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PubMed2005

Hypogonadism in hereditary hemochromatosis.

Hypogonadism, usually hypogonadotropic in origin, is the most common nondiabetic endocrinopathy in hereditary hemochromatosis (HH). Early studies, usually evaluating small numbers of patients with advanced HH, report prevalence rates of 10-100%. The clinical presentation of HH has changed in recent years as a result of increased awareness and screening. We assessed the prevalence of hypogonadism in a large group of patients with HH diagnosed in a single center over the past 20 yr, the period of follow-up spanning the time before and after widespread screening was introduced and the HFE gene was recognized. Abnormally low plasma testosterone levels, with low LH and FSH levels, were found in nine of 141 (6.4%) male patients tested. Eight of nine (89%) had associated hepatic cirrhosis; three of nine (33%) had diabetes. Inappropriately low LH and FSH levels were found in two of 38 females (5.2%) in whom the pituitary-gonadal axis could be assessed. This is the largest detailed study of hypogonadism reported in HH. The lower prevalence of hypogonadism compared with other reported series reflects the earlier diagnosis of HH in an unselected group of patients attending a single center. Patients with lesser degrees of hepatic siderosis at diagnosis are unlikely to develop hypogonadism.

Adult↗
PubMed1976

A study of pituitary function in patients with idiopathic hemochromatosis.

Pituitary function was assessed in twelve male patients with idiopathic hemochromatosis. Though clinical features suggestive of hypogonadism were noted in nine cases, impaired pituitary function was demonstrated in only two instances. Our findings suggest that factors other than pituitary or testicular failure contribute significantly to the occurrence of sexual hypofunction and other features suggestive of hypogonadism seen in many of these patients.

Aged↗
PubMed1985

Conversion of androgens to estrogens in idiopathic hemochromatosis: comparison with alcoholic liver cirrhosis.

Hypogonadism is common in patients with some liver diseases, such as idiopathic hemochromatosis (IHC) and alcoholic cirrhosis (AC). However, gynecomastia, a typical feature in AC, does not occur in IHC. To determine the hormonal basis for this difference, the following parameters were determined in patients with IHC and AC as well as in normal men: plasma concentrations of androgens and estrogens, metabolic clearance and production rates of androstenedione and testosterone, and the contribution of peripheral conversion of androstenedione and testosterone to the circulating estrogens. Severe impotence in both patients with IHC and those with AC was associated with more than 50% reduction in plasma testosterone. The reduction was due to 63% and 70% decreases in testosterone production in IHC and AC, respectively. The MCRs were less affected in IHC and AC (19% and 37% reductions, respectively). In IHC, the fall in testosterone concentrations was accompanied by decreased production and plasma concentrations of androstenedione, a precursor for estrogen synthesis. In contrast, production and plasma concentrations of androstenedione were significantly increased in AC. Patients with IHC had estradiol und estrone levels similar to those in normal men (mean +/- SD, 16.2 +/- 4.6 vs. 20.3 +/- 3.7 pg/ml; P = NS), whereas in AC, estradiol and estrone were significantly elevated (38.0 +/- 5.3 and 68.5 +/- 17.2 pg/ml, respectively). In IHC, sex hormone-binding globulin levels were in the same range as in the normal men, whereas sex hormone-binding globulin was increased in AC. In IHC, the instantaneous contribution of plasma androstenedione to estrone and estradiol was normal, whereas that of plasma testosterone to plasma estrogens was decreased by about 50%. In contrast, in AC, the instantaneous contribution of plasma androstenedione to estrogens was greatly enhanced, and that of testosterone was in the normal range. Since the MCRs of androgens and the conversion ratios of androgens to estrogens indicate normal peripheral metabolism of sex hormones in IHC, decreased androgen formation implies decreased testicular synthesis. This was confirmed by a significantly decreased LH level in IHC (5.5 +/- 1.9 vs. 10.5 +/- 3.1 mU/ml in normal men), indicating pituitary failure. In AC, however, increased LH (20.0 +/- 2.7 mU/ml) may be indicative of primary testicular failure. These results confirm clinical features of hypogonadism and normal estrogenic activity in patients with IHC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS.

Iron misregulation promotes oxidative stress and abnormally high iron levels have been found in the spinal cords of patients with ALS. The authors investigated whether HFE gene polymorphisms, linked to hemochromatosis, are associated with ALS using two independent populations of patients with sporadic ALS and controls (totaling 379 patients and 400 controls). They found that the H63D polymorphism is overrepresented in individuals with sporadic ALS (odds ratio 1.85, CI: 1.35 to 2.54).

Adult↗
PubMed1983

Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs.

Idiopathic hemochromatosis (IHC) is a genetically determined impairment in control of iron absorption that results in excessive parenchymal iron deposition, particularly in the liver. Of patients with IHC, 50% have little or no chemical evidence of liver dysfunction. Cirrhosis may be clinically occult, but still cause a syndrome of chronic hepatocerebral degeneration. Two patients are reported with IHC and a syndrome of ataxia, rigidity, myoclonic jerks, and dementia. Other associated symptoms may include diminished libido, decreased hearing, peripheral neuropathy, and large joint disease. Because symptoms of IHC can be reversed by phlebotomy, appropriate laboratory studies should be considered to exclude IHC in any patient with unexplained dementia, encephalopathy, and gait ataxia.

Aged↗
PubMed2007

Exercise capacity of cardiac asymptomatic hereditary hemochromatosis subjects.

PURPOSE: The exercise capacity of cardiac asymptomatic subjects with hereditary hemochromatosis (HH) has not been well described. In this study, we tested whether the iron overload associated with HH affected exercise capacity with a case control study design. METHODS: Forty-three HH and 21 normal control subjects who were New York Heart Association functional class I underwent metabolic stress testing using the Bruce protocol at the clinical center of the National Institutes of Health. Exercise capacity was assessed with minute ventilation (.VE), oxygen uptake (.VO2), and carbon dioxide production (.VCO2) using a breath-by-breath respiratory gas analyzer. RESULTS: The exercise capacity of HH subjects was not statistically different from that of control subjects (exercise time 564 +/- 135 vs 673 +/- 175 s, P = 0.191; peak .VO2 29.6 +/- 6.4 vs 32.5 +/- 6.7 mL.kg(-1).min(-1), P = 0.109; ventilatory threshold 19.0 +/- 3.4 vs 21.0 +/- 5.0 mL.min(-1).kg(-1), P = 0.099; data are for HH vs control subjects). Ventilatory efficiency was comparable between groups (.VE/.VCO2 slope 23.7 +/- 3.2 vs 23.4 +/- 4.2, P = 0.791). No significant correlation between the markers of iron levels and the markers of exercise capacity was noted. Iron depletion by 6-month phlebotomy therapy in 18 subjects who were newly diagnosed did not affect exercise testing variables (exercise time 562 +/- 119 vs 579 +/- 118 s, P = 0.691; peak .VO2 29.5 +/- 3.7 vs 29.1 +/- 4.7 mL.kg(-1).min(-1), P = 0.600; ventilatory threshold 18.5 +/- 2.8 vs 17.9 +/- 3.8 mL.kg(-1).min(-1), P = 0.651; data are from before and after phlebotomy therapy). Abnormal ischemic electrocardiographic responses and complex arrhythmias were more frequently seen in HH subjects. CONCLUSIONS: The aerobic exercise capacity of asymptomatic HH subjects seems not to be statistically different from that of normal subjects. The iron levels do not seem to affect exercise capacity in asymptomatic HH subjects.

Adult↗
PubMed2000

Phlebotomy increases cadmium uptake in hemochromatosis.

The intestinal absorption of the nephrotoxic environmental pollutant cadmium increases markedly when iron stores are depleted. This may be mediated by an up regulation of the recently identified mucosal transporter DMT1 (Nramp2 or DCT1) for divalent cations. We tested whether the highly increased iron absorption in hereditary hemochromatosis (HH) was accompanied by an enhanced absorption of cadmium and lead. Cadmium and lead in blood and iron status markers were determined in 21 nonsmoking subjects with HH genetically tested for the HFE mutations and in 21 nonsmoking controls matched for age and sex. In subjects with HH on maintenance phlebotomy treatment, blood concentrations of cadmium, but not lead, were significantly higher than in paired controls. There was a strong age-independent positive association between blood cadmium and the number of years of phlebotomy treatment. Blood lead showed a similar but less pronounced consequence of treatment. All HH subjects with lower blood cadmium than the corresponding controls had either no mutation in the HFE gene, were not phlebotomized, or were phlebotomized for only a limited time. Our findings indicate that the treatment rather than the disease increased the cadmium uptake in homozygous HH. Further studies are needed to confirm whether the disease decreased cadmium absorption and whether the absorption was dependent on the genotype.

Absorption↗
PubMed2001

Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum.

Hepatocellular carcinoma (HCC) is a well-known complication of genetic hemochromatosis (GH). However, the frequency of primary liver carcinoma (PLC) with biliary differentiation, such as cholangiocarcinoma (CC) and combined hepatocholangiocarcinoma (CHCC), in GH remains unclear We analyzed the histologic type of 20 PLCs occurring in the background of GH; all patients were homozygotic for the C282Y mutation. Ten were depleted of iron by successive phlebotomies, while the remaining 10 were untreated. Histologically, 13 cases were classified as HCC, 3 as CC, and 4 as CHCC. Immunohistochemical detection of Hep Par 1, cytokeratin 19 (CK19), and MUC1 supported this classification; PLC with biliary differentiation was immunoreactive for MUC1 in 86% (6/7) of cases and for CK19 in 100% (7/7) of cases. The nontumoral liver exhibited no cirrhosis or extensive fibrosis in 6 cases. Von Meyenburg complexes were present in 11 cases and intraparenchymal bile duct adenomas in 3. These data suggest that PLCs in patients with GH present a wide histologic spectrum, with tumors showing frequent biliary differentiation; may arise on a nonfibrotic or a cirrhotic liver; and often are associated with Von Meyenburg complexes and to a lesser extent with bile duct adenomas.

Adenoma, Bile Duct↗
PubMed2004

Skeletal changes in hemochromatosis of Salers cattle.

Hemochromatosis is an inherited defect in Salers cattle, characterized by increased iron absorption and wasting in young animals. Loss of teeth and soft bones has been reported. This study details bone changes in a prospective study of an affected Salers heifer and an age-matched, half-sibling control. The heifer fell 2 weeks before euthanasia, developed non-weight bearing lameness, and then became recumbent. At necropsy, the heifer was smaller than the control and had fractures of the humerus, femur, and ribs. Distinctive circumferential laminations in the outer third of the cortex were seen radiographically as layers of variably decreased density. In midshaft cross sections, the cortex was wider in some long bones, and fluorescent labeling revealed irregular and intermittent mineralization in the outer cortical layers. Mineral apposition rates in osteons of the inner cortex were decreased as compared with the control, and longitudinal bone formation at the growth plate was markedly decreased. Histologically, there were buried layers of osteopenic, poorly mineralized plexiform bone in outer circumferential lamellae. There was stainable iron in woven bone cores of the matrix. Iron was found in occasional osteoclasts as well. The mandible was severely affected, with loss of cortical bone as well as trabecular bone around the teeth and resorption of dental roots. Bone analysis revealed iron levels in the affected calf that were 30-50 times greater than the control and decreased percent ash in the outer cortex. These results indicate that periosteal dysplasia and osteopenia are responsible for pathologic fractures and tooth loss.

Animals↗
PubMed2003

Probable veno-occlusive disease after treatment with gemtuzumab ozogamicin in a patient with acute myeloid leukemia and a history of liver transplantation for familial hemochromatosis.

A 69-yr-old male with a history of familial hemochromatosis and status after liver transplantation was found to have severe thrombocytopenia (platelet count of 8000/microL). He was also anemic and was diagnosed with acute myeloid leukemia (AML) after a bone marrow biopsy. He was started on gemtuzumab ozogamicin (Mylotarg) and developed hepatic and multiorgan failure consistent with veno-occlusive disease within 2 wk. He did not have a history of hematopoietic stem cell transplantation, which is usually the case in AML patients who develop veno-occlusive disease of the liver after treatment with Mylotarg.

Acute Disease↗
PubMed2005

Disparate clinical presentation of neonatal hemochromatosis in twins.

Neonatal hemochromatosis (NH) is a rare disease of gestation that results in fetal liver injury and extrahepatic siderosis. The etiology of NH is not fully understood. However, the rate of recurrence of NH in the pregnancy after an affected one is approximately 80%. A spectrum of liver disease has been recognized, spanning from liver failure in the fetus or neonate to infants that survive with medical therapy. Here we report on 2 sets of fraternal twins, each set with a gross disparity in the severity of presentation: 1 infant with liver failure and the other nearly unaffected. These findings suggest a need to look carefully for subclinical disease in the siblings of patients with NH by using sensitive tests such as those for ferritin and alpha-fetoprotein. They also suggest that affected infants may be missed when using routine clinical testing, which would lead to the apparent rate of recurrence, understating the actual recurrence rate.

Diseases in Twins↗
PubMed1996

Urinary concentrating defect in experimental hemochromatosis.

We studied the urinary concentrating capacity in experimental hemochromatosis. Sprague-Dawley rats were randomized into iron (Fe)-loaded (injected sc with 1.2 g elemental iron/kg body weight as iron dextran) and pair-fed control groups. The urinary concentrating ability was studied after 10 months of iron loading. At basal condition, urine osmolality (Uosm) was significantly lower (P < 0.05) in the Fe-loaded rats compared with the control animals despite comparable urinary arginine-vasopressin (AVP) excretion in the two groups. Although 48-h water deprivation resulted in comparable rises in plasma concentration and urinary excretion of AVP in the two groups, maximal Uosm in the Fe-loaded animals was significantly lower than that seen in the control group (P < 0.01). Moreover, the observed urinary concentrating defect could not be corrected by pharmacological doses of exogenous AVP. There was no significant difference in renal chloride, sodium, calcium, or magnesium handling at either basal or sodium depleted states. Histologic studies showed marked iron deposition in the cortex and outer medulla accompanied by mild tubular atrophy particularly in the distal convoluted tubules. Thus, chronic experimental iron overload leads to nephrogenic diabetes insipidus marked by AVP-resistant urinary concentrating defect.

Animals↗
PubMed1999

Rapid genetic screening for hemochromatosis using automated SSCP-based capillary electrophoresis (SSCP-CE).

Hereditary hemochromatosis (HHC) represents an autosomal recessive disease in which increased iron absorption causes iron overload and irreversible tissue damage. The recently detected association between two point mutations in the HFE gene on chromosome 6p and HHC has made it possible to screen for the disease before the onset of irreversible tissue damage. Conventional genetic testing is based on restriction fragment-length polymorphisms (RFLP) using two endonuclease recognition sites in codon 63 or 282, respectively. In this study, we have adapted single-strand conformation polymorphism analysis for capillary electrophoresis (SSCP-CE) to detect homozygote or heterozygote point mutations. Two HFE gene fragments spanning codons 63 and 282 were amplified by a duplex PCR using genomic DNA from peripheral blood or from tissue sections of paraffin-embedded liver biopsies as template. Thereby, rapid genotyping of both HFE mutations was achieved with a single PCR, omitting the need of further analysis by restriction digest. Eighty-five patients with liver disease and/or suspected iron overload were genotyped using SSCP-CE, and all results were verified by conventional RFLP analysis. In summary, SSCP-CE proved to be a reliable, cost-effective, sensitive and rapid method for genotyping HFE mutations. This method will further facilitate high-throughput genetic screening using capillary array electrophoretic devices.

Adult↗
PubMed1992

Beta(+)-thalassemia with hemochromatosis.

A 64-year-old man was admitted due to ascites. Laboratory data showed hemoglobin 6.7 g/dl, mean corpuscular volume 82 fl, and ferritin 2,360 ng/ml. Liver biopsy showed hemochromatosis. The diagnosis of beta-thalassemia was suggested by a decreased ratio of beta/alpha-globin synthesis in vitro (0.26). Cloning of the beta-globin gene showed A-to-G mutation in the first base of the ATA box. He was confirmed to be homozygous for this specific allele by beta-gene complex analysis and analysis of Southern blot hybridization of the alpha- and beta-globin genes. His two sons were confirmed to be heterozygous for this allele.

Adult↗
PubMedDate not supplied

Correlation between the depth of inverted T waves and the serum level of ferritin in a deferoxamine-treated patient with primary hemochromatosis and hyperthyroidism.

A 74-year-old female having primary hemochromatosis and hyperthyroidism is described. The initial ECG showed sinus rhythm, and depression of ST segment and inversion of T waves in I, II, III, aVF, and V4-6. By deferoxamine and propylthiouracil, the serum level of ferritin was decreased from 4,500 ng/ml to 440 ng/ml in a period of 6 months. The thyroid function was also returned to normal. After cessation of both drugs, the serum ferritin level increased gradually reaching a level of 3,100 ng/ml in the next 15 months but the thyroid function remained normal. During and after the deferoxamine administration, the depth of inverted T waves became more shallow and gradually deeper again, respectively. There seemed to be a correlation between the depth of inverted T waves and the serum level of ferritin. It was, however, unlikely that toxic iron may have induced the hyperfunction of the thyroid gland.

Aged↗
PubMed1977

Retinopathy and plasma growth hormone levels in idiopathic hemochromatosis with diabetes.

In patients with idiopathic hemochromatosis, retinopathy was investigated by ophthalmoscopy and fluorescein angiography and was present in eight out of 23; this prevalence is similar to that reported in patients with diabetes aged between 30 and 60 years at onset of diabetes and with the same duration of the disease; in these eight patients retinopathy was of mild degree, with no impairment of visual acuity, fewer than 10 microaneurysms in each fundus, and no other retinal abnormatic islets directly. These studies confirm that anticholinergic drugs may be useful adjuvants in treating these patients.

Adult↗
PubMed2003

MR imaging of hepatocellular carcinoma arising in genetic hemochromatosis.

A case of a 51-year-old male with previously unsuspected genetic hemochromatosis (GH) associated with hepatocellular carcinoma (HCC), for which MR imaging was useful in diagnosis, is presented. Contrast-enhanced ultrasonography depicted a mass in segment 8 of the liver and a liver tumor was suspected. The mass could not be revealed on unenhanced or enhanced CT examination. MR imaging with unenhanced T1-weighted FLASH and T2-weighted gradient echo sequences clearly depicted the tumor; the tumor appeared hyperintense against a background of low hepatic signal intensity caused by iron overload. The iron-overloaded liver provided a natural source of paramagnetic contrast for detection of HCC. Studies are required to further assess the accuracy of these sequences in detection of HCC in patients with GH.

Carcinoma, Hepatocellular↗
PubMed1979

Hemoglobin Lepore Washington and hemochromatosis in a Hungarian patient.

A Hungarian family with four heterozygotes for Hb Lepore Washington is described. One, a 43-year-old male, had high levels of serum iron, saturated iron-binding capacity, and ferritin, and normal levels of folic acid and vitamin B12. Liver biopsy showed slight cirrhosis and marked iron deposition in parenchymal cells and in cells of the reticuloendothelial system. Heavy iron deposition was also found in the bone marrow. The patient is not an alcoholic and has no disease that requires blood transfusion. The hemochromatosis thus seems to be of idiopathic nature.

Adolescent↗