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Involvement of the liver in hemochromatosis is generally a diffuse process. A review of the recent radiologic literature showed no reports of focal involvement of the liver by hemochromatosis. We report a case of focal hepatic lesions seen on magnetic resonance images which, when biopsied, proved to be an area of focal hemochromatosis.
To determine the frequency of liver profile abnormalities in hereditary hemochromatosis, we under took a retrospective survey in 100 patients, all of whom had undergone liver biopsy. Liver histology was compared with the biochemical profile, which included aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin and albumin determinations. Mild abnormalities in the AST and ALT levels were seen in more than 65% of patients. Patients with cirrhosis had significantly greater elevations in AST, ALT, and alkaline phosphatase, and a significant decrease in albumin (p less than 0.05). Proband cases had more frequent abnormalities than discovered cases within families. Accordingly, we find that mild abnormalities in the biochemical liver profile are common in hemochromatosis and suggest that patients with an unexplained abnormality in the liver profile should be screened for hemochromatosis with a serum ferritin and transferrin saturation.
Hereditary hemochromatosis is the most common cause of iron overload in adults and is probably the second most common cause of iron overload in children in the United States next to transfusional overload. Serious morbidity from this disorder of iron absorption can occur in early as well as in middle and advanced age, iron overload having been reported in children with hereditary hemochromatosis as early as 2 years of age. Younger persons differ from older persons in that the risk for iron loading in females appears to be equal to the risk for males, in contrast to a preponderance of males among older patients. Also, younger patients frequently demonstrate cardiac and gonadal involvement, with cardiac failure commonly leading to death, whereas older patients are more likely to have liver involvement and diabetes mellitus, with liver failure and hepatoma commonly leading to death. Because early diagnosis and treatment can prevent the toxicities of iron overload, appropriate screening can be lifesaving. Transferrin saturation is the most reliable screening test. Liver biopsy with objective measurement of hepatic iron stores is the most important diagnostic criterion at present, although reliable noninvasive methods for quantitating body iron are being developed. Young individuals who should be screened for iron overload include patients with cardiac myopathies, hypogonadism, amenorrhea, loss of libido, diabetes mellitus, other endocrine disorders, cirrhosis of the liver, and arthritis, as well as the siblings, parents, and children of patients with hereditary hemochromatosis or iron loading of unknown cause.
PURPOSE: To survey physicians about knowledge of hemochromatosis. METHODS: A questionnaire was faxed to American physicians. RESULTS: A total of 2,563 evaluable responses were obtained. There were > or = 70% correct responses about at-risk population, associated abnormalities, and population screening. There were 32% and 53% correct answers about diagnosis and treatment, respectively. A total of 8.0% and 4.9% reported asking > 75% of patients about family history of hemochromatosis and iron overload, respectively. Less than 25% requested HFE mutation analysis in the previous year. Correct answers were associated with academic practice, internal medicine specialty, and medical school graduation within 10 years. CONCLUSION: Many physicians have inadequate knowledge about hemochromatosis diagnosis and treatment.
PURPOSE: Hemochromatosis is a treatable disorder with a major genetic predisposition. It provides an example in which genotypic and phenotypic strategies for screening may be compared. We previously showed noninferiority of uptake of a genotypic population screening strategy for hemochromatosis compared with a phenotypic strategy. In this article we present the psychologic effects of each strategy. METHODS: A sample of 3000 individuals from primary care were randomly allocated to a phenotypic or genotypic screening strategy for hemochromatosis, and the 939 individuals who accepted screening provide the sample for this article. Standardized assessments of anxiety, general health, and depression were made at invitation, testing, result-giving, and 6 months. RESULTS: Screening did not lead to significant changes in the self-rated assessments of anxiety, depression, and general health over time, and there were no significant differences between the two screening strategies. The unemployed or permanently disabled had lower ratings of health and higher anxiety and depression. CONCLUSION: The two screening strategies appeared to cause little adverse psychologic disturbance in the short term, and there was no difference between the two strategies This study provides some empiric data to support arguments against "genetic exceptionalism" and suggests that genetic testing when used for population screening for a treatable disease has few adverse effects.
Transferrin saturation was determined in 11,431 men and 10,639 women aged 15 or more drawn from different areas in southern and central Finland and attending a multiphasic health screening examination in 1967-1972. All the 163 men and 66 women with transferrin saturation greater than or equal to 70% at the initial examination and still alive at the end of 1983 were invited to a re-examination. Of the invited persons, 76% attended the re-examination. Transferrin saturation and serum ferritin were the initial screening methods in the re-examination. All persons with suspected hemochromatosis were clinically examined and a laparoscopy was performed. Four men and four women were found with unequivocal hemochromatosis. Only one of these cases was diagnosed beforehand. According to these data the prevalence of hemochromatosis in Finland is about 50/100,000.
The molecular basis of hereditary hemochromatosis (HH) is more complex than previously expected. More than 80% of hemochromatosis probands of Northern European descent are homozygous for the C282Y HFE gene mutation. However, five novel non-related-HFE HH forms have now been identified. The transferrin receptor(TFR2)-linked form is inherited in an autosomal recessive pattern and is considered to be an adult-onset syndrome. Until now, it has been associated with five mutations that have only been detected in Japanese and southern European patients. Here, we report the identification of a novel TFR2 nonsense mutation in two related French adolescents. We discuss the phenotype of this sibling pair from precedent biological and clinical findings as well as the expected role of TFR2 in iron homeostasis. Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes.
Screening for hereditary hemochromatosis, although largely discussed, is not yet implemented in clinical practice. We evaluated the cost-effectiveness of 165 hemochromatosis population-screening algorithms involving two or three of several screening tests by developing a computer program that simulates all possible screening scenarios. Input data comprised government estimates of health services data and costs and a virtual population with user-defined demographic characteristics (including variable HFE mutation frequencies and penetrance values). We show that when C282Y homozygote prevalence is set at 3:1000, population screening appears cost-effective when penetrance of the biochemical phenotype is >0.70. When only hepatocellular carcinoma and cirrhosis are considered as the cost-driving complications, population-based screening is not significantly more cost-efficient than no screening, but life expectancy of individuals identified with hereditary hemochromatosis and treated is still improved by 7 years. Among the 165 screening algorithms tested in 91 different virtual populations of one million individuals, biochemical tests usually perform better as the initial test than genetic testing. Indeed, the genetic testing is most cost-effective as the final confirmatory test. Finally, for most combinations of prevalence and penetrance of HFE, one screening algorithm--unbound iron-binding capacity + transferrin saturation--appeared robust enough to be always within the top 5 most cost-effective strategies.
The clinical manifestations of primary or idiopathic hemochromatosis include mainly hepatomegaly, diabetes mellitus, and hypogonadism. Most investigators postulated that the hypogonadism is caused by pituitary dysfunction and that the deposition of iron in the testes is of little importance. We found not only pituitary failure in a 45-year-old man with idiopathic hemochromatosis (low LH and FSH levels, no response to GnRH) but could also detect by light microscopy deposition of iron in capillary endothelial cells and in the perivascular space of the testicular tissue. Electron microscopic study of tissue from the testes showed intracytoplasmic hemosiderin deposits in capillary endothelial cells. Abundant lipofuscin granules were present in Sertoli cells and Leydig cells. The serum testosterone levels were also lowered. In our opinion, the androgenic deficiency in idiopathic hemochromatosis is not only caused by pituitary failure but also by testicular dysfunction due to deposits of hemosiderin and lipofuscin in the testes.
OBJECTIVE: In hemochromatosis, areas of normal hepatic magnetic resonance (MR) signal intensity indicate the presence of iron-free-nodules, which are strongly suspected of being neoplastic. The goal of the study was to define the prevalence and the nature of these iron-free MR nodules at the time of diagnosis in 116 patients included in a prospective study assessing the accuracy of MR imaging (MRI) in the quantification of liver iron overload. METHODS: Seventy-nine of the 116 patients had homozygous hemochromatosis on a phenotypic basis. Fifteen-millimeter-thick contiguous slices were performed using T1- and T2-weighted gradient echo sequences with a 0.5 Tesla magnet. RESULTS: Six of 79 homozygous hemochromatotic patients had one or more MR iron-free nodules. Five of the six patients proved to have malignant tumors. Four of six iron-free nodules were hepatocellular carcinoma (5% in the hemochromatosis group and 17.5% in hemochromatotic patients with severe fibrosis). CONCLUSIONS: The present data confirm the high prevalence of liver cancer at the time of diagnosis, mainly in cirrhotic patients greater than 45 years of age, and indicate that, when performing MRI for liver iron quantification, a complete hepatic MRI examination is preferable to a simple signal measurement in patients at risk for hepatocellular carcinoma.
OBJECTIVE: The aim of this study was to evaluate patient compliance with phlebotomy therapy of hemochromatosis-associated iron overload. METHODS: We reviewed medical records of white adults with hemochromatosis and iron overload diagnosed during medical care. We defined three elements of compliance: 1) achieving iron depletion (serum ferritin </= 20 ng/ml); 2) timeliness of phlebotomies on a weekly or biweekly schedule to achieve iron depletion; and 3) participation in therapy to maintain serum ferritin </= 50 ng/ml. We evaluated associations of timeliness of phlebotomy and participation in maintenance therapy with these variables: age at diagnosis, sex, pretreatment serum ferritin concentration, HFE genotype, units of blood removed to achieve iron depletion, and presence or absence of cirrhosis at diagnosis. RESULTS: A total of 118 patients were evaluable for iron depletion and 142 for maintenance therapy; 96.6% achieved iron depletion, and 33.1% and 43.2% followed weekly and biweekly schedules, respectively. Timeliness was not significantly associated with the variables we evaluated. In the first year of maintenance therapy, 84.0% of patients complied; the percentage of C282Y homozygotes complying was significantly greater than that of other patients. Average compliance with maintenance therapy decreased 6.8% annually; the mean follow-up after achieving iron depletion was 4.1 +/- 2.8 yr (range 0.6-9.7 yr). CONCLUSIONS: Most patients with hemochromatosis diagnosed in medical care achieve iron depletion with phlebotomy; one-third tolerate and adhere to weekly phlebotomy. There is a constant rate of decline in the percentage of patients who comply with maintenance therapy.
PURPOSE: To assess the relationship between magnetic resonance (MR) imaging pituitary signal intensity reduction in patients with transfusional hemochromatosis and the clinical manifestation of hypogonadotropic hypogonadism. MATERIALS AND METHODS: Pituitary MR imaging at 0.5 T was performed in 38 consecutive patients affected by secondary hemochromatosis and in 20 healthy volunteers. Serum ferritin levels were estimated in the affected population. Twenty (53%) of the 38 patients had hypogonadotropic hypogonadism diagnosed. Pituitary-to-fat signal intensity ratios were calculated from coronal gradient-echo (GRE) T2*-weighted MR images. The relationship between the quantitative reduction of the pituitary-to-fat signal intensity ratio and the clinical manifestation of pituitary dysfunction was assessed in the affected population. Signal intensity reduction in the anterior lobe of the pituitary gland was also correlated with the serum ferritin level. RESULTS: The degree of reduction of the pituitary-to-fat signal intensity ratio correlated with the presence of hypogonadotropic hypogonadism, with a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89%. In addition, the reduction of pituitary signal intensity was greater in patients with higher ferritin levels (r = -0.55, r(2) = -0.30, P <.001). CONCLUSION: The degree of signal intensity reduction, measured as the pituitary-to-fat signal intensity ratio for GRE T2*-weighted images, in patients with secondary hemochromatosis correlates with the severity of pituitary dysfunction.
The gene for hereditary hemochromatosis is linked to the HLA locus on chromosome 6. Four cloned DNA probes originating from the HLA class I region were used to detect seven restriction fragment length polymorphisms (RFLPs). Allele frequencies and segregation of each RFLP was determined. Analysis of RFLPs in 38 unrelated homozygotes with hemochromatosis revealed differences in allele frequencies between the control and the hemochromatotic groups but these differences did not reach statistical significance. Some differences persisted, however, even when only controls with the A3 antigen were compared with A3 hemochromatotics. Since both control and hemochromatotic groups were small, further studies will be necessary to ascertain whether these RFLPs could serve to locate the gene responsible for hereditary hemochromatosis.
In the present study, we have evaluated the relationship between serum ferritin (SF) levels, 'hemochromatosis allele(s)', blood transfusions and iron parenteral administration in 69 hemodialysis patients. We demonstrated significantly higher SF levels in patients with hemochromatosis allele(s) (HA+) than in patients without hemochromatosis alleles (HA-). In addition, HA+ patients who had received blood transfusions up to 15 months prior to the study had SF levels even higher than those without blood transfusions. On the other hand, HA- patients had normal levels of SF, independent of blood transfusions. After intravenous administration of 1 g iron saccharate, SF levels were significantly higher only in HA+ transfused patients. In conclusion, our study demonstrated that HA+ patients are at a higher risk of iron overload and therefore the use of transfusional and/or parenteral iron should be strictly limited.
The arthropathy of hemochromatosis mimics aspects of both rheumatoid arthritis and degenerative joint disease. The negative latex fixation, involvement of weightbearing and non-weightbearing joints, as well as the peculiar involvement of the second and third metacarpophalangeal joints serve to distinguish this rare arthropathy from other inflammatory and degenerative arthritides. The purpose of this paper is to present a case of hemochromatosis arthritis with unusual bilateral involvement of the naviculocuneiform and tarsometatarsal joints. Only two cases of hemochromatosis of the foot have been previously reported, and those had involvement limited to the first metatarsophalangeal joint.
Hemochromatosis is a disorder of excess iron deposition in tissues that may cause multiorgan dysfunction. Because the early symptoms of hemochromatosis are nonspecific, the diagnosis is frequently overlooked until significant organ failure has developed. The primary cause of death in these patients is usually liver cancer related to cirrhosis. Patients who are candidates for liver transplantation should be referred for evaluation. For patients with severe cardiomyopathy, in addition to end-stage liver disease, combined transplantation may be performed. Although there is a limited number of combined heart-liver transplantations that have been performed, successful outcomes can be achieved with close monitoring and a multidisciplinary team approach. In this case report, we will discuss the prevalence, pathophysiology, and treatment of hemochromatosis and potential complications of combined heart-liver transplantation.
SFT, a stimulator of iron (Fe) transport, has been described as a transmembrane protein that facilitates the uptake of ferrous and ferric iron in mammalian cells. This study was initiated to investigate the 5' regulatory region of SFT and its role in the etiology of hereditary hemochromatosis. Sequence analyses of the putative 5' regulatory region revealed that the SFT cDNA sequence corresponds to intron 6/exon 7 of UbcH5A, a member of E2 ubiquitin-conjugating enzymes, which is involved in the iron-dependent ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Further mRNA expression studies using a sequence-specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay showed that UbcH5A is significantly up-regulated in the liver of iron-overloaded patients with hereditary hemochromatosis, as previously published for SFT. However, in vitro studies on HepG2 cells failed to demonstrate any significant UbcH5A regulation in response to iron loading or iron chelation. In conclusion, in vivo mRNA expression data previously obtained for SFT might be attributed to UbcH5A. The role of UbcH5A and the ubiquitination pathway in the etiology of hereditary hemochromatosis remains to be elucidated further.
Ferroportin (FPN) mediates iron export from cells; FPN mutations are associated with the iron overloading disorder hemochromatosis. Previously, we found that the A77D, V162del, and G490D mutations inhibited FPN activity, but that other disease-associated FPN variants retained full iron export capability. The peptide hormone hepcidin inhibits FPN as part of a homeostatic negative feedback loop. We measured surface expression and function of wild-type FPN and fully active FPN mutants in the presence of hepcidin. We found that the Y64N and C326Y mutants of FPN are completely resistant to hepcidin inhibition and that N144D and N144H are partially resistant. Hemochromatosis-associated FPN mutations, therefore, either reduce iron export ability or produce an FPN variant that is insensitive to hepcidin. The former mutation type is associated with Kupffer-cell iron deposition and normal transferrin saturation in vivo, whereas patients with the latter category of FPN mutation have high transferrin saturation and tend to deposit iron throughout the liver parenchyma. FPN-linked hemochromatosis may have a variable pathogenesis depending on the causative FPN mutant.