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Biomedical subjects

L W Powell

Publications and source records attributed to L W Powell.

At least 37 records · Page 2Linked to original sources
PubMed2000

HFE-associated hereditary hemochromatosis.

Hereditary hemochromatosis is a common inherited disorder of the iron metabolism. Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis gene (HFE) in 1996 and two candidate mutations; the C282Y mutation has been shown to be responsible for the majority of the hereditary hemochromatosis cases worldwide. The gene discovery has led to rapid advances in the field of iron metabolism. Although the basic defect is still not fully understood, much is known about the sequence of events leading to iron overload. Hereditary hemochromatosis is a major candidate for population screening and meets the screening criteria of the World Health Organization, and Wilson and Jungner. It is one of the most prevalent genetic diseases in white populations, and, importantly, early diagnosis and simple effective treatment allow normal life expectancy. The discovery of the HFE gene and the frequency of the single C282Y mutation as a cause of most cases of hereditary hemochromatosis allow the possibility of widespread genetic testing. However, the logistics, and the psychological and social consequence of this, coupled with incomplete expression of the genotype, necessitate further studies before population screening can be justified.

Genotype↗
PubMed2000

Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women.

BACKGROUND: Women who inherit heterozygosity for the C282Y mutation of the HFE gene may have increased serum iron indices and hemoglobin and are less likely to develop iron deficiency compared with women with the wild-type genotype. METHODS: We performed a cross-sectional analysis of 497 women 20-44 years of age and 830 women >51 years of age drawn from the Busselton (Australia) population study to assess the effects of the HFE genotype on serum iron and hematology indices. RESULTS: Heterozygosity for the C282Y mutation occurred in 13.8% of the study population, comprising 11.8% C282Y wild-type heterozygotes and 2.0% C282Y/H63D compound heterozygotes. In the younger age group, C282Y wild-type women did not have significantly increased serum iron, transferrin saturation, or hemoglobin values, and were not protected from developing iron deficiency, compared with women of the same age with the wild-type genotype. Young compound heterozygous women had higher means for serum iron (25.0 vs 16.9 micromol/L; P <0.001), transferrin saturation (42.0% vs 25.6%; P <0. 05), hemoglobin (139.4 vs 132.3 g/L; P <0.05), and corpuscular volume (91.1 vs 87.7 fL; P <0.05), and a higher median ferritin (53 vs 44 microg/L; P <0.05) compared with the wild-type genotype. Similar results were observed for compound heterozygotes in the >51 years age group. CONCLUSIONS: Women with the compound heterozygous HFE genotype C282Y/H63D, but not the C282Y wild-type genotype, had increased values for serum iron and transferrin saturation, and the younger age group also had increased hemoglobin values. We conclude that the compound heterozygous genotype may have a beneficial effect in protecting women from iron deficiency.

Adult↗
PubMed1999

A population-based study of the clinical expression of the hemochromatosis gene.

BACKGROUND AND METHODS: Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. RESULTS: Sixteen of the subjects (0.5 percent) were homozygous for the C282Y mutation, and 424 (14.1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. CONCLUSIONS: In a population of white adults of northern European ancestry, 0.5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

Adult↗
PubMed1999

Linkage disequilibrium analysis in Australian haemochromatosis patients indicates bipartite association with clinical expression.

BACKGROUND/AIMS: Hereditary haemochromatosis shows a wide variation in phenotypic expression, which is thought to be due, in part, to genetic factors. A single missense mutation in HFE, leading to an amino acid substitution (C282Y) has been shown to be the causative mutation, clearly responsible for clinical expression of the disorder. Since homozygosity for the C282Y mutation can give rise to a disorder which shows wide variation in clinical expression, we investigated the possibility that genetic modifiers of HFE may exist. METHODS: Linkage disequilibrium analysis was performed on chromosome 6p21.3 in 74 patients homozygous for the C282Y mutation using microsatellite markers spanning the haemochromatosis gene region. Phenotypic expression was evaluated based on transferrin saturation, serum ferritin, hepatic iron concentration and index, and iron grade. RESULTS: Linkage disequilibrium (LD) analysis showed a predominant ancestral haplotype from D6S265 to D6S2236 covering a region of approximately 5 Mb. The overall LD distribution in this region showed two peaks of highly significant association at D6S105 (2 Mb proximal to HFE) and at D6S2239 approximately 50 kb distal to HFE. Male patients homozygous for D6S105 allele 8, had significantly higher hepatic iron indices than patients heterozygous or nullizygous for D6S105-8 (p<0.038). CONCLUSION: This analysis indicates that modifying gene(s) or another mutation affecting HHC clinical expression may be located in the region of D6S105.

Alleles↗
PubMed1999

Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis.

BACKGROUND/AIM: Hereditary haemochromatosis can now be diagnosed by genetic testing, although determining the presence or absence of cirrhosis remains crucial to patient management. While many studies have investigated the utility of various serum markers of cirrhosis in chronic liver diseases, few have examined specifically patients with hereditary haemochromatosis. The aim of this study was to assess the utility of serum type IV collagen and serum laminin in diagnosing hepatic fibrosis and cirrhosis in patients with hereditary haemochromatosis. METHODS: The study group consisted of 42 patients with hereditary haemochromatosis and 19 Caucasian controls. Serum type IV collagen, laminin, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-1) concentrations were measured by enzyme-linked immunosorbant assay in serum from patients with haemochromatosis and control subjects. Liver biopsies from patients with haemochromatosis were graded for fibrosis and correlated with serum markers of hepatic fibrosis. RESULTS: Serum type IV collagen concentration was significantly increased in haemochromatosis patients compared to controls (130+/-79 ng/ml vs 81 +/- 17 ng/ml, p<0.05) and was significantly correlated with both the grade of histological fibrosis (r=0.67, p<0.0001) and serum MMP-2 levels (r=0.42, p<0.05). A serum type IV collagen concentration > 115 ng/ml (mean+2 SD of controls) was 100% sensitive and 69% specific in detecting severe (grade 3) fibrosis and cirrhosis. The sensitivity results of serum laminin and TIMP-1 were 11% and 56% respectively. CONCLUSIONS: Elevated serum type IV collagen is a sensitive indicator of the presence of severe fibrosis and cirrhosis in patients with haemochromatosis. Useful markers of hepatic fibrosis in other chronic liver diseases may not be applicable to haemochromatosis.

Biomarkers↗
PubMed1999

Interrelationships of alcohol and iron in liver disease with particular reference to the iron-binding proteins, ferritin and transferrin.

It is known that the regular consumption of alcohol is responsible for the disruption of normal iron metabolism in humans, resulting in the excess deposition of iron in the liver in approximately one-third of alcoholic subjects. The mechanisms involved are largely unknown; however, it is likely that the two major proteins of iron metabolism, ferritin and transferrin are intimately involved in the process. Tissue damage in alcoholic liver disease and the inherited iron-overload disease, haemochromatosis, are caused by excess alcohol and iron, respectively. The mechanisms of this damage are believed to be similar in both disease conditions and involve free radical-mediated toxicity. A high proportion of haemochromatosis sufferers consume excessive amounts of alcohol and synergistic hepatotoxic events may occur leading to the earlier development of liver cirrhosis. This review describes briefly the role of ferritin and transferrin in normal iron metabolism and in iron overload disease and explores the possible involvement of these proteins in the pathophysiology of excess iron deposition in alcoholic subjects.

Ferritins↗
PubMed1999

The haemochromatosis gene: a co-factor for chronic liver diseases?

There is increasing evidence that hepatotoxins, such as alcohol and the hepatitis viruses, act as co-factors in causing hepatic fibrosis and cirrhosis. For example, alcohol aggravates the hepatic damage produced by iron in hereditary haemochromatosis. We present evidence that the reverse is also true, that is, that iron loading of mild to moderate degree due to heterozygosity or homozygosity for the haemochromatosis genetic mutations acts as a significant hepatotoxin aggravating hepatic damage from other causes of liver disease. These include non-alcoholic steatohepatitis, chronic hepatitis C, porphyria cutanea tarda and possibly primary liver cell cancer. However, any additional hepatotoxic effect is due to the hepatic iron concentration and not the mutations in the haemochromatosis genes.

Chronic Disease↗
PubMed1999

The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region.

Mutations in the haemochromatosis (HFE) gene cause most of the cases of hereditary haemochromatosis among people of Northern European ancestry while remaining a rare cause of iron overload among indigenous persons of the Asia-Pacific region. Advances in understanding of the role of the HFE protein product and other recently cloned iron transporters signify an exciting period, as previously unknown components of the iron metabolism pathway are revealed one by one. Epidemiological studies have shown that this gene is more widespread than its phenotypic expression would suggest and that the heterozygous state may be implicated in the expression of other diseases of the liver such as porphyria cutanea tarda, hepatitis C virus infection and non-alcoholic steatohepatitis. The diagnosis, management and ethical implications for clinical practice in the aftermath of this discovery are discussed.

Asia↗
PubMed1999

Genetics of hemochromatosis.

Hereditary hemochromatosis (HHC) is a common autosomal recessive disorder of iron metabolism that results in progressive iron overload and can be fatal if untreated. The hemochromatosis gene (HFE) was identified by positional cloning in 1996. Two missense mutations have been described in HFE. The majority of HHC patients are homozygous for a cysteine-to-tyrosine substitution (C282Y); however, a small number are homozygous for a histidine-to-aspartic-acid substitution (H63D) or are heterozygous for both of these mutations. Mechanisms by which C282Y and H63D may disrupt the normal functioning of HFE have been suggested, but the role of HFE in the process of normal iron metabolism has yet to be clearly defined.

Amino Acid Substitution↗
PubMed1998

Diagnosis of hemochromatosis.

If untreated, hemochromatosis can cause serious illness and early death, but the disease is still substantially under-diagnosed. The cornerstone of screening and case detection is the measurement of serum transferrin saturation and the serum ferritin level. Once the diagnosis is suspected, physicians must use serum ferritin levels and hepatic iron stores on liver biopsy specimens to assess patients for the presence of iron overload. Liver biopsy is also used to establish the presence or absence of cirrhosis, which can affect prognosis and management. A DNA-based test for the HFE gene is commercially available, but its place in the diagnosis of hemochromatosis is still being evaluated. Currently, the most useful role for this test is in the detection of hemochromatosis in the family members of patients with a proven case of the disease. It is crucial to diagnose hemochromatosis before hepatic cirrhosis develops because phlebotomy therapy can avert serious chronic disease and can even lead to normal life expectancy.

Biopsy↗
PubMed1998

Management of hemochromatosis. Hemochromatosis Management Working Group.

The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of 1) removal of 1 unit (450 to 500 mL) of blood weekly until the serum ferritin level is 10 to 20 microg/L and 2) maintenance of the serum ferritin level at 50 microg/L or less thereafter by periodic removal of blood. Hyperferritinemia attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrinopathic abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation; reduce retention of nonferrous metals; and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.

Diet↗
PubMed1998

Hereditary hemochromatosis: gene discovery and its implications for population-based screening.

OBJECTIVE: To evaluate the role of genetic testing in screening for hereditary hemochromatosis to help guide clinicians, policymakers, and researchers. PARTICIPANTS: An expert panel was convened on March 3, 1997, by the Centers for Disease Control and Prevention (CDC) and the National Human Genome Research Institute (NHGRI), with expertise in epidemiology, genetics, hepatology, iron overload disorders, molecular biology, public health, and the ethical, legal, and social implications surrounding the discovery and use of genetic information. EVIDENCE: The group reviewed evidence regarding the clinical presentation, natural history, and genetics of hemochromatosis, including current data on the candidate gene for hemochromatosis (HFE) and on the ethical and health policy implications of genetic testing for this disorder. CONSENSUS PROCESS: Consensus was achieved by group discussion confirmed by a voice vote. A draft of the consensus statement was prepared by a writing committee and subsequently reviewed and revised by all members of the expert group over a 1-year period. CONCLUSIONS: Genetic testing is not recommended at this time in population-based screening for hereditary hemochromatosis, due to uncertainties about prevalence and penetrance of HFE mutations and the optimal care of asymptomatic people carrying HFE mutations. In addition, use of a genetic screening test raises concerns regarding possible stigmatization and discrimination. Tests for HFE mutations may play a role in confirming the diagnosis of hereditary hemochromatosis in persons with elevated serum iron measures, but even this use is limited by uncertainty about genotype-phenotype correlations. To address these questions, the expert group accorded high priority to population-based research to define the prevalence of HFE mutations, age and sex-related penetrance of different HFE genotypes, interactions between HFE genotypes and environmental modifiers, and psychosocial outcomes of genetic screening for hemochromatosis.

Female↗