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PubMed1980

Studies on the rat liver following iron overload.

Sprague-Dawley rats were given Jectofer injections to obtain iron overload in rat liver Kupffer and parenchymal cells. The release of iron was studied on the light and electron microscopical level by bleeding of the iron loaded animals and comparing the results with non bled controls. During the mobilization of iron. Kupffer cells showed a rapid and almost complete disappearance of electron dense iron containing particles (IP) while there was only limited decline of IPs in the parenchymal cells. Iron was demonstrated with X-ray microanalysis at the ultrastructural level, and presence of acid phosphatase was revealed using a histochemical method based on precipitation of lead phosphate at sites of enzyme activity in combination with X-ray microanalysis. It was demonstrated that all IP-containing cytoplasmic bodies also showed presence of acid phosphatase implying that all of them represented lysosomes. The mechanism of release of iron from Kupffer and parenchymal cells was discussed with special emphasis on the role of the lysosomes and the relationship between their contents and other cellular structures.

Acid Phosphatase↗
PubMed1989

Myocardial iron grading by endomyocardial biopsy. A clinico-pathologic study on iron overloaded patients.

Endomyocardial biopsy was performed in 13 patients with primary or secondary iron overload. Prussian blue staining showed visible iron in the biopsy fragments of 8 out of 13 patients. Because of the inhomogeneity of iron deposition in the biopsy fragments, a semi-quantitative myocardial iron grading system was used in which the percentage of Perls' positive cells on 4 to 6 biopsy fragments was averaged from each case. The presence of stainable iron in the myofibrils was not predictable from serum iron, transferrin saturation, serum ferritin or liver iron grading, nor from evidence of endocrine dysfunction. In patients with Perls' positive material in the myocardium, there was a significant correlation between the endomyocardial iron grade and serum iron and transferrin saturation. These results suggest that other factors besides the body iron load determine cardiac iron deposition. The fact that myocardial siderosis was documented only in patients with hepatic cirrhosis, irrespective of the hepatic iron load, suggests that severe liver damage may be a prerequisite for the accumulation of iron in the heart.

Adult↗
PubMed2004

Clinical consult: iron overload--hereditary hemochromatosis.

One of the most common genetic causes of iron overload is hereditary hemochromatosis (HHC), a condition characterized by overabsorption of dietary iron from the gastrointestinal tract. This condition can lead to excessive iron accumulation with resulting dysfunction in multiple organs, including the liver, skin, heart,joints, pancreas, and testes. The clinical consequences of HHC if undetected and untreated can be severe and include liver cirrhosis,hepatocellular carcinoma, diabetes mellitus, cardiac arrhythmias and failure, arthritis, and hypogonadism. HHC is one of the most common heritable conditions in white populations of Northern European origin. This article presents a case study of HHC, describing inheritance and genetics, disease characteristics and natural history, diagnosis, differential diagnosis, and management.

Hemochromatosis↗
PubMed1995

A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract.

The only genetic disorder with elevated serum ferritin levels so far described is hereditary HLA-related haemochromatosis. On the other hand, hereditary cataract is both genotypically as well as phenotypically heterogenous, and no specific locus or any useful marker has been yet identified. We studied two Italian families in whom a combination of elevated serum ferritin not related to iron overload and congenital nuclear cataract is transmitted as an autosomal dominant trait. Affected individuals have normal serum iron and transferrin saturation, but high serum ferritin. Red cell counts are normal and venesection therapy rapidly produces iron-deficiency anaemia. This genetic disorder, which is characterized by hyperferritinaemia, differs from hereditary HLA-related haemochromatosis mostly for the absence of iron overload. A gene responsible for the congenital nuclear cataract likely maps on chromosome 19q close to the ferritin L-subunit gene. Within families with autosomal dominant congenital cataract, serum ferritin might be an early marker of disease.

Adult↗
PubMed2003

Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload.

BACKGROUND AND OBJECTIVES: From 1954 to 1986, flour in Denmark was fortified with 30 mg carbonyl iron per kilogram. This mandatory enrichment of cereal products was abolished in 1987. The aim was to evaluate iron status in the Danish female population before and after abolishment of iron fortification. METHODS: Iron status, serum ferritin and haemoglobin, was assessed in population surveys in 1983-1984 comprising 1221 Caucasian women (1089 non-blood-donors, 130 donors) and in 1993-1994 comprising 1261 women (1155 non-blood-donors, 104 donors) equally distributed in age cohorts of 40, 50, 60 and 70 yr. RESULTS: In the 1984 survey, median ferritin values in the four age cohorts in non-blood-donors were 44, 57, 84 and 80 microg/L, and in the 1994 survey 40, 67, 97 and 95 microg/L, respectively. In 1984, premenopausal women had median ferritin of 43 microg/L and in 1994 of 39 microg/L (NS). In 1984, postmenopausal women had median ferritin of 75 microg/L and in 1994 of 93 microg/L (P < 0.0001). The prevalence of depleted iron stores (ferritin < 16 microg/L) was not significantly different in 1984 and 1994 either in premenopausal or in postmenopausal women. The prevalence of small + depleted iron stores (ferritin 300 microg/L) was unchanged in premenopausal women and had increased from 2.4% to 5.5% in postmenopausal women (P = 0.003). During the study period there was an increase in body mass index both in premenopausal and postmenopausal women (P = 0.06 and P = 0.008). Postmenopausal women displayed an increase in alcohol consumption (P < 0.0001) and a decrease in tobacco smoking (P < 0.001). In premenopausal women, there was a marked increase in the use of non-steroid anti-inflammatory drugs (P < 0.0001) in the study period, while this was unchanged in postmenopausal women. In premenopausal blood donors, median ferritin decreased from 1984 to 1994 (36 microg/L vs. 24 microg/L, P < 0.06). In postmenopausal blood donors, ferritin was not significantly different from 1984 to 1994 (50 microg/L vs. 41 microg/L, P = 0.15). CONCLUSION: Abolition of iron fortification reduced the median dietary iron intake in Danish women from 12 to 9 mg/d. Despite the absence of food iron fortification, from 1984 to 1994, body iron stores were unchanged in premenopausal women, whereas iron stores and the prevalence of iron overload in postmenopausal women had increased significantly. The reason appears to be the changes in dietary habits with a lower consumption of dairy products and eggs, which inhibit iron absorption, and a higher consumption of alcohol, meat and poultry, containing heme iron and enhancing iron absorption.

Adult↗
PubMed1981

Long-term survival and reversal of iron overload after marrow transplantation in dogs with congenital hemolytic anemia.

Severe hemolytic in Basenji dogs secondary to pyruvate kinase deficiency was corrected by marrow transplantation from hematologically normal littermates. These dogs have now been followed for more than 5.5 yr. Essentially normal hematopoiesis has persisted, and the dogs remain in good health without cirrhosis or osteosclerosis. Furthermore, hepatic iron overload present before transplantation has gradually decreased. These results in dogs suggest that marrow transplantation could prevent the morbidity and mortality of severe hemolytic anemia and associated iron overload in man.

Anemia, Hemolytic, Congenital↗
PubMed1999

Iron overload in patients with sideroblastic anaemia is not related to the presence of the haemochromatosis Cys282Tyr and His63Asp mutations.

Forty Caucasian patients with primary acquired sideroblastic anaemia (SA), were investigated for the presence of the Cys282Tyr and/or His63Asp mutation as possible cofactor(s) for iron overload. One patient was heterozygous for the Cys282Tyr mutation and 13 heterozygotes and one homozygote for the His63Asp mutation were found (no difference compared with controls). SA patients with normal codon 63 had a mean ferritin level of 923+/-815 microg/l whereas those with codon 63 mutation had 769+/-577 microg/l (P=0.64). We conclude that ineffective erythropoiesis with no associated mutation in the HFE gene can lead to iron overload in SA patients.

Aged↗
PubMed1984

[Diagnosis and therapy of iron overload with desferrioxamine].

In polytransfused patients the diagnostics of the iron overload belongs to the strategic programme of the treatment. It is particularly referred to the value of the desferal test. In the therapy of the transfusion haemosiderosis desferrioxamine is the remedy of choice. Its at present most favourable form of application is the subcutaneous infusion by means of the infusion group. A success of the treatment is only to be guaranteed, when the therapy is consequently performed over years under balancing the iron supply and excretion.

Blood Transfusion↗
PubMed1997

Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Italian Cooperative Group for Phlebotomy Treatment of Transplanted Thalassemia Patients.

In thalassemia after successful bone marrow transplantation (BMT), iron overload remains an important cause of morbidity. After BMT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy so that this procedure can be contemplated as a method of mobilizing iron from overloaded tissues. A phlebotomy program (6 mL/kg blood withdrawal at 14-day intervals) was proposed to 48 patients with prolonged follow-up (range, 2 to 7 years) after BMT. Seven patients were not submitted to the program (five because of refusal and two because of reversible side effects). The remaining 41 patients (mean age, 16 +/- 2.9 years) were treated for a mean period of 35 +/- 18 months. All were evaluated before and after 3 +/- 0.6 years of follow-up. Values are expressed as mean +/- standard deviation (SD) or as median with a range (25 to 75 percentile). Serum ferritin decreased from 2,587 (2,129 to 4,817) to 417 (210 to 982) microg/L (P < .0001), total transferrin increased from 2.34 +/- 0.37 to 2.7 +/- 0.58 g/L (P = .0001), transferrin saturation decreased from 90% +/- 14% to 50% +/- 29% (P < .0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5 to 28.1) to 4.2 (1.6 to 14.6) mg/g dry weight (P < .0001). Aspartate transaminase decreased from 2.7 +/- 2 to 1.1 +/- 0.6 (P < .0001) and alanine transaminase from 5.2 +/- 3.4 to 1.7 +/- 1.2 (P < .0001) times the upper level of normality. The Knodell score for liver histological activity decreased from 6.9 +/- 3 to 4.9 +/- 2.8 (P < .0001). These data indicate that phlebotomy is safe, efficient, and widely applicable to ex-thalassemics after BMT.

Adolescent↗
PubMed1989

Effects of iron overload on transferrin secretion by cultured fetal rat hepatocytes.

Primary cultures of fetal rat hepatocytes were maintained in an arginine-free medium deprived of serum but supplemented with 0.03 mM L-ornithine and 10(-8) M dexamethasone. Ferric nitrilotriacetate was added to the culture medium in order to obtain iron concentrations ranging from 10 to 100 microM. After 24 h of treatment, iron was visualized inside the hepatocytes by the staining method of Perls and electron microscope study. The present data demonstrate that iron overload decreases transferrin secretion; this effect appears not to be specific, since albumin production is affected in a similar manner. This depressed transferrin secretion is not the consequence of hepatocyte death, as the phenomenon is confirmed when expressed per cell. Since the corresponding mRNA is unaffected, it may be postulated that iron overload decreases transferrin secretion at some post-transcriptional level.

Albumins↗
PubMed1995

Hepatic iron overload associated with self-medication.

A patient with the incidental finding of an elevated serum ferritin level was found to have hepatic iron overload associated with iron injections. Liver disease is an example of one of the potential complications of folk remedies or patient self-medication that physicians may encounter, especially along the US-Mexican border.

Diagnosis, Differential↗
PubMed1997

Time-course of iron overload and biochemical, histopathological and ultrastructural evidence of pancreatic damage in hypotransferrinaemic mice.

1. The time course of iron overload of the pancreas in hypotransferrinaemic mice maintained on a standard rodent diet was compared with biochemical and histological markers of tissue damage. 2. Pancreatic iron levels increased linearly from weaning till 9 months of age [73.3 nmol/mg of tissue (SEM 9.9; n = 5) compared with 0.9 nmol/mg of tissue (SEM 0.1; n = 4) in age-matched controls] then decreased linearly till at least 18 months of age. 3. Investigation of tissue distribution of newly absorbed radioiron suggested that significant redistribution of iron from liver to pancreas (rather than direct dietary iron sources) must be invoked to explain the rate of pancreatic iron loading in hypotransferrinaemic mice. 4. Pancreatic epithelial cells first showed altered morphology at 9 months of age. At 12 months of age, the pancreatic epithelium had developed a micronodular appearance, with large numbers of acini replaced by atrophic, degenerated acinar cells. Increased collagen fibre deposition was evident by trichrome staining and by electron microscopy. Biochemical markers of pancreatitis (serum lipase, tissue pancreatitis-associated protein mRNA) were elevated before 9 months of age, whereas the levels of pancreatic amylase mRNA declined from 9 months of age. 5. The data suggest that iron loading of hypotransferrinaemic mouse pancreas proceeds up to a threshold level at 9 months of age followed by a progressive atrophy of secretory epithelium. The hypotransferrinaemic mouse pancreas is a useful model system for investigation of parenchymal cell damage by iron.

Acute-Phase Proteins↗
PubMed1989

Iron overload complicating sideroblastic anemia--is the gene for hemochromatosis responsible?

Idiopathic hemochromatosis is a hereditary disease that is associated with human leucocytic antigens A3, B7, and B14. A genetic association between human leucocytic antigen-linked hemochromatosis and idiopathic refractory sideroblastic anemia has been suggested that may predispose some patients with idiopathic refractory sideroblastic anemia to develop gross iron overload. Study of the family of a patient with idiopathic refractory sideroblastic anemia and hemochromatosis revealed that 2 of 5 first-degree relatives had significant elevations of serum ferritin, and a shared human leucocytic antigen haplotype, supporting the concept that patients with idiopathic refractory sideroblastic anemia and significant iron overload have at least one allele for hemochromatosis.

Aged↗
PubMed1994

Low-dose oral chloroquine in patients with porphyria cutanea tarda and low-moderate iron overload.

OBJECTIVE: to assess the efficacy, tolerance and determinants for relapse in patients with porphyria cutanea tarda treated with low-dose oral chloroquine. DESIGN: open trial with a median follow-up of 3 years. SETTING: outpatient referral unit of a university hospital. PATIENTS: 53 patients with low-moderate iron overload or intolerance to phlebotomies. INTERVENTION: 250 mg twice weekly oral chloroquine diphosphate until remission or failure to respond. MEASUREMENTS: porphyrin excretion, biochemical changes and development of side effects. RESULTS: after administration of a median dose of 23.5 g of chloroquine (limits 12.6-56 g) during a median time of 8 months (limits: 1-26 months), 50 patients (94%) reached a metabolic remission (urinary uroporphyrin excretion < 100 micrograms/l). In 14 of these patients (28%), porphyrin excretion further decreased after finishing chloroquine therapy. Metabolic remission persisted during 24 months (limits 6-97 months). Side-effects (severe pruritus) appeared only in one patient. Twenty-two patients relapsed, the relapses being associated with greater basal values of serum AST, ALT, gammaglobulin, urinary uroporphyrin and to the time needed to achieve remission. One year and three years after finishing therapy the probabilities of relapse were 12% (95% C.I.: 5-27%) and 49% (95% C.I.: 34-67%), respectively. Time to achieve remission was the only independent predictor of relapse (hazard ratio: 1.2, 95% C.I.: 1.05-1.21, P < 0.01). CONCLUSION: low-dose oral chloroquine is a safe therapy that promotes a high proportion of remission and sustained control of porphyria cutanea tarda associated with low-moderate iron overload.

Administration, Oral↗
PubMed2006

Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

OBJECTIVE: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. DESIGN: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group. RESULTS: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P<.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P<.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions. CONCLUSION: HFE C282Y and H63D genotype frequencies vary significantly between racial/ethnic groups and within some racial/ethnic groups across geographic regions.

Adult↗
PubMed2002

H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers.

BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism. The HFE gene implicated in this disorder has been identified on chromosome 6 (6p21.3). The most prevalent mutation in HH patients changes the 282 cysteine residue to tyrosine (C282Y). The role of a second mutation which changes the 63 histidine to aspartic acid (H63D) in iron overload has been controversial. The aim of this study was to evaluate the effect of the H63D mutation on the ferritin levels of beta-thalassemia carriers. DESIGN AND METHODS: beta-thalassemia carriers have a tendency to increase iron absorption because of mild anemia and slightly increased erythropoiesis. Differences in ferritin levels between homozygotes for H63D and wild type may indicate a modulator effect of the HFE mutation on iron absorption. We studied 152 healthy males, heterozygous for beta-thalassemia. Serum ferritin was measured by chemiluminescence. H63D genotypes were determined by digestion of polymerase chain reaction (PCR) products with MboI restriction enzyme. RESULTS: Forty-five subjects were H63D heterozygotes and four subjects were H63D homozygotes. Ferritin levels were (mean +/- SD): 250 +/- 138 microg/L in homozygotes for the wild type H/H; 295 +/- 186 microg/L in H/D heterozygotes; and 389 +/- 75 microg/L in homozygotes for the mutation D/D. The difference in ferritin values between H/H and D/D is statistically significant (p=0.022). INTERPRETATION AND CONCLUSIONS: beta-thalassemia carriers who are homozygotes for the H63D mutation have higher ferritin levels than beta-thalassemia carriers with the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron absorption.

Ferritins↗
PubMed1987

Ferritin synthesis by monocyte-derived macrophages in thalassemic patients with intrinsic iron overload.

Macrophage ferritin content was determined following culture of peripheral blood monocytes for a period of 8 d in 40% autologous plasma to render them mature macrophages. Ferritin content was measured prior to and following culture using the radioimmunoassay. The normal range of values was established in a group of 22 healthy volunteer blood donors. A significant increase in the ratio of macrophage/monocyte ferritin was observed in every donor studied (range 1.2 - 1.8, p less than 0.001). Also, a further significant increase was observed when these macrophages were additionally incubated for 6 h with heterologous antibody-coated sheep red blood cells (range 1.2 - 1.57, p less than 0.001). Finally, the same studies were performed on a group of thalassemic patients with and without intrinsic iron overload. Again there were significant increases in monocyte ferritin content following culture as well as ingestion of heterologous sheep red cells, with magnitudes similar to those obtained with normal donor monocytes. Therefore we could not demonstrate the presence of a cellular ferritin synthesis defect in macrophages of thalassemic patients with intrinsic iron overload to explain the uncontrolled absorption of dietary iron from their gut.

Cell Differentiation↗