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PubMed1997

Evaluation of the hepatic iron index as a diagnostic criterion for genetic hemochromatosis.

The hepatic iron index was originally described as a useful test to discriminate genetic hemochromatosis from alcoholic siderosis. To evaluate the hepatic iron index as a diagnostic criterion, it is essential to evaluate a cohort of hemochromatosis patients in whom the diagnosis has been established with great certainty. The presence of a sibling with identical human leukocyte antigen (HLA) and with iron overload was considered to be the gold standard for the diagnosis. Hepatic iron index was reviewed retrospectively in 55 homozygotes and in 189 patients who did not have hemochromatosis and were referred for hepatic iron analysis. Four of 55 homozygotes (7%) had a hepatic iron index of < or = 1.9. Hepatic iron concentration was increased in all 4 patients, ranging from 36 to 100 micromol/gm dry weight, (normal value <35.5 micromol/gm). Twelve of 189 (6%) patients without hemochromatosis had hepatic iron indexes > 1.9. The positive likelihood ratio for a hepatic iron index of 1.9 was 12.4. Area under the receiver operating characteristic curve was 0.94 (0.9 to 0.99, 95% confidence interval). The hepatic iron index remains a useful tool in the diagnosis of genetic hemochromatosis. However, it should not be an absolute criterion for the diagnosis and should be interpreted in combination with clinical assessment and genetic studies.

Adult↗

PubMed1998

Bone mineral density in prepubertal children with beta-thalassemia: correlation with growth and hormonal data.

Patients with beta-thalassemia major (beta-thalassemia) frequently have bone disorders of multifactorial etiology. We attempted to analyze the relationship between the bone mineral density ([BMD] measured by dual-photon absorptiometry) and auxanologic parameters, degree of siderosis, function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein-3 (IGFBP3) axis, calcium-phosphate balance, parathyroid hormone (PTH), and cytokines (interleukin-1beta [IL-1] and tumor necrosis factor-alpha [TNF-alpha]) in 30 prepubertal children with beta-thalassemia major and 15 age-matched children with constitutional short stature (CSS), who have normal glucose tolerance and thyroid function. Children with beta-thalassemia had a significantly decreased BMD and mean BMD% for age and sex (0.75+/-0.24 g/cm2 and 71%+/-10%, respectively) versus children with CSS (1.06+/-0.3 g/cm2 and 92%+/-7%, respectively). Thalassemic patients had significantly lower circulating concentrations of IGF-I and IGFBP3 (49+/-21 ng/mL and 1.2+/-0.25 mg/L, respectively) compared with control children (153+/-42 ng/mL and 2.1+/-0.37 mg/L, respectively). The GH response to provocation by clonidine and glucagon was defective (peak GH < 7 microg/L) in 12 of the 30 thalassemic children. Serum concentrations of IL-1beta and TNF-alpha did not differ among the two study groups. Hypocalcemia was detected in five of the 30 thalassemic patients: hypoparathyroidism was diagnosed in two of the five and rickets in the other three. BMD was highly correlated with the circulating concentrations of IGF-I and IGFBP3, as well as with the auxanologic parameters (age, weight, height, height standard deviation score [HSDS], and body mass index [BMI]). It is suggested that increasing the circulating IGF-I concentration through aggressive nutritional therapy and/or GH/IGF-I therapy with supplementation with vitamin D and/or calcium might improve bone growth and mineralization and prevent the development of osteoporosis and consequent fractures in these patients. Such therapy requires blinded controlled trials.

Absorptiometry, Photon↗

PubMed1981

Diseases of the pericardium: morphologic study of surgical specimens from 35 patients.

The gross and microscopic features of 35 pericardial surgical specimens are described. Nineteen specimens were associated with pericardial effusion, and microscopic study showed nonspecific fibrous changes in eight, tuberculous granulomatous inflammation in four, purulent inflammation in four, neoplastic involvement in four, and siderosis of the pericardium in one. Twelve of these were clinically associated with constriction. Calcification of the pericardium was the predominant feature in eight of the specimens. None of these eight specimens showed features of tuberculous infection. Of the remaining four, two showed chronic fibrinous changes and the other two showed granulomatous inflammation of presumed tuberculous origin. Four pericardial cysts were seen. Pericardial disease was an incidental finding in 13 instances (37 per cent), suggesting the frequent underdiagnosis and asymptomatic nature of disease of the pericardium. The associations of infections, trauma, hemopericardium, and collagen diseases and pericardial diseases are discussed.

Adolescent↗

PubMed1997

Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda.

BACKGROUND: Sporadic porphyria cutanea tarda is a skin disease associated with hepatic siderosis. Depletion of iron stores by phlebotomy is curative. The role of haemochromatosis genes in determining susceptibility to this disorder is controversial. We have examined the frequency in sporadic porphyria cutanea tarda of mutations (Cys282Tyr, His63Asp) in a novel MHC class-I-like gene, one of which (Cys282Tyr) is believed to cause haemochromatosis. METHODS: 41 patients with sporadic porphyria cutanea tarda, in whom the frequency of microsatellite alleles that define the ancestral haemochromatosis haplotype had previously been determined, and 101 healthy blood donors were studied for the presence of the Cys282Tyr and His63Asp mutations. We used restriction-enzyme digestion of PCR-amplified genomic DNA. FINDINGS: The Cys282Tyr mutation occurred in 18 (44%) of patients compared with 11 (11%) of controls (relative risk 6.2, 95% CI 2.6-14.5, p = 0.00003). Seven (17%) patients, aged 48-79 years, were homozygotes. In 12 patients, the Cys282Tyr mutation was associated with markers of the HLA-A3-containing ancestral haemochromatosis haplotype. Ages at presentation were the same for those with or without the Cys282Tyr mutation. There was no difference in the frequency of the His63Asp mutation. INTERPRETATION: Inheritance of one or more haemochromatosis genes is an important susceptibility factor for sporadic porphyria cutanea tarda. Some homozygotes for the Cys282Tyr mutation present late in life with porphyria cutanea tarda, indicating that not all homozygotes present clinically with haemochromatosis. The relation between this genotype and disease needs further investigation.

Adult↗

PubMed1999

A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria.

BACKGROUND/AIMS: The HFE gene is a crucial candidate gene for hemochromatosis. The aims of this study were to assess the HFE genotypic profile in a large series of unrelated probands diagnosed as having phenotypic hemochromatosis, to characterize the sub-group of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE-identical siblings. METHODS: In 217 patients, the phenotypic diagnosis of hemochromatosis was based on strict bioclinical and/or histological criteria, and their genotypic profile (C282Y and H63D mutations) was determined. RESULTS: 1) 209 of the 217 probands were C282Y +/+. In 33 cases, an HFE-identical sibling was identified. Two of them had neither a clinical nor a biochemical phenotypic profile of hemochromatosis in the absence of any external factor which might have attenuated this expression. 2) Eight patients (seven males) were not C282Y +/+. Their genotypic profiles were: (C282Y +/-): six cases (four were H63D +/- and two H63D -/-); (C282Y -/-): two cases (one was H63D +/+, one H63D +/-). Phenotypic expression consisted of six cases of mild liver siderosis (among whom were the four compound heterozygotes and one case of alcoholic cirrhosis) and two severe cases of hepatic iron overload (one with alcoholic cirrhosis). Three HFE-identical siblings were identified, none of them presenting with iron excess. CONCLUSIONS: In our population: 1) The classical phenotypic criteria fitted, in 96.3% of cases, with a homogeneous genotypic entity defined by homozygosity for the C282Y mutation. Incomplete penetrance of the homozygous status was shown by the absence of the hemochromatosis phenotypic profile in 6% of the HFE-identical siblings. 2) A minority (3.7%) were not homozygous for C282Y. These were essentially men with mild iron overload, and might present with distinct iron overload entity(ies) as suggested by the presence in three of an HFE-identical sibling with absence of iron overload.

Adult↗

PubMed1983

Iron overload of spleen, liver and kidney as a consequence of hemolytic anaemia.

Iron overload in spleen, liver and kidney induced by hemolytic anaemia due to a 90-day oral exposure of rats to diuron (N-3,4-dichlorphenyl-N,N-dimethylurea), an urea herbicide, was studied by histochemistry, transmission electronmicroscopy, morphometry and energy dispersive X-ray microanalysis. Increasing dosages of diuron provoked a hemosiderosis in the spleen followed by erythrocytic sequestration and the formation of haemopoietic foci coinciding with Kupffer cell siderosis of the liver. A strong enlargement of the spleen red pulp on the one hand faces an unchanged total white pulp volume as well as no alterations of the white pulp microscopic structure on the other. The electron dense bodies of the endothelial cells did not contain iron whereas hepatocytes possess two types of lysosomes, homogeneous iron containing ones at the sinusoidal site and complex structured ones without detectable iron at the biliary site. The formation of the homogeneous lysosomes is suggested to be due to the hepatocytic reception of hemoglobin-haptoglobin-complexes after intravascular hemolysis. The lysosomes of the biliary site seem to be engaged in hemoglobin degradation. A partial nephrohydrosis due to hemosiderotic events in succession of intravascular hemolysis including hemoglobin reabsorption from the primary urine could be observed. It is assumed that exocytosis might play a major role in hemosiderin removal from kidney tubule cells.

Anemia, Hemolytic↗

PubMed1998

Iron supplementation.

Iron deficiency affects approx. 20% of the world population. Due to predominantly vegetarian diets that reduce the bioavailability of food iron drastically, deficiency states are most widely distributed in developing countries. In addition, iron demand is increased by blood losses and by fast growth which increases the risk of iron deficiency in infants, young adolescents, and in menstruating and pregnant women. The symptoms of iron deficiency include impaired physical and intellectual performance. Iron supplementation may help to break the vicious cycle between inadequate nutrition and poverty. Fortification programs have to consider social and health aspects, including provision against iron overload. Excess iron stores may promote cancer and increase the cardiovascular risk, though the latter is a subject of current debate. The best approach to control such risks is individual iron supplementation geared to the demand by adequate laboratory controls. However, this approach is too costly for general application in developing countries. Food-iron fortification has successfully reduced iron deficiency in many trials and, in comparison, is much cheaper. As iron deficiency is widely distributed in most developing countries, the risk of inducing iron overload in the general population is low. Genetically determined diseases that may lead to siderosis, such as hereditary haemochromatosis or thalassaemia major, show a limited geographic and ethnic distribution. Such subgroups can be largely avoided by targeting food-iron fortification to infants, young adolescents, or pregnant women. Food vehicle and iron compound have to be matched in order to optimise iron bioavailability and to avoid rancidity in food, spoiling its taste and odour. The fortification of salt, sugar and spice mixtures or of bakery products with a short shelf-life are valid approaches to this end. Alternatively, haem iron can be used to fortify cereal-based food staples in developing countries such as tortillas or chappaties. Thus, a variety of options is available to solve the technical problems of food iron fortification. However, optimal solutions have to be tailored to the individual situation in each country.

Anemia, Iron-Deficiency↗

PubMed2002

Iron overload disorders.

Because hepatic siderosis is a frequent finding, there is a risk of making it trite when elaborating the pathology report. Iron is increasingly considered an important cofactor of morbidity. Its finding in hepatic cells must be recognized, indicated, qualified, quantified, and interpreted. A systematic reasoning based on a strict semiological approach allows for guiding the clinician. Iron overload syndromes do not amount to genetic hemochromatosis only.

Ceruloplasmin↗

PubMed2005

Hard and soft X-ray absorption spectroscopic investigation of aqueous Fe(III)-hydroxamate siderophore complexes.

Microorganisms release organic macromolecules, such as siderophores, to obtain Fe(III) from natural systems. While the relative stabilities of Fe(III)-siderophore complexes are well-studied, the structural environments of Fe(III) and ligands in the complex are not well-understood. Using the X-ray absorption spectroscopy (XAS) at the Fe- and N-K absorption edges, we characterized the nature of Fe(III) interactions with a hydroxamate siderophore, desferrioxamine B (desB), and its small structural analogue, acetohydroxamic acid (aHa), as a function of pH (1.4-11.4). These experimental studies are complemented with DFT calculations. The Fe-XAS studies suggest that Fe(aHa)3 is the dominant species in aqueous solutions in the pH range of 2.8-10.1, consistent with thermochemical information. However, the N-XAS and resonance Raman studies show that the chemical state of the ligand in the Fe(aHa)3 complex changes significantly with pH, and these variations are correlated with further deprotonation of the Fe(aHa)3 complex. The N-XAS studies also indicate that the overlap of Fe 3d orbitals with the molecular orbitals of the hydroxamate group is significant. The Fe- and N-XAS studies of Fe(III)-desB complexes indicated that Fe(desB)+ is the dominant species between pH values of 1.4 and 11.4, consistent with predicted stability constants. This information is useful in understanding the role of iron in bacterial transport, siderosis treatment, and actinide sequestration at contaminated sites. This is the first N-XAS study of aqueous metal ligand complexes, which demonstrates the applications of soft-XAS in studying the electronic structure of metal complexes of organic macromolecules in aqueous solutions.

Ferric Compounds↗

PubMed2003

Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelation.

OBJECTIVES: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8-10 h) i.v. DFO. PATIENTS: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. RESULTS: The median age at diagnosis of cardiac disease was 17.5 yr (range 14-21), and the median follow-up time was 84 months (range, 36-120). In the majority of patients (seven of eight) high-dose DFO (mean 95 +/- 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 +/- 2016 ng/mL to 1585 +/- 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 +/- 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. CONCLUSIONS: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8-10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM.

Adolescent↗

PubMed1998

Bile duct adenocarcinoma mimicking veno-occlusive disease after autologous bone marrow transplantation for acute leukaemia.

A 52-year-old female underwent autologous BMT because of acute myeloid leukaemia FAB M4 in second remission. Since the patient had no HLA-identical sibling she received a purged autologous BM transplant. On day +5 she developed signs of a sepsis syndrome with fluid retention and was treated with broad-spectrum antibiotic therapy. However, her body weight remained high, ascites and an increase of total serum bilirubin and alkaline phosphatase developed. The icterus worsened to a total bilirubin level of 25 mg/100 ml. Sonographic and endoscopic imaging showed a dilated gall bladder but disclosed a post-hepatic cause for the icterus. A transjugular liver biopsy on day +71 revealed severe cholestasis and siderosis. The patient remained aplastic with constantly increased bilirubin levels. On day +73 septic shock syndrome occurred and the patient died of multiorgan failure 3 days later. At autopsy, a highly differentiated bile duct adenocarcinoma at the porta hepatis, so-called Klatskin tumour, was found, explaining the fatal course with intractable cholestasis.

Adenocarcinoma↗

PubMed2000

Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients.

This retrospective study has aimed at determining the prevalence, aetiology and clinical evolution of chronic liver disease (CLD) after allogeneic bone marrow transplantation (BMT). A total of 106 patients who had been transplanted in a single institution and who had survived for at least 2 years after BMT were studied. The prevalence of CLD was 57.5% (61/106). In 47.3% of cases more than one aetiopathogenic agent coexisted. The causes of CLD were iron overload (52.4%), chronic hepatitis C (47.5%), chronic graft-versus-host disease (C-GVHD) (37.7%), hepatitis B (6.5%), non-alcoholic steatohepatitis (NASH) (4.9%), autoimmune hepatitis (AIH) (4.9%) and unknown two (3.3%). Twenty-three patients with iron overload underwent venesections which were well tolerated. An improvement in liver function tests (LFTs) was observed in 21 (91%) patients. All six patients with siderosis as the only cause of CLD normalized LFT as well as three patients with HCV infection. Clinical evolution was satisfactory for patients with GVHD, AIH, NASH and hepatitis B. At the last visit 23 patients continued with abnormal LFTs, and 19 of them were infected by the HCV. A sustained biochemical and virologic response was achieved in only one case out of six patients with CHC who received interferon. We have found that CLD is a common complication in long-term BMT survivors. The aetiology is often multifactorial, iron overload, CHC and C-GVHD being the main causes. The CLD followed a rather 'benign' and slow course in our patients as none of them developed symptoms or signs of liver failure and we did not observe an increase in morbidity or mortality in these patients, but a longer follow-up is necessary in HCV infected patients based on the natural history of this infection in other populations.

Adolescent↗

PubMed1989

Desialylation of transferrin by liver endothelium is selective for its triantennary chain.

Liver endothelium can remove and transport the glycoprotein transferrin (TF). During this process the molecules are desialylated; however, in contrast with other such glycoproteins, for example caeruloplasmin, only half of transported TF is desialylated. To explore which component of TF is desialylated, we double-labelled fully sialylated TF with [3H]sialic acid residues and a 125I-protein moiety. This was then 'chased' through purified liver endothelium in pulse-chase experiments. Endothelium-conditioned TF was fractionated on an RCA120 affinity column into sialylated and desialylated components. Each component was then re-fractionated on a concanavalin A affinity column, which separates the glycoprotein according to the branching pattern of its glycan chain. The desialylated fraction was eluted only as a triantennary component, whereas the non-desialylated fraction consisted only of bi- and tetra-antennary chains. The significance of this selective desialylation of triantennary chain of TF in the subsequent metabolism of its iron content and its possible role in the pathogenesis of alcohol-induced hepatic siderosis are discussed.

Animals↗

PubMedDate not supplied

Idiopathic pulmonary haemosiderosis: an Oriental experience.

OBJECTIVES: Idiopathic pulmonary haemosiderosis (IPH) is a rare but potentially lethal disorder. A retrospective analysis of documented cases of IPH in our hospital was conducted in order to study the clinical spectrum and radiographic features, and to explore therapeutic strategies. METHODS: A retrospective chart review was carried out, collecting medical records of patients with pulmonary haemo-siderosis at Chang Gung Children's Hospital (CGCH), a tertiary children's hospital in northern Taiwan. Secondary causes of pulmonary haemosiderosis were excluded. RESULTS: Five patients were diagnosed as having IPH over a 25-year period. The classical triad of IPH was found at initial presentation in only 2/5 patients. One patient had well-established pulmonary fibrosis, but no pulmonary symptoms. The clinical course of IPH was exceedingly variable, with a mean delay of 9 months before diagnosis was made. Bronchoalveolar lavage (BAL) confirmed IPH in 3/5 patients. Immunological abnormalities were noted in two patients, without progression to immune disorders during follow up. While using corticosteroids alone, 4/5 patients continued to have recurrent bleeding episodes. All five patients required immunosuppressive therapy for maintenance of a symptom-free period, but survived to a mean follow up of 2 years. CONCLUSIONS: Early definitive diagnosis and aggressive immunosuppressive therapy of IPH are imperative in order to avoid pulmonary fibrosis and mortality in IPH. A chest radiograph should be included in a serial work-up of unexplained anaemia in children. An examination using BAL can confirm IPH and high-resolution thoracic computed tomography scans are useful for early detection of pulmonary fibrosis.

Adrenal Cortex Hormones↗

PubMed1976

[Diabetes mellitus in idiopathic haemochromatosis (author's transl)].

In 28 out of 40 patients with idiopathic haemochromatosis manifest diabetes mellitus could be demonstrated 19 patients required insulin. Treatment of diabetes with or without insulin was problem-free. In only two patients there was an insulin resistance which required high doses of insulin some of the time. There was a family history of diabetes in eleven patients. Minimal diabetic retinopathy in two patients was the only typical complication specific to diabetes. Severe forms of microangiopathy are seldom seen in haemochromatosis diabetes. This form of diabetes is probably mainly of genetic origin. Liver cirrhosis and fibrosis and possibly pancreatic siderosis are additional factors to be considered. A sufficiently long and intensive venesection treatment leads to clinical improvement in the diabetes in only a small fraction of the haemochromatosis patients.

Adult↗

PubMed2003

[Interstitial pulmonary siderofibrosis: requirements for acceptance as new occupational disease].

BACKGROUND: Pulmonary siderosis is a well established disorder in welders. Internationally more than 150 cases of interstitial pulmonary siderofibrosis are associated with long-standing and heavy exposure to welding fumes at poorly ventilated working places. PATIENTS: Characteristic job histories, lung function analyses and histological examinations as well as elemental microanalysis by energy dispersive X-ray analysis (EDX) are demonstrated from 3 welders with pulmonary siderofibrosis. RESULTS: Histological examinations show a patchy interstitial fibrosis with accumulations of particulate material typical for welding fumes. EDX disclose an increase of iron-load in activated macrophages as well as in lung tissue and a close topographical relationship of welding fume particles and interstitial fibrotic reactions. Lung function analysis showed predominantly loss of pulmonary performance during spiroergometry. CONCLUSIONS: Regarding the actual knowledge about the pathomechanisms of ultrafine particles on lung tissue, the evidence from animal experiments, the histological and electron microscopical results, our own clinical examinations of welders and some epidemiological evidence, we assume a causal relationship of interstitial pulmonary siderofibrosis in welders with long-standing exposure to high concentrations of welding fumes under poor working conditions.

Adult↗

PubMed1993

[Septic shock with acute abdomen in idiopathic hemochromatosis].

The case of a patient with abdominal crisis and shock without any discernible origin who died 36 hours after hospital admission despite maximal therapy is described. Gram-negative sepsis, peritonitis and haemochromatosis with hepatic siderosis was the post-mortem diagnosis. We consider spontaneous peritonitis arising from translocation of normal intestinal flora (E. coli) through the intact wall of the gut combined with the impaired ability of the reticulo-endothelial system to remove endotoxin to be the causative factors. It is unknown whether the adrenal insufficiency due to siderophilic adrenal hypophysis and adrenal glands contributed to the fulminant course of the disease. Undiagnosed liver cirrhosis and especially haemochromatosis should therefore be included in the differential diagnostic considerations in patients presenting with these symptoms, and in whom no obvious cause for a septic focus can be found.

Abdomen, Acute↗

PubMed1992

[The diagnosis of bone marrow lesions in the MR tomogram in children with diseases of the hematopoietic system with special reference to post-therapy changes].

119 MR-examinations of both tibiae, knees and the lower part of both femur were performed in 41 children suffering from bone marrow disease (27 ALL, 4 AML, 3 NHL, 1 agranulocytosis, 6 anaemia). T1- and T2-spin-echo sequences and a T2-gradient-echo sequence were used. Bone marrow changes in leukaemia were diffuse before therapy and patchy after therapy. Due to their different signal in T2-weighted images, differentiation of the post-therapeutic patchy findings into infiltrations, fibrosis, necrosis and siderosis seems to be possible. In future, MRI will be the method of choice for screening and controlling bone marrow disease if the examination time is shortened by using only a T1-spin-echo sequence and a T2-gradient-echo sequence.

Adolescent↗