Arthropathy in hemochromatosis

Early diagnosis of hemochromatosis may prevent the numerous risks of iron overload. One of the most common early manifestations of this disease is arthropathy. The clinical and radiologic findings of hemochromatosis arthropathy are discussed. Diagnosis is suggested by simple laboratory tests and confirmed by liver biopsy with measurement of hepatic iron content. Treatment includes the removal of the excess body iron by phlebotomy. Unfortunately, symptoms of arthropathy tend to be resistant to phlebotomy.     

Hereditary hemochromatosis

Genetic (hereditary) hemochromatosis is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39. Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excess iron storage eventually produces pituitary, pancreatic, cardiac, and liver dysfunction and death may result from cardiac arrhythmias, congestive heart failure, and/or hepatic failure or cancer. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations. Patients at risk for genetic hemochromatosis should be screened, identified, and treated as early as age 20 to prevent or minimize the deadly complications of hemochromatosis. Population screening should include measurements of serum iron concentration, total iron binding capacity (TIBC), percent saturation of transferrin, and serum ferritin concentrations. Family members of hereditary hemochromatosis patients are at increased risk and should be tested. Screening, identification and early treatment (phlebotomies, sometimes in combination with the use of Desferal or other iron-chelating agents) may help prevent or reduce iron-related organ damage and premature deaths. Early diagnosis and treatment will reduce the population of aging individuals with severe, complicated hemochromatosis and dramatically reduce medical costs (billions of U.S. dollars per annum) associated with the management of this disease.     

Histologic quantification of hemochromatotic and non-hemochromatotic liver siderosis. A stidu of 254 liver biopsies

Non hemochromatotic liver siderosis often present an heterogeneous iron distribution, but histological scoring of iron overload are validated only in case of genetic hemochromatosis, where iron is homogeneously distributed. The aim of this work was to study the improvement of histological scoring by introducing a coefficient of heterogeneity in cases of heterogeneous liver siderosis. Thus, on 254 liver biopsies with siderosis were determined: i) the histologic total iron score (TIS) as previously described; ii) the coefficient of heterogeneity, leading to corrected TIS (corTIS); iii) the liver iron content (LIC). Liver siderosis was homogeneously distributed in 160 biopsies and heterogeneously distributed in 94. Correlation between histological scoring and LIC, in the group with heterogeneous liver siderosis, was improved by the use of the coefficient of heterogeneity. This coefficient leads to accurately quantify all liver siderosis.     

Lexical effects and lexical properties associated with National Adult Reading Test (NART) stimuli in healthy young adults and healthy elderly adults

Among patients with hepatic iron overload, the distinction between hereditary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discovery of a specific homozygous mutation (C282Y) in a novel major histocompatibility complex class I-like gene (named HLA-H or HFE) in 80% to 100% of well-characterized cases of HH suggests that direct DNA-based mutation analysis may help resolve this dilemma. To assess the clinical utility of direct HLA-H mutation analysis in a typical diagnostic setting, we measured genotypic and phenotypic parameters of iron overload in 37 subjects with biopsy-proven hepatic siderosis (2+ or greater) and in 127 healthy control subjects. The prevalence of C282Y homozygotes was significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozygous mutation and hepatic iron overload. In the hepatic siderosis group, C282Y homozygotes had significantly higher hepatic iron and ferritin levels, a significantly lower prevalence of hepatitis C virus or alcoholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HII) in the previously defined "hemochromatosis range" (>1.9), 9 (45%) were C282Y homozygotes. Of the 11 nonhomozygous subjects with an HII greater than 1.9 (presumed false-positive HIIs), 10 (91%) had hepatic cirrhosis compared with 3 of 9 (33%) homozygotes with an HII greater than 1.9 who had cirrhosis (P<.02). The HII thus has poor diagnostic specificity for predicting genotypic HH in patients with cirrhosis. We conclude that direct determination of the HLA-H C282Y genotype may be the single best diagnostic test for HH, particularly in patients with cirrhosis, for whom the HII is quite nonspecific.     

Current diagnosis: hereditary metabolic diseases of the liver (primary hemochromatosis, Wilson disease)

Primary hemochromatosis is characterized by a specific pattern of clinical manifestations. It includes liver disease with hepatomegaly, glucose intolerance, e.g. diabetes, hyperpigmentation oft the skin, impotence/ amenorrhea, arthropathy, cardiomyopathy and fatigue. Laboratory investigation reveals significantly elevated serum ferritin and transferrin saturation with iron. The diagnosis is confirmed by liver biopsy and quantitative determination of elevated liver iron content. Wilson's disease represents a copper storage disease. Prominent clinical features are hepatomegaly and splenomegaly. Neurological alterations and detection of Kayser-Fleischer corneal rings are typical. In the acute initial phase the often young patients present with Coombs-negative hemolysis. Psychiatric alterations, cardiomyopathy, arthropathy, nephropathy, as well as thrombocytopenia and leucopenia are other clinical features. Laboratory parameters of Wilson's disease include low serum ceruloplasmin and serum copper. There is an elevated urinary copper excretion and elevated serum free copper concentration. The diagnosis is confirmed by liver biopsy with quantitative determination of an elevated liver copper content.     

Diagnosis of hemochromatosis probands in a community hospital

PURPOSE: To evaluate factors that lead to the diagnosis of hemochromatosis probands in a community hospital, including education of physicians about hemochromatosis and iron overload, specialty of physicians, diagnostic indicators of hemochromatosis, and clinical manifestations of hemochromatosis probands. PATIENTS AND METHODS: We conducted a hemochromatosis education program for health care personnel associated with a community hospital and the public during 1990 to 1994. Data on physicians who diagnosed probands, diagnostic indicators of hemochromatosis, and manifestations of hemochromatosis and associated illnesses were tabulated. Iron grades of all hospital liver biopsy specimens obtained from Caucasian subjects during 1990 to 1994 were also analyzed. RESULTS: We identified 162 hemochromatosis probands; 66.7% were diagnosed by physicians who participated in our education program. Primary care and internal medicine subspecialty physicians diagnosed 66.7% and 29.6% of probands, respectively, based on elevated serum iron parameters and hepatic enzyme concentrations (51.9% and 36.4% of probands, respectively). Iron overload occurred in 90.7%, and was associated with clinical manifestations in most. Of 844 hospital liver biopsy specimens from Caucasians, 8.5% had increased iron grades; 4.6% represented hemochromatosis. CONCLUSIONS: Physicians with current education readily diagnose hemochromatosis probands during routine health care delivery, but most probands identified in this manner have iron overload. Our results suggest that community physicians and hospitals could contribute substantially to hemochromatosis screening programs, permitting detection of more homozygotes before the development of iron overload.     

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.     

Prediction of the helix/strand content of globular proteins based on their primary sequences

Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease. The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes. Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures a family history of hemochromatosis, or consistent early signs and symptoms of the disease.     

Delayed presentation of 50 years after a World War II vascular injury with intraoperative localization by duplex ultrasound of a traumatic false aneurysm

The cause of the hepatic siderosis and iron overload that is common in porphyria cutanea tarda (PCT) is uncertain. Heterozygosity for genetic hemochromatosis has been supported by some studies of the association between the HLA-A3 antigen and porphyria cutanea tarda but not by others. The hemochromatosis gene is now believed to be located telomeric to HLA-A3 and close to the DNA microsatellite marker D6S1260. We have used this and other microsatellite markers, which together define an ancestral haplotype that is strongly linked to hemochromatosis, to reinvestigate the relationship between these disorders in 41 British patients with sporadic PCT. Fifteen patients carried the hemochromatosis-associated alleles D6S265-1 and D6S105-8. Four of these were homozygous for the ancestral haplotype D6S265-1 : D6S105-8: D6S1260-4. We estimate that approximately 37% of British patients with sporadic PCT carry at least one hemochromatosis gene compared with 10% of the general population.     

Gender differences in general practice consultations: methodological challenges in epidemiological research

The present study is an analysis of the frequencies of HFE mutations in patients with different forms of iron overload compared with the frequencies found in healthy subjects from the same region. The frequencies of HLA-A and -B antigens and HLA haplotypes were also analyzed in the same subjects. The study population included: 71 healthy individuals; 39 genetically and clinically well-characterized patients with genetic hemochromatosis (HH); and 25 patients with non-classical forms of iron overload (NCH), excluding secondary hemochromatosis. All subjects were HLA-typed and HFE-genotyped by the oligonucleotide ligation assay (OLA). The gene frequencies found for the C282Y and H63D mutations of HFE were respectively: 0.03 and 0.23 in healthy individuals, 0.86 and 0.04 in HH patients, and 0.08 and 0.48 in NCH patients. An expected significant association between HH and HLA-A3 was observed, which was found to be in linkage disequilibrium with the C282Y mutation. A new association was seen, however, between HLA-A29 and NCH, in linkage disequilibrium with the H63D mutation. Again as expected, the HLA-B antigen B7 was associated with HH in linkage disequilibrium with HLA-A3. In addition, the HLA-B antigen B44 was found to be associated with NCH but not in linkage disequilibrium with either A29 or the H63D mutation. In conclusion, a new association of the HFE H63D mutation with forms of hemochromatosis other than HH and a new association between the HLA phenotype A29 and the HFE H63D mutation were found in the same patients. These findings reinforce evidence for the involvement of the major histocompatibility class I in iron metabolism, supporting the notion of a physiological role for the immunological system in the regulation of iron load.     

Interaction of the hemochromatosis gene product HFE with transferrin receptor modulates cellular iron metabolism

Mutations of a novel MHC class I-like protein, termed HFE, have been found in the vast majority of patients with the iron overload disease heredity hemochromatosis. Identification of HFE is likely to shed light on one of the major enigmas of mammalian iron homeostasis: How is intestinal iron absorption regulated?     

Drug use patterns and gender differences among heroin addicts hospitalized for detoxification

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.     

Iron-overload in patients on maintenance hemodialysis: diagnostic criteria, indications and treatment by desferrioxamine (author's transl)

33 patients with chronic renal failure were divided into two groups. Group I consisted of 8 non-dialysed patients without any clinical or biochemical sign of liver disturbance nor any iron supplementation. Group II consisted of 25 maintenance hemodialysis (MHD) patients treated from 2 to 13 years. 19 subjects had chronic B hepatitis. Total exogenous iron load parenteral iron and/or blood transfusions) was calculated. Body iron overload (hemosiderosis) was assessed by liver iron concentration (LIC) in needle biopsy specimens according to Barry's method (less than 200 microgram/100 mg dry weight) and serum ferritin levels (less than 360 ng/ml). 4 patients whose serum ferritin was increased with or without hepatic fibrosis and with or without any organ dysfunction due to hemochromatosis received i.v. infusions of desferrioxamine in doses of 2 g at each dialysis. Serum ferritin levels were correlated with LIC (p less than 0.001) and iron load (p less than 0.001). Hemosiderosis was noted in 16 MHD patients (group II) and correlated with iron load. Hemochromatosis was noted in 4 patients (group II). 4 hemodialysed patients with iron overload were treated by desferrioxamine from 6 to 18 months. During this therapy, body iron stores fell and organ dysfunction (heart failure, hepatic cytolysis, anaemia, diabetes mellitus improved. Long-term chelation therapy by desferrioxamine was effective and the chelated iron was readily removed by dialysis. These data show the importance of precise evaluation of iron stores in MHD patients.     

Deforming arthropathy or lupus and rhupus hands in systemic lupus erythematosus

OBJECTIVE: Although deforming arthropathy in systemic lupus erythematosus (SLE) is characterised by a number of manifestations, definitive criteria for the different forms have not yet been established. To define deforming arthropathy and its different types a study was undertaken of 176 SLE patients. METHODS: Using as criterion any deviation from any of the metacarpus finger axes 17 patients (16 women, one man) were identified with clinical deforming arthropathy. These patients were evaluated according to a standardised protocol that covered all known characteristics of deforming arthropathy. By means of "Jaccoud's arthropathy index" three different forms were identified. RESULTS: Three patients had an erosive form of deforming arthropathy (or rhupus hand) such as those seen in frank rheumatoid arthritis (RA), eight patients were identified as having Jaccoud's arthropathy (or lupus hand), and the remaining six patients had mild deforming arthropathy. Jaccoud's arthropathy is characterised by severe deformation of the hands (ulnar deviation, swan neck deformities, and Z deformity of the thumb) and feet with multiple non-erosive subluxations, mild aching and little or no evidence of synovitis. All patients, but one, fulfilled just four criteria of the ACR classification and joint symptoms were always found to precede the diagnosis of SLE. Furthermore a remarkable association of Jaccoud's arthropathy with fetal loss, thrombosis--both venous and arterial--and the presence of antiphospholipid antibodies was found. CONCLUSIONS: These data suggest that Jaccoud's arthropathy represents a subset of SLE. Subdivision of deforming arthropathy into several clinical forms can facilitate the clinical management of this disorder.     

Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data

BACKGROUND: Hemochromatosis, which can lead to serious chronic diseases resulting from iron overload, has an estimated prevalence of 50 to 80 cases per 10000 persons. However, little population-based information is available on the impact of hemochromatosis on morbidity and mortality. OBJECTIVE: To evaluate trends over 14 years in deaths and medical conditions associated with hemochromatosis in the United States. DESIGN: We searched Multiple-Cause Mortality Files compiled by the National Center for Health Statistics for the years 1979 to 1992 for all records listing hemochromatosis. We used these data to calculate age-adjusted and age-specific mortality rates, identify medical conditions associated with a known diagnosis of hemochromatosis at death, and calculate proportionate mortality ratios for these medical conditions. RESULTS: The listing of hemochromatosis on death certificates increased 60% from 1979 to 1992. Decedents with hemochromatosis were 23, 13, and 5 times more likely to have liver neoplasms, liver disease, and cardiomyopathy, respectively, than were decedents without hemochromatosis. Conversely, decedents with liver neoplasms, liver disease, and cardiomyopathy were 26, 14, and 5 times more likely, respectively, to have hemochromatosis than were decedents without these conditions. Hemochromatosis was 82 times more likely in persons with the combination of liver neoplasms and diabetes and 43 times more likely in those with the combination of liver disease and diabetes than in those without these conditions. CONCLUSIONS: Comparison of the reported prevalence of hemochromatosis among decedents with estimates of prevalence in the general U.S. population suggests that either the penetrance or the recognition of hemochromatosis, or both, is low. Nevertheless, substantial mortality resulting from liver disease, liver neoplasms, cardiomyopathy, and a combination of liver disease and diabetes in patients with hemochromatosis argues for the improved diagnosis and treatment of hemochromatosis in persons with these conditions.     

Research priorities in hereditary hemochromatosis

The Working Group on Research Priorities used a formal nominal group technique to identify and prioritize the specific aims of applied research needed to provide the scientific basis for population screening for iron overload disorders. The most important applied research goal was characterization of the natural history of the relation between genotype and phenotype in hereditary hemochromatosis and other iron overload disorders. Three other important research objectives were development of an optimal approach to screening for iron overload; analyses of the cost-effectiveness of screening; and assessment of the ethical, legal, and social implications of screening. To achieve these specific aims, two research studies were recommended as being of the highest priority: a multicenter, cross-sectional, population-based study of the natural history of iron overload and a multicenter, case-control study of patients with disease manifestations potentially attributable to hereditary hemochromatosis in primary care and subspecialty clinics.     

Iron as a hepatotoxin

Although essential for life, iron in excessive amounts may be toxic. The liver is particularly subject to the toxic effects of iron, since it is the major site of iron storage. Several inherited and acquired human disorders may result in hepatic iron overload, the most common of which are genetic hemochromatosis (GH) and transfusional iron overload. GH is an inherited disorder of iron metabolism, and in patients with GH excess iron absorbed from the gut is transported through the portal vein to the liver. The mechanisms by which excess iron exerts its cytotoxic effects include enhanced formation of free radicals and peroxidation of organelle membrane lipids. Lipid peroxidation can lead to structural and functional alterations in lysosomes, mitochondria and the endoplasmic reticulum. With massive iron overload, such iron-induced alterations may cause cell death, also known as sideronecrosis. At this stage, fibrogenesis is initiated and, if the excess iron is not removed, the increased deposition of collagen progresses to cirrhosis. However, the mechanisms underlying iron-induced fibrosis remain unclear. Transformation of fat-storing cells to collagen-producing myofibroblasts has been proposed to be induced either by iron; by lipid peroxides or other cellular factors released from iron-loaded, damaged hepatocytes; or by profibrogenic factors produced by activated Kupffer cells. In addition, iron may enhance the cytotoxic and, possibly, fibrogenic effects of other liver cell-damaging agents, such as alcohol or hepatotrophic viruses. Once cirrhosis is manifest, patients with GH demonstrate a 200-fold increase in the risk for development of hepatocellular carcinoma. In vitro, iron has been shown to possess mutagenic properties, but the results from in vivo models in which the genotoxic effects of iron overload have been studied are variable. Similarly, although iron has mitostimulatory effects on hepatocytes in vivo and preneoplastic cells in vitro, its role in tumor promotion and/or progression still remains unclear. Cirrhosis itself is of central importance in the carcinogenic process, but whether or not iron acts as an additional risk factor in this process, alone or by enhancing the tumorigenic properties of other hepatocarcinogens, has yet to be established.     

Iron overload is a risk factor for zygomycosis

Well-recognized risk factors for zygomycosis include diabetic ketoacidosis, immunocompromise, and deferoxamine therapy for iron or aluminum overload, usually in patients undergoing kidney dialysis. We report a case of fatal nasal-orbital-cerebral zygomycosis in an 82-year-old man with known myelodysplasia and well-controlled diabetes. He was not receiving deferoxamine. Despite radical surgery and amphotericin B therapy, he died; primary hemochromatosis with gross iron overload was found post mortem. Experimental evidence suggests iron overload without deferoxamine therapy may be a risk factor for zygomycosis; the findings in this case would support this hypothesis.     

Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome

Hereditary hemochromatosis is one of the most common inherited disorders among Caucasians of European ancestry. Malregulation of iron absorption from the duodenum eventually leads to iron overload. Although the time required to become iron loaded is variable, it is clear that most homozygotes will eventually become symptomatic. The clinical manifestations can be prevented by prophylactic phlebotomy therapy. Screening young populations is therefore a key to the prevention of disease-related morbidity. Protocols based on the phenotype of high transferrin saturation already exist. The recent identification of a candidate gene for hemochromatosis now allows for a potential genetic screen. Both the phenotypic and the genotypic methods of screening have inherent advantages and disadvantages. Iron-depletion therapy of homozygotes before the development of disease-related morbidity results in normal longevity. National initiatives for hemochromatosis screening will prevent morbidity by identifying and treating young, healthy homozygotes. Healthy, iron-depleted homozygotes should be eligible for health and life insurance at standard rates. Furthermore, healthy homozygotes would make ideal blood donors.