels. Forty per cent of the respondents indicated that they had been refused from voluntary donation. Despite the fact that in May 2001 the Canadian Blood Services, in collaboration with the Canadian Hemochromatosis Society, began a promotion campaign to encourage hemochromatosis patients to become voluntary blood donors, the present study found that 15% of the respondents reported having been refused from the voluntary blood donation service due to the diagnosis of hemochromatosis. With respect to quality of life, it was found that individuals who donate blood were generally healthier with respect to physical functioning and bodily pain, however, these findings may indicate that hemochromatosis patients who are healthier are better able to donate at public blood banks, rather than that voluntary blood donation has an effect on the donors' physical functioning over phlebotomy clinic users. These study findings suggest that although there may be other medical factors limiting individuals from donating, hemochromatosis patients are interested in being voluntary blood donors and this potential resource is currently under-used.
BACKGROUND & AIMS: The discovery of a genetic test for hereditary hemochromatosis has identified many individuals who are homozygous for the C282Y mutation of the HFE gene with a normal transferrin saturation and serum ferritin level. The long-term prognosis, rate of iron accumulation, and surveillance guidelines for these individuals are unknown. METHODS: To determine the degree of iron accumulation over time, an updated serum ferritin level was obtained in patients initially identified as homozygous for the C282Y mutation with a normal serum ferritin level. RESULTS: Twenty-two asymptomatic untreated C282Y homozygotes with a normal serum ferritin level were identified, 10 through population screening, 9 through pedigree analysis, and 3 through a general medical work-up. There were 18 women (4 postmenopausal) and 4 men with a median age of 46 years, range 28-76 years. The median follow-up interval was 4 years, range 2-23 years. The serum ferritin levels of 20 of 22 patients remained below the upper limit of normal during the follow-up period. A decline in serum ferritin level was observed in 13 of 22 patients. Three patients had an increase in serum ferritin level of greater than 50%, with only 1 male patient exceeding the upper limit of normal by having a serum ferritin level increase from 295 to 344 microg/L during a 3-year period. CONCLUSIONS: In C282Y homozygotes with a normal ferritin level at the time of diagnosis, 20 of 22 patients failed to show any significant increase in serum ferritin level during a median follow-up of 4 years. This has clinical and economic implications for follow-up and surveillance of this selected population.
BACKGROUND: The HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. METHODS: Participants undergo testing for serum iron measures and common mutations of the hemochromatosis gene ( ) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. RESULTS: Of the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. CONCLUSIONS: Information from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.
Genetic testing of hemochromatosis has not been widely used as a diagnostic test because of unawareness of its existence and concerns about genetic discrimination. We developed a nomogram for the prediction of C282Y homozygotes for hemochromatosis from transferrin saturation and ferritin using Bayes theorem. The results of transferrin saturation and C282Y genotyping were available for 8,572 participants (5,042 men, and 3,530 women). The study group included patients in population-screening projects, referred cases, and family members. Likelihood ratios were calculated for transferrin saturation in predicting C282Y homozygotes. Pretest probabilities were estimated on the basis of serum ferritin concentration, and a predictive nomogram for men and women was created with the use of Bayes' theorem. In the highest-risk region of the nomogram in men, the probability of C282Y hemochromatosis was 89.7% (95% confidence interval = 85.1-94.3); in the lowest-risk zone it was 1.1% (0.4-1.9). The corresponding regions in women were 88.9% in the high zone (95% confidence interval = 77.0-100.0) and 6.5% in the lowest (95% confidence interval = 4.9-8.1). This approach allows the clinician to predict the probability of a patient's being a C282Y homozygote over a wide range of ferritin and transferrin saturation values instead of above a particular threshold.
PURPOSE: To study the clinical outcomes of subjects who are homozygous for the C282Y mutation of the hemochromatosis gene. SUBJECTS AND METHODS: All patients referred to a tertiary referral centre for hemochromatosis were included. The study also included 16 C282Y homozygotes detected in a population screening study. RESULTS: The study comprised 277 C282Y homozygotes, including 16 nonexpressing C282Y homozygotes. The mean follow-up period was 7.3 years (range zero to 44 years). The actuarial survival rates of C282Y homozygotes at five, 10 and 20 years were 95%, 93% and 66%, respectively. Life-threatening diseases (cirrhosis, hepatocellular carcinoma, diabetes, heart disease) were present in 36% of male C282Y homozygotes and 19% of female C282Y homozygotes. Cirrhosis of the liver and diabetes were the major clinical symptoms affecting long term survival. Only one nonexpressing homozygote required venesection therapy during the follow-up period. CONCLUSIONS: Long term survival is excellent in C282Y homozygotes diagnosed and treated before the development of cirrhosis and diabetes.
Hemochromatosis is a common genetic disease in which early diagnosis and treatment results in an excellent long-term prognosis. Population screening projects have been completed that included iron tests and genetic testing. In this review, the controversial issues surrounding population screening for hemochromatosis are explored in the context of available information from large screening studies.
OBJECTIVE: To increase family physicians' awareness of the prevalence of hemochromatosis and to suggest strategies for diagnosis and management of hemochromatosis with the goal of decreasing the development of associated life-threatening conditions. QUALITY OF EVIDENCE: A MEDLINE search from January 1966 to January 2002 using the MeSH term hemochromatosis/therapy found no randomized controlled trials. A further search from January 1990 to January 2002, using the heading hemochromatosis and subheadings diagnosis, epidemiology, genetics, and therapy, found articles with level II evidence (case-control and cross-sectional studies) and level III evidence (descriptive studies and reports from expert committees). Articles were selected based on clinical relevance. MAIN MESSAGE: Hemochromatosis is the most common hereditary condition in populations of Northern European descent, affecting three to five people per thousand. Many of these people remain undiagnosed with this condition. The iron overload associated with hemochromatosis can lead to serious, life-threatening conditions, such as diabetes, hepatic cirrhosis, primary liver cancer, and cardiomyopathy. Family physicians can screen patients they suspect are at risk of hemochromatosis with simple indirect serum iron measurements (transferrin saturation and serum ferritin) and with widely available genetic tests (C282Y and H63D). Studies of families can help uncover further cases of hemochromatosis; population screening is currently under study. CONCLUSION: Family physicians can facilitate early diagnosis of hemochromatosis by maintaining a high index of suspicion in patients with early signs or symptoms or in high-risk groups, and screening these patients for hemochromatosis.
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Iron-regulated transporter protein 1 (IREG1 or ferroportin 1) is a transmembrane iron transporter that has been described in macrophages and hepatocytes. Ferroportin mutations have been described to result in hepatic iron overload in human pedigrees. The role of hepatic ferroportin in the pathogenesis of C282Y-linked hemochromatosis has not been clearly established. The objective was to study the expression of ferroportin mRNA and protein in C282Y-linked hemochromatosis liver and in controls. Human liver biopsies were stained with an anti-ferroportin antibody and quantitation of ferroportin at 62 kDa was done by Western blotting. mRNA was studied by real time RT-PCR. Ferroportin protein expression was increased in C282Y homozygotes (n = 23) compared to wild-type patients (n = 37) (P < 0.003). There was no significant correlation between ferroportin protein or mRNA expression (n = 25) and liver iron concentration or serum ferritin. Immunohistochemical staining demonstrated ferroportin in hepatocytes and macrophages. In conclusion, ferroportin protein is increased in iron-loaded hemochromatosis liver. The increase in ferroportin protein without an increase in mRNA is consistent with iron-mediated translational regulation through the 5'IRE in the mRNA.