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PubMed1977

A family study of a patient with idiopathic hemochromatosis.

A family study of a patient with idiopathic hemochromatosis using noninvasive techniques is presented. All 6 of the patient's asymptomatic children had an increase in transferrin saturation and/or an increase in the absorption of Co57. The Co57 absorption test was the most sensitive index of family involvement since one of the children had an increase in absorption at a time when transferring saturation was normal. The family data strongly support the hereditary nature of the disorder, with the mode of inheritance not clearly established from the available data.

Cobalt Radioisotopes↗
PubMed1990

Percent transferrin saturation in segregating hemochromatosis.

The segregation of genetic hemochromatosis was analyzed by using percent transferrin saturation (TS) as a phenotypic marker of the disease. Homozygotes for the disease were readily discernable with the added information provided by the quantitative indicator. However, there was no evidence of partial expression of TS abnormalities in heterozygotes, contrary to previous studies.

Adult↗
PubMed1982

Articular cartilage in the degenerative arthropathy of hemochromatosis.

Iron was readily demonstrated in chondrocytes in 3 of 4 hemochromatosis articular cartilages studied. Either apatite, calcium pyrophosphate dihydrate crystals, or both were found in all cartilages including those of 3 patients who had no radiographic or light microscopic evidence of calcification. These crystals, which may be secondary to degenerative changes or may play a role in cartilage degeneration, were not seen in any consistent morphologic relationship with the iron deposits. In fact, apatite was found in one cartilage in which no iron was identified in the sections studied. If iron, as demonstrated in the chondrocytes, is contributing to the calcium crystal deposition, it would most likely do so indirectly, for example by altering chondrocyte enzymes or connective tissue components.

Aged↗
PubMed1987

Arthritis in hereditary hemochromatosis.

Seven pedigrees with 45 members were evaluated for arthropathy associated with hereditary hemochromatosis (HC). Patients with symptomatic extraarticular disease were compared with asymptomatic patients who had evidence of HC on laboratory findings, and with normal subjects. Patients who were homozygous for HC were compared with heterozygous patients and normal subjects. HC arthritis does not appear to be an early predictor of disease, and chondrocalcinosis is a late manifestation of HC arthropathy.

Adult↗
PubMedDate not supplied

HLA typing in idiopathic hemochromatosis: distinction between homozygotes and heterozygotes with biochemical expression.

In a study of 20 families with idiopathic hemochromatosis, relatives of probands were classified as either homozygous, heterozygous, or normal according to their HLA phenotype. An abnormality in the serum iron concentration, total iron-binding capacity, or serum ferritin concentration was present in all homozygotes and in 25% of heterozygotes. In heterozygotes, the mean total iron-binding capacity was significantly decreased, and the mean hepatic iron concentration was significantly increased compared to normals. However, in contrast to homozygotes, clinical evidence of iron overload was not observed in heterozygotes, and there was no biochemical or histological evidence of liver disease resulting from excessive iron stores. Progressive iron overload did not develop in 44 heterozygotes who were studied for up to 16 yr.

Adolescent↗
PubMedDate not supplied

Evaluation of liver iron content by computed tomography: its value in the follow-up of treatment in patients with idiopathic hemochromatosis.

The therapeutic management of patients with idiopathic hemochromatosis (IH) implies the evaluation of excess hepatic iron. This work was undertaken to confirm the value of computed tomography for the assessment of liver iron overload in such patients and to evaluate this technique during the course of treatment by phlebotomy. The study included 24 patients with initially untreated IH and 7 patients previously treated by phlebotomy for 10 months to 7 years. Follow-up was obtained in 15 subjects. In patients with untreated IH, liver attenuation coefficient (LAC) was always markedly increased (92.4 +/- 7.1 Hounsfield units) as compared with LAC of subjects with normal liver (60.2 +/- 3.1 Hounsfield units) and that of patients with chronic liver disease (53.8 +/- 4.8 Hounsfield units), and was found to be specific for liver iron overload. LAC decreased progressively during phlebotomy, and this diminution was correlated with the amount of mobilized iron (r = 0.79, p less than 0.001); it returned to normal values only after complete removal of iron overload. LAC was closely correlated with liver iron concentration (r = 0.83, p less than 0.001), better than usual biochemical parameters, especially serum ferritin (r = 0.70, p less than 0.01). This study confirms that the determination of LAC on computed tomography provides a reliable index of hepatic iron stores in patients with IH, without requiring a liver biopsy, and shows that this noninvasive method is of particular interest for the follow-up of patients treated by phlebotomy.

Adult↗
PubMedDate not supplied

Androgen and estrogen response to adrenal and gonadal stimulation in idiopathic hemochromatosis: evidence for decreased estrogen formation.

Gonadal function in idiopathic hemochromatosis (IHC) was evaluated by comparing clinical features and levels of sex hormones in 10 male patients with IHC (cirrhosis, 4; fibrosis, 6), 6 male patients with alcoholic cirrhosis (AC) and 10 healthy, age-matched controls. Impotence was present in 9 IHC and all AC patients and was associated with decreased plasma testosterone levels. However, gynecomastia, a feature in all patients with AC, was not present in IHC, and plasma sex hormone binding globulin was normal. Patients with IHC showed significantly lower basal estradiol levels (17.7 +/- 6.3 pg per ml) than did controls (28.5 +/- 8.5 pg per ml), and low LH levels (p less than 0.01), which were insufficiently stimulated by luteinizing hormone releasing hormone (n = 8) as well as a decrease in prolactin concentration (2.9 +/- 1.4 vs. 5.9 +/- 1.9 ng per ml in the controls) suggesting pituitary failure. Synthesizing capacity of sex hormones was determined by adrenocorticotropic hormone and human chorionic gonadotropin administration. Basal and stimulated levels of androstenedione and cortisol indicated normal function of the adrenals in IHC. However after adrenocorticotropic hormone, estrone levels increased to only 16.2 +/- 8.4 pg per ml (controls, 27.3 +/- 4.7 pg per ml; p less than 0.01). Increments of estrone (12.5 +/- 9.2 pg per ml) and estradiol (17.9 +/- 11.6 pg per ml) were also lower in IHC following human chorionic gonadotropin administration than in controls (26.0 +/- 7.2 and 37.5 +/- 11.4 pg per ml, respectively). In contrast, plasma human chorionic gonadotropin raised testosterone levels 3.3-fold in IHC and 2.2-fold in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Function Tests↗
PubMedDate not supplied

Serum type III procollagen peptide in alcoholic liver disease and idiopathic hemochromatosis: its relationship to hepatic fibrosis, activity of the disease and iron overload.

To assess the value of type III procollagen peptide (sPIIIP) as a marker of hepatic fibrosis, sera from 73 patients with alcohol-related liver disease and 30 patients with idiopathic hemochromatosis (IHC) were studied by a specific radioimmunoassay. sPIIIP was increased in 87% of 30 patients with cirrhosis, in 16% of 32 with steatofibrosis but in none of 11 with steatosis. There was a significant correlation with histologic hepatocellular necroinflammation (r = 0.42, p less than 0.01), but not with hepatic fibrosis. sPIIP was increased in 33% of 30 patients with IHC, whether or not they had cirrhosis or fibrosis, and whatever the level of iron overload or the extent of the hepatic deterioration. IHC patients with increased levels of sPIIIP had a higher prevalence of superimposed hepatic damage than did those with normal procollagen levels (p less than 0.05). Our findings, therefore, weaken the diagnostic value of sPIIIP as an index of connective tissue deposition in the liver, and suggest that, at least in alcohol-related liver disease and IHC, hepatocellular necroinflammation influences the results.

Adult↗
PubMedDate not supplied

Hepatic heme synthesis in a new model of experimental hemochromatosis: studies in rats fed finely divided elemental iron.

Rats fed chow containing finely divided elemental iron (from carbonyl-iron) develop hepatic iron overload resembling human hereditary hemochromatosis in that deposition of iron is primarily in periportal hepatocytes and with hepatic iron concentrations sufficiently high to be associated in the human disease with hepatic fibrosis or cirrhosis. In recent studies using this model, we reported changes in hepatic hemoproteins and heme oxygenase, the rate-controlling enzyme of heme breakdown. We now report effects of iron-loading on three enzymes of heme synthesis: 5-aminolevulinate synthase; the first and rate-controlling enzyme of the pathway, 5-aminolevulinate dehydrase (or porphobilinogen synthase), and uroporphyrinogen decarboxylase, the activity of which is decreased in porphyria cutanea tarda, a liver disease in which iron is known to play an important but still poorly understood role. Of the three enzymes, only activity of the dehydrase was altered by iron-loading: it was decreased significantly as early as 1 week after starting iron feeding, and with marked iron overload was 30 to 32% of control values. The degree of decrease was inversely related (r = -0.77 to -0.88) to the degree of iron overload and was partially reversed within 1 to 3 days when feeding of the iron-supplemented diet was stopped. The decrease in dehydrase activity was not attributable to lack of reduced glutathione or other disulfide-reducing agents or to zinc deficiency; nor was evidence found for inhibition by iron compounds or other possible inhibitors present in iron-loaded livers.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Aminolevulinate Synthetase↗
PubMed1992

Saturability of hepatic iron deposits in genetic hemochromatosis.

The relationship of pretreatment serum ferritin and hepatic iron concentration to body iron removed by venesections was evaluated in 33 patients with genetic hemochromatosis. The median values of the three variables considered were 1,950 micrograms/L (range = 255 to 10,000), 1,175 micrograms/100 mg dry weight (range = 270 to 4,310) and 10 gm (range = 2 to 41), respectively. At basal liver biopsy 18 patients had cirrhosis, 6 patients had fibrosis and 9 patients had a normal pattern; siderosis was degree 3 in 6 patients and degree 4 in 27 patients. The results of fitting a polynomial regression of second degree showed that the curve of serum ferritin on iron removed was a straight line (R2 = 0.79, with a significant coefficient of linearity, p less than 0.01, and a nonsignificant coefficient of curvature), whereas that of hepatic iron concentration on iron removed showed a curvature (R2 = 0.62, with significant coefficient of linearity and curvature, p less than 0.01) and reached a plateau. The sigmoid model fit the curve of hepatic iron concentration on iron removed (R2 = 0.61), which suggested a saturation of hepatic iron storage capability; the asymptote corresponded to a hepatic iron concentration of about 2,000 micrograms/100 mg. In alcoholic patients (17 cases) the location of the sigmoid was greater than in nonalcoholic patients. Our results suggest that iron deposition occurs in the liver before other organs are involved and that with massive iron overload hepatic deposits reach saturation, after which hepatic iron concentration does not always reflect the amount of total stores. Alcohol consumption could slow the saturation of hepatic iron deposits.

Adult↗
PubMed1994

Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis.

To identify factors that might be useful as prognostic indexes for the risk of hepatocellular carcinoma in Italian patients with genetic hemochromatosis, 152 homozygotes were studied prospectively for 1 to 229 mo. Factors that were considered in estimating the risk of developing hepatocellular carcinoma were age, sex, cirrhosis (Child class), HBsAg, antibodies to HBsAg, antibodies to HBcAg, hepatitis C antibodies, alcohol abuse and the amount of iron removed during therapeutic phlebotomy to produce iron depletion. At diagnosis, cirrhosis was present in 97 patients and absent in 55. During follow-up, hepatocellular carcinoma developed in 28 of the 97 patients with cirrhosis but in none of those without. Among patients with cirrhosis, the cumulative probability of being free of hepatocellular carcinoma at 10 yr was 70%. For patients with and without HBsAg the probabilities of being free of liver cancer at 10 yr were, respectively, 54% and 75%; for those with and without history of alcoholism, 58% and 78%; and for those younger and older than 55 yr, 90% and 54%. In patients with cirrhosis, multivariate analysis using proportional-hazards (Cox) regression found that the only factors contributing significantly to the estimation of a prognostic index were age, presence of HBsAg and alcohol abuse. Age over 55 yr increased the relative risk of hepatocellular carcinoma 13.3-fold (p < 0.001), the presence of HBsAg increased it 4.9-fold (p < 0.02) and alcohol abuse increased it 2.3-fold (p < 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis.

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.

Adult↗
PubMed1997

Prevalence of hereditary hemochromatosis in a Massachusetts corporation: is Celtic origin a risk factor?

The prevalence of homozygous hereditary hemochromatosis (HHC) is estimated at 1:250 in Caucasian adults. Little is known about ethnic subpopulations that might be at increased risk for this disease. HLA data have suggested a Celtic origin for HHC. Screening for HHC was offered to all employees of the Massachusetts Polaroid Corporation. Participants with a transferrin saturation of >55% or >45% and an elevated serum ferritin concentration on two screenings were referred for liver biopsy. The diagnosis of HHC was based on histological criteria, quantitative hepatic iron determination, hepatic iron index, and the phlebotomy requirement for iron depletion. Participants completed a questionnaire regarding their ethnic background. Two thousand two hundred ninety-four employees were screened, and 5 cases of HHC were detected. All 5 cases involved Caucasian men, yielding a prevalence of 1:395 for the Caucasian population. Four of the 5 cases were of 100% British-Irish ancestry based on the country of origin of their grandparents. Additional analysis revealed that the majority of grandparents of all 4 individuals came from Ireland or Wales. The exact two-tailed trend test showed a significant association of HHC with Celtic background (P = .012). The estimated cost of screening per patient identified was $18,041. Polaroid Corporation has a high representation of employees of British-Irish ancestry. Our data suggest that they are at high risk for developing HHC. A significant association of HHC with Celtic ancestry was found in this subpopulation, supporting the concept of a Celtic origin for this disease.

Adult↗
PubMed1997

Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis.

Genetic hemochromatosis (GH) is associated with excess iron deposition in hepatocytes, which results in progressive hepatic injury. The pathogenesis of hepatic injury in GH is poorly understood. In this study, we found enhanced oxidative stress in patients with GH, as evidenced by hepatic malondialdehyde (MDA)-protein adducts and by increased oxidatively modified serum proteins. MDA-lysine epitopes and oxidatively modified serum proteins, as well as immunoglobulin G autoantibodies against MDA-lysine epitopes, were increased in untreated GH patients and to a lesser extent in GH heterozygotes compared with normal individuals. These markers of ongoing oxidative stress decreased with phlebotomy treatment in GH patients. In addition, TGF-beta1 colocalized with hepatic iron and MDA protein adducts in hepatocytes and sinusoidal cells of hepatic acinar zone 1 and normalized after iron removal. Our data suggest that iron overload increases both lipid peroxidation and TGF-beta1 expression, which together could promote hepatic injury and fibrogenesis.

Adult↗
PubMed2004

HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis.

Hepcidin is a recently identified hormone peptide involved in regulation of iron homeostasis. HAMP gene mutations have been described to date in five families with iron overload. We have identified the c.208T>C (p.C70R) mutation in the HAMP gene in a patient affected by a severe form of hereditary hemochromatosis. The variant, occurring in a highly conserved amino acid, disrupts one of the 4 intramolecular disulphide bonds present in hepcidin molecules of all vertebrates, and is presumably able to destabilize the peptide structure. The investigated patient was also found to harbor a heterozygous HFE c.845G>A (p.C282Y) mutation that may have contributed in increasing his iron burden.

Amino Acid Substitution↗
PubMed2006

Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients.

Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.

Aged↗
PubMed2006

Expression of the hemochromatosis gene modulates the cytotoxicity of doxorubicin in breast cancer cells.

The antineoplastic agent doxorubicin inhibits cell growth through mechanisms that include an interaction with iron, resulting in the generation of cytotoxic reactive oxygen species (ROS). Prior studies have shown that the wild-type hemochromatosis gene (wt HFE) may downregulate iron uptake and alter iron homeostasis in cells. We therefore tested the hypothesis that expression of wt HFE would affect the cytotoxicity of doxorubicin. Human breast cancer MCF-7 cells were transfected with an expression plasmid for a FLAG-tagged wt HFE gene [fwtHFE(+) cells], to examine the impact of wt HFE expression on doxorubicin-induced apoptosis. Our results show that, in MCF-7 cells, fwtHFE expression resulted in a reduction in cellular iron uptake and a decrease in the growth inhibitory effects of doxorubicin. Two micromolar doxorubicin inhibited the growth of fwtHFE(+) and fwtHFE(-) MCF-7 cells by 34% and 61%, respectively. In parallel, doxorubicin induced caspase-3-like activity in fwtHFE(-) cells, but not in fwtHFE(+) cells. On analysis with a DCF fluorescence assay, ROS could be detected in fwtHFE(-) cells but not in fwtHFE(+) cells exposed to doxorubicin. Western blot analysis of breast biopsy samples from patients revealed immunoreactive HFE and transferrin receptor proteins in both normal and malignant breast tissues. Our studies suggest that HFE expression and its consequent effect on cellular iron homeostasis may modulate doxorubicin-induced oxidative stress and apoptosis in breast cancer cells. Further investigation is warranted to determine whether HFE expression in tumor cells impacts on the clinical efficacy of doxorubicin.

Apoptosis↗
PubMed2002

In hereditary hemochromatosis, red cell apheresis removes excess iron twice as fast as manual whole blood phlebotomy.

The current treatment of hereditary hemochromatosis (HH) consists of performing periodic manual whole blood phlebotomies. Erythroapheresis (EPH) is considered to be an alternative procedure if the classic treatment is contra-indicated. A prospective study of 13 consecutive cases of HH were included in a periodic EPH program with the aim of assessing the efficacy, feasibility, and tolerability of EPH in the treatment of HH by induction and maintenance. Iron depletion (ferritin <20 microg/l) was achieved in all patients after a mean of 6.7 +/- 2.9 months of treatment and a mean of 13.5 +/- 7.2 EPH sessions. The procedure was well tolerated and there were no complications. After a follow-up period of 10.5 +/- 6.6 months, only four patients have required further maintenance sessions beyond 6 months after completing the induction therapy. The efficacy, speed, tolerability, and more favorable schedule of an EPH program facilitate treatment of HH.

Adult↗