Dysmetabolic hyperferritinemia is associated with normal transferrin saturation,mild hepatic iron overload,and elevated hepcidin

Hyperferritinemia is common in individuals with the metabolic syndrome (dysmetabolic hyperferritinemia), but its pathophysiology and the degree to which it reflects tissue iron overload remains unclear. We conducted a cross-sectional study evaluating ten cases with dysmetabolic hyperferritinemia for liver iron overload and compared their serum iron indices and urine hepcidin levels to healthy controls. Seven out of ten cases had mild hepatic iron overload by magnetic resonance imaging (MRI) (median, 75 μmol/g dry weight). Cases had higher serum ferritin than controls (median, 672 μg/L vs. 105 μg/L, p < 0.001), but the median transferrin saturation was not significantly different (38% vs. 36%, p = 0.5). Urinary hepcidin was elevated in dysmetabolic hyperferritinemia (median; 1,584 ng/mg of creatinine vs. 799 ng/mg of creatinine, p = 0.05). Dysmetabolic hyperferritinemia is characterized by hyperferritinemia with normal transferrin saturation, elevated hepcidin levels, and mild liver iron overload in a subset of patients.     

Hyperferritinemia in the Chinese and Asian community: a retrospective review of the University of British Columbia experience.

BACKGROUND AND METHODS: Elevated serum ferritin is a common clinical finding. The etiology of hyperferritinemia in the Asia-Pacific population is less clear due to a low prevalence of known HFE mutations such as C282Y and H63D, as well as an increased prevalence of viral hepatitis and hereditary anemia. A retrospective case review of 80 patients of Asian ethnicity referred to three subspecialists in tertiary care teaching hospitals between January 1997 and March 2005 for assessment of hyperferritinemia was performed. RESULTS: Only four patients (5%) had iron overload on liver biopsy or quantitative phlebotomy. Forty-nine patients (61%) had secondary causes for their hyperferritinemia, of which 26 had liver disease; 16 of those patients also had viral hepatitis. Thirteen patients fulfilled criteria for the insulin resistance syndrome. Other causes included hematological disorders (n=10), malignancy (n=2) and inflammatory arthritis (n=2). Twenty-seven cases (34%) of unexplained hyperferritinemia were found. Of a total of 22 patients who underwent liver biopsy, significant iron deposition was found in one patient. Fifteen patients underwent C282Y and H63D genotyping, with two cases of H63D heterozygosity. Fourteen patients had first-degree relatives with hyperferritinemia. Three families were identified with more than two members affected, which is suggestive of a possible hereditary hyperferritinemia syndrome. CONCLUSION: Secondary causes of elevated ferritin in the Asian population, particularly liver disease, are common, but primary iron overload syndromes appear to be rare. In a significant proportion of patients, the etiology remains unexplained. The genetic basis for hyperferritinemia in Asians is poorly defined and requires further study.     

A Japanese family with ferroportin disease caused by a novel mutation of SLC40A1 gene: hyperferritinemia associated with a relatively low transferrin saturation of iron

Ferroportin disease, autosomal-dominant reticuloendothelial iron overload, may be more prevalent than hemochromatosis in Japan. Hyperferritinemia of 822 ng/ml with 24.8% transferrin saturation of iron was incidentally noted in a 43-year-old man. His iron overload was selective in Kupffer cells of the liver. Subsequently, his father was found to have asymptomatic hyperferritinemia of 2,283 ng/ml with 62.1% saturation. These affected subjects were heterozygous for 1467A>C (R489S) in SLC40A1, and without other mutations of the hemochromatosis genes. Here, we report a Japanese family with ferroportin disease, characterized by hyperferritinemia with relatively low transferrin saturations of iron.     

A point mutation in the iron-responsive element of the L-ferritin in a family with hereditary hyperferritinemia cataract syndrome.

BACKGROUND: Hereditary hyperferritinemia cataract syndrome is an autosomal dominant condition that is characterized by a high serum ferritin level and bilateral early-onset cataracts in the absence of iron overload. The genetic abnormality is identified as a mutation in the 5' regulatory region of the L-ferritin messenger RNA known as the iron-responsive element (IRE). The IRE controls ferritin synthesis in response to cytoplasmic iron pools by interacting with regulatory proteins called iron responsive proteins. Mutations in the IRE decrease its affinity for iron responsive proteins, leading to the constitutive synthesis of L-ferritin which results in hyperferritinemia and the intracellular accumulation of ferritin in the lens and eventual cataract formation. PATIENTS AND METHODS: A 22-year-old woman who was being investigated for hyperferritinemia was diagnosed with hereditary hyperferritinemia cataract syndrome after an extensive workup, including genetic testing for hemochromatosis and a liver biopsy to rule out iron overload. She developed anemia with phlebotomy treatments and subsequently developed symptomatic cataracts. The pedigree of her family affected with cataracts was consistent with an autosomal dominant transmission pattern. DNA was extracted from peripheral leukocytes of eight family members, four of whom were affected by cataracts. Polymerase chain reaction amplification of the 5' region of the L-ferritin gene was performed and a heterozygous point mutation (G32T) was identified in the bulge region of the IRE. CONCLUSION: The combination of early-onset cataracts and an elevated ferritin level should suggest this genetic syndrome.     

Two novel mutations in the SLC40A1 and HFE genes implicated in iron overload in a Spanish man

The most common form of hemochromatosis is caused by mutations in the HFE gene. Rare forms of the disease are caused by mutations in other genes. We present a patient with hyperferritinemia and iron overload, and facial flushing. Magnetic resonance imaging was performed to measure hepatic iron overload, and a molecular study of the genes involved in iron metabolism was undertaken. The iron overload was similar to that observed in HFE hemochromatosis, and the patient was double heterozygous for two novel mutations, c.-20G>A and c.718A>G (p.K240E), in the HFE and ferroportin (FPN1 or SLC40A1) genes, respectively. Hyperferritinemia and facial flushing improved after phlebotomy. Two of the patient's children were also studied, and the daughter was heterozygous for the mutation in the SLC40A1 gene, although she did not have hyperferritinemia. The patient presented a mild iron overload phenotype probably because of the two novel mutations in the HFE and SLC40A1 genes.     

Estimating Iron Overload in Patients with Suspected Liver Disease and Elevated Serum Ferritin

BackgroundIron status evaluation in patients with suspected liver disease and elevated serum ferritin is often challenging because hyperferritinemia does not always indicate iron overload. A reliable approach to estimate iron overload without exposing the patient to unnecessary investigations would help the clinician to identify patients who may take advantage of iron-removal therapy.MethodsWe analyzed all liver biopsies, including measurement of hepatic iron concentration, performed at the University Hospital Zurich from 1997 to 2010 to identify clinical and laboratory predictors of iron overload in patients with elevated serum ferritin (n = 147).ResultsHyperferritinemia was predictive of iron overload only in patients with a high level of serum ferritin (>2000 μg/L). In patients with moderate hyperferritinemia, liver transaminases inversely correlated with hepatic iron concentration. A combination of both parameters expressed as ferritin/aspartate transaminase ratio was highly predictive of tissue iron overload (sensitivity 83.3%, specificity 78.6%). Receiver operating characteristic analysis resulted in an area under the curve of 0.83.ConclusionsWe established a simple and reliable method to correctly estimate iron overload in patients with suspected liver disease and elevated serum ferritin.     

Hyperferritinemia

Many causes provoke elevated serum ferritin levels including not only iron overload, but also many pathological situations where hyperferritinemia or modified isoferritin profiles have no direct relationship with body iron stores. There are five general categories of hyperferritinemia: hemochromatosis, inflammatory syndromes, cytolysis, hemophagocytosis, Still's disease, and other etiologies.     

The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities

The number of new genes implicated in iron metabolism has dramatically increased during the last few years. Alterations of these genes may cause hyperferritinemia associated or not with iron overload. Correct assignment of the specific disorder of iron metabolism requires the identification of the causative gene mutation. Here, we propose a rational strategy that allows targeting the gene(s) to be screened for a diagnostic purpose. This strategy relies on the age of onset of the disease, the type of clinical symptoms, the biochemical profile (elevated or normal serum transferrin saturation (TfSat)), the presence or not of visceral iron excess, and the mode of inheritance (autosomal recessive or dominant). Then, two main entities can be differentiated: genetic (adult or juvenile) hemochromatosis characterized by elevated TfSat, and hereditary hyperferritinemias where TfSat is normal (or only slightly modified). Adult genetic hemochromatosis (GH) is related mainly to mutations of the HFE gene, and exceptionally to mutations of the TFR2 gene. Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for hepcidin. Hereditary hyperferritinemias are linked to mutations of three genes: the L-ferritin gene responsible for the hereditary hyperferritinemia cataract syndrome (without iron overload), the ferroportin gene leading to a dominant form of iron overload, and the ceruloplasmin (CP) gene corresponding to an iron overload syndrome with neurological symptoms. The proposed strategic approach may change with the identification of other genes involved in iron metabolism.     

Plasma ferritin and type 2 diabetes mellitus: a critical review.

Multiple factors appear to be involved in the pathogenesis of type 2 (non insulin dependent) diabetes mellitus (DM). One of these factors may be iron overload. This critical review summarizes the major studies on the link between type 2 DM, insulin resistance, glycemic control, diabetic complications and hyperferritinemia. Although some studies suggested that plasma ferritin concentration is positively correlated with insulin resistance and with the risk of acquiring type 2 DM, substantial iron overload is not a typical feature of DM. There is no correlation between plasma ferritin level and glycemic control or diabetic microangiopathic complications.     

Management of high ferritin in long-term survivors after hematopoietic stem cell transplantation

Management of high serum ferritin levels after allogeneic hematopoietic stem cell transplantation (allo-HSCT) should, from the diagnostic standpoint, be based on the pathophysiological mechanisms underlying the development of hyperferritinemia. This knowledge is essential for differentiating increased serum ferritin due to iron overload from "non-iron overload" situations such as inflammation, metabolic syndrome, or hepatitis. Once body iron overload has been proven, especially by quantifying tissue iron excess with the noninvasive magnetic resonance imaging (MRI) method, it is important, considering the damaging effects of chronic iron overload in these patients, to start iron depletive therapy by oral chelation or phlebotomy. At present, more data are needed to assess the long-term deleterious effects of iron excess in the HSCT population, and to define the most appropriate therapeutic strategy for removing iron burden. Also, preventing iron overload prior to HSCT might prove essential for improving patient prognosis through decreasing HSCT-related mortality.     

Lack of enterocyte iron accumulation in the ferroportin disease

Ferroportin-associated iron overload (also known as the ferroportin disease) is a common cause of hereditary hyperferritinemia. It was originally proposed that loss-of-protein function mutations account for iron overload in the FD. This hypothesis is consistent with the phenotype reported in most patients with FD of early iron accumulation in tissues, particularly in macrophages, in spite of relatively normal-low circulatory iron. It was still unclear, however, how FPN mutations would affect iron retention in enterocytes. We studied histologically the intestine of six patients with different FPN mutations as compared to other subjects with various iron disorders. We found that regardless of the underlying FPN mutation, no iron accumulation was found in absorbing enterocytes while, intestinal villi showed marked signs of iron accumulation in the cells of lamina propria. Not surprisingly, in the liver, iron excess was found mainly in Kupffer cells. These results indicate that FPN haploinsufficiency is not limiting for iron export from enterocytes.     

Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis

BACKGROUND: Insulin resistance is a key feature of nonalcoholic fatty liver disease. Patients with hereditary hemochromatosis, a disease characterized by progressive iron overload due, in most cases, to homozygosity for C282Y mutation in the HFE gene, have often decreased insulin sensitivity and release. AIMS: To determine whether increased iron parameters/heterozygosity for the mutations of the HFE gene confer susceptibility to nonalcoholic fatty liver disease. PATIENTS: One hundred and thirty-four consecutive Italian patients with clinical and ultrasonographic diagnosis of nonalcoholic fatty liver disease (82 with hyperferritinemia), half confirmed by liver biopsy. METHODS: Insulin was determined by radioimmunoassay. HFE gene mutations were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: (1) Prevalence of C282Y HFE mutation was significantly higher in patients with nonalcoholic fatty liver disease compared to controls, the difference being more striking in patients with hyperferritinemia than in those without. (2) The presence of mild iron overload was associated with a lower insulin release. (3) Carriers of C282Y mutation developed nonalcoholic fatty liver disease despite lower body mass index and triglycerides. CONCLUSION: The mild iron overload associated with heterozygosity for C282Y HFE mutation confers susceptibility to nonalcoholic fatty liver disease, causing relative insulin deficiency.     

Does iron overload really matter in stem cell transplantation?

A growing body of evidence suggests that iron overload is associated with inferior outcomes after myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). However, all of those studies used surrogate markers of iron overload, especially serum ferritin, and most had a retrospective design. We conducted a prospective observational study in patients with myelodysplastic syndrome or acute leukemia undergoing myeloablative HSCT. Forty-five patients who were followed for over 1 year, with serial measurements of serum iron parameters, as well as liver and cardiac magnetic resonance imaging. There was no significant increase in ferritin, liver or cardiac iron content in the 12 months following HSCT. Although serum ferritin still appeared to have prognostic significance, as previously reported, pre-HSCT iron overload (as reflected in liver iron content) was not associated with increased mortality, relapse, or graft-versus-host disease. These results raise the possibility that the adverse prognostic impact of pre-HSCT hyperferritinemia may be related to factors independent of iron overload.     

Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis

OBJECTIVE: The aim of this study was to define in patients with hyperferritinemia and normal transferrin saturation the relationships among hyperferritinemia, iron overload, HFE gene mutations, the presence of metabolic alterations, and nonalcoholic steatohepatitis (NASH). METHODS: Forty patients with increased serum ferritin, resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic evidence of hepatic steatosis, and 60 obligate heterozygotes for hemochromatosis, all negative for alcohol abuse, hepatitis virus infections, and inflammation were studied. Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed. RESULTS: Of the 40 patients with hyperferritinemia, 29 (72%) had biochemical metabolic abnormalities, 18 of the 26 examined (69%) had insulin resistance, 26 (65%) had the presence of one of the two HFE gene mutations (normal controls, 33 of 128 [26%], p < 0.0001), and all had increased liver iron concentration. Thirty-one patients (77%) had histology compatible with NASH. At univariate analysis, NASH was significantly associated with the presence of metabolic alterations, the C282Y mutation, and severity of fibrosis. At multivariate analysis, NASH was associated with the coexistence of multiple metabolic alterations (odds ratio = 5.2, 95% CI = 0.95-28.7). The risk of having NASH augmented in the presence of higher values of ferritin and liver iron concentration. Among the 90 patients with ultrasonographic evidence of hepatic steatosis, 24 (27%) had increased serum ferritin with normal transferrin saturation, but only six remained hyperferritinemic after dietary restriction. CONCLUSION: Increased ferritin with normal transferrin saturation is frequently found in patients with hepatic steatosis, but it reflects iron overload only in those patients in whom it persists despite an appropriate diet. The simultaneous disorder of iron and glucose and/or lipid metabolism, in most of the cases associated with insulin resistance, is responsible for persistent hyperferritinemia and identifies patients at risk for NASH.     

Non-invasive methods for iron overload evaluation in dysmetabolic patients

IntroductionAlthough hyperferritinemia may reflect the inflammatory status of patients with non-alcoholic fatty liver disease (NAFLD), approximately 33% of hyperferritinemia cases reflect real hepatic iron overload.AimTo evaluate a non-invasive method for assessing mild iron overload in patients with NAFLD using 3T magnetic resonance imaging (MRI) relaxometry, serum hepcidin, and the expression of ferritin subunits.MethodsThis cross-sectional study assessed patients with biopsy-proven NAFLD. MRI relaxometry was performed using a 3T scanner in all patients, and the results were compared with iron content determined by liver biopsy. Ferritin, hepcidin, and ferritin subunits were assessed and classified according to ferritin levels and to siderosis identified by liver biopsy.ResultsA total of 67 patients with NAFLD were included in the study. MRI revealed mild iron overload in all patients (sensitivity, 73.5%; specificity, 70%). For mild (grade 1) siderosis, the transverse relaxation rate (R₂*) threshold was 58.9 s^?1 and the mean value was 72.5 s^?1 (SD, 33.9), while for grades 2/3 it was 88.2 s^?1 (SD, 31.9) (p < 0.001). The hepcidin threshold for siderosis was > 30.2 ng/mL (sensitivity, 87%; specificity, 82%). Ferritin H and ferritin L subunits were expressed similarly in patients with NAFLD, regardless of siderosis. There were no significant differences in laboratory test results between the groups, including glucose parameters and liver function tests.ConclusionsMRI relaxometry and serum hepcidin accurately assessed mild iron overload in patients with dysmetabolic iron overload syndrome.     

Acquired iron overload associated with antitransferrin monoclonal immunoglobulin: a case report

We describe a patient with an unusual combination of hypersideremia (700 microg/dL), hypertransferrinemia (570 mg/dL), hyperferritinemia (800 microg/L), and monoclonal gammopathy of undetermined significance (MGUS), in which the monoclonal immunoglobulin showed specific transferrin-binding activity. Liver histology revealed hepatic iron overload, prominent in periportal hepatocytes, suggesting intestinal iron hyperabsorption. We demonstrate that low urinary hepcidin, likely due to impaired iron delivery to erythroid cells via the transferrin cycle pathway over time, may be the mechanism for iron loading. We suggest that MGUS associated with monoclonal antibodies with antitransferrin activity should be added to the list of acquired causes of hemochromatosis.     

H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload

Ferritin, the iron-storing molecule, is made by the assembly of various proportions of 2 different H and L subunits into a 24-mer protein shell. These heteropolymers have distinct physicochemical properties, owing to the ferroxidase activity of the H subunit, which is necessary for iron uptake by the ferritin molecule, and the ability of the L subunit to facilitate iron core formation inside the protein shell. It has previously been shown that H ferritin is indispensable for normal development, since inactivation of the H ferritin gene by homologous recombination in mice is lethal at an early stage during embryonic development. Here the phenotypic analysis of the mice heterozygous for the H ferritin gene (Fth(+/-) mice) is reported, and differences in gene regulation between the 2 subunits are shown. The heterozygous Fth(+/-) mice were healthy and fertile and did not present any apparent abnormalities. Although they had iron-overloaded spleens at the adult stage, this is identical to what is observed in normal Fth(+/+) mice. However, these heterozygous mice had slightly elevated tissue L ferritin content and 7- to 10-fold more L ferritin in the serum than normal mice, but their serum iron remained unchanged. H ferritin synthesis from the remaining allele was not up-regulated. This probably results from subtle changes in the intracellular labile iron pool, which would stimulate L ferritin but not H ferritin synthesis. These results raise the possibility that reduced H ferritin expression might be responsible for unexplained human cases of hyperferritinemia in the absence of iron overload where the hereditary hyperferritinemia-cataract syndrome has been excluded. (Blood. 2001;98:525-532)     

Hereditary hyperferritinemia-cataract syndrome (HHCS) presenting with iron deficiency anemia associated with a new mutation in the iron responsive element of the L ferritin gene in a Swiss family

Hereditary hyperferritinemia-cataract syndrome (HHCS) is one of the differential diagnoses of hyperferritinemia (HF) with low or normal transferrin saturation but is usually not associated with anemia. Here, we report a case of a microcytic, hypochromic anemia with hyperferritinemia as the initial presentation of a combination of iron deficiency anemia and HHCS. The latter is an autosomal dominant disorder characterized by distinctive cataracts and HF in the absence of iron overload. Sequencing studies were carried out to look for mutations in the iron responsive element (IRE) of the L ferritin gene. A heterozygous single point mutation for a +24T to C substitution in the IRE of the L ferritin gene (=HGVS c.-176T>C) was detected which has not been described before. To evaluate the pathogenetic relevance of this new mutation, we performed family studies of parents and siblings. We could identify the father and one brother with HF, cataract, and the heterozygous +24T>C mutation. Neither the mother nor the five other siblings had HF, cataract or that mutation. We therefore conclude that this newly described heterozygous +24T>C mutation in the IRE of the L ferritin gene causes HHCS.