Measurement Of Hepatic Iron Concentration Research Articles

Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis.

Ferritin is purported to have proinflammatory and profibrogenic effects on hepatic stellate cells. Thus, rather than acting as a passive indicator of hepatic iron concentration (HIC) in haemochromatosis, ferritin may directly influence fibrosis. This study evaluated whether serum ferritin is a better predictor of hepatic fibrosis compared to variables previously associated with increased fibrosis risk in haemochromatosis. We identified 291 C282Y HFE-homozygous patients who had undergone liver biopsy for histological fibrosis staging and measurement of HIC. Ordinal logistic regression determined the best model for fibrosis stage not including serum ferritin. Then, serum ferritin was introduced into this model to assess whether the predictive power of the model was significantly increased and to evaluate the effect on other predictors of fibrosis. Ordinal logistic regression analyses without serum ferritin demonstrated that log HIC (OR 2.89; P<.001), male gender (OR 2.93; P=.005), alcohol consumption (g/day) (OR 1.01; P=.004), steatosis (OR 2.86; P=.01), arthritis (OR 2.46; P=.01) predicted increasing fibrosis stage (n=217). Addition of serum ferritin in multivariate analysis substantially improved the predictive power of the model (χ2 =37.15; P<.01) and was highly predictive of fibrosis stage (OR 5.44; P<.001). Inclusion of serum ferritin in this model rendered the effects of HIC, gender, alcohol and steatosis to non-significance. In haemochromatosis, serum ferritin is a better predictor of fibrosis stage than HIC, gender, steatosis and alcohol. These data support a hypothesis that ferritin may play a role in fibrosis rather than simply acting as a passive indicator of iron storage.

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.

Screening for hereditary haemochromatosis

Hereditary haemochromatosis (HH) is a common autosomal recessive disorder of iron overload in Caucasian populations. Clinical manifestations usually occur in individuals homozygous for the C282Y mutation in the HFE gene product and who have developed significant iron loading. Current screening methods can detect affected individuals either prior to or early during disease evolution, enabling early introduction of phlebotomy treatment that can normalise life expectancy. Evaluation of possible iron overload, via measurement of serum transferrin saturation and ferritin level, is the most appropriate initial test for those subjects presenting clinically for evaluation. HFE genotyping, when combined with serum biochemical measurements, defines the presence of likely iron overload and the underlying genetic disorder and is the preferred initial screening modality for families of an affected individual. Definitive proof of iron overload requires measurement of hepatic iron concentration or total iron burden via therapeutic phlebotomy; elevated serum ferritin level alone is not adequate. We now recognise that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH. In fact, a minority of C282Y homozygotes develop classical 'iron overload disease', although it has recently emerged that the disorder may predispose to breast and colorectal cancer. Uncertainties as to the true clinical impact of the condition at a population level lead to current recommendations of cascade screening of families of affected patients, case-finding in high-risk groups, such as patients with clinical manifestations consistent with the diagnosis, and a high level of clinical awareness in the community to facilitate early diagnosis. Generalised population screening is not presently recommended.

MO‐F‐211‐03: A Practical Approach for Liver Iron Measurement in Clinical Setting

Purpose: To quantitatively and noninvasively determine a wide range of hepatic iron concentration (HIC) for hematologic oncology patients in a routine clinical setting. Methods: A total of 28 consecutive patients who underwent a bone marrow stem cell transplant at our institution within last five years were included in this study. A breath‐hold multiecho gradient‐echo sequence was used to acquire T2*‐weighted images using a 1.5‐T MRI scanner. To cover a wide range of clinically relevant T2* values, we used three HIC measurement protocols with different temporal resolutions to acquire data for each patient in three breath‐holds. Of the three measurement protocols, the one that provided the most reliable T2* values was selected for clinical use. An in‐house image post‐processing software tool was developed to generate T2*, R2*, and HIC maps for each patient. To validate the repeatability and reproducibility, a Ferri phantom consisting with different T2* tubes was used to measure T2* values with the same protocol for patients in every three to four months over a period of one year. Results: This technique is successfully used to measure a wide range of liver T2* values from 1.0 msec to 25.0 msec. Those T2* values correspond to HIC values ranging from 1.3 mg/g to 26.0 mg/g (dry weight). Phantom test for T2* tubes (range from 4.0 msec to 32.0 msec) demonstrated very good repeatability and reproducibility, with standard deviation error less than 2.0%. Conclusions: Although it is well known that T2* is proportional iron deposition in liver, clinical iron measurements using MRI are still far from routine. With the technique developed in this work, a wide range of clinically relevant HIC values can be accurately and noninvasively quantified in routine clinical settings by carefully combining breath‐holding protocols and using in‐house image post‐processing software.

The investigation and management of disturbed iron metabolism

Whilst iron is an essential trace element required by nearly all living organisms, deficiencies or excesses can lead to pathological conditions such as iron deficiency anaemia or haemochromatosis, respectively. Diagnosis of iron depletion is based on serum ferritin level less than 20 µg/L and iron deficiency by a serum ferritin 1000 µg/L will have done so by the age of 55 years. Definitive diagnosis of iron overload requires measurement of body iron content (usually based on measurement of hepatic iron concentration) using imaging (MRI), liver biopsy or quantitative phlebotomy. Serum ferritin levels do not correlate well with hepatic iron concentration outside of the presence of hereditary haemochromatosis or haematological disorders with secondary iron overload. Treatment of iron overload is based on iron removal, usually by phlebotomy therapy or in those who cannot tolerate phlebotomy, chelation.

Hepatic Iron Quantitation and Its Relationship with Disease Measures and Histologically Assessed Iron Content

The study was undertaken to determine the relationships between the histological finding of hepatic injury, necrosis, fibrosis and iron staining with biochemical measures of hepatic injury and hepatic iron content. One hundred fourteen consecutive subjects undergoing liver biopsy were studied. Data pertaining to biopsy reports, histology activity index, hepatic iron concentration, hepatic iron index, and histological grading of iron were recorded and analyzed using regression analysis. Statistical relationships were found between the hepatic iron index, histological grading of iron and hepatic iron concentration, whereas histology activity index was related to hepatic grading of iron, but not to hepatic iron concentration. The pathologist's assessment of the histological grading of iron relates directly to the histology activity index and hepatic iron concentration. Serum measures of iron, total iron-binding capacity and ferritin can be used to monitor hepatic iron content more economically and simply than with hepatic iron concentration measurement on liver biopsy.

Iron overload (with attention to genetic testing and diagnosis/management of HFE wild type patients)

The discovery of the HFE, HJV, HAMP, TfR2, and SLC40A1 genes and preliminary understanding of their roles in iron homeostasis have contributed tremendously to our understanding of the pathogenesis of genetic hemochromatosis. Although several new models of iron metabolism have been proposed, some key "sensor" steps of iron absorption in the enterocytes and of iron storage in hepatocytes and other cells remain unclear. A diagnosis of non-HFE genetic hemochromatosis should be considered in patients with unexplained iron overload who do not have the common mutations in the HFE genes. Phenotypic evaluation such as liver biopsy and measurement of hepatic iron concentration remain important in non-HFE hemochromatosis because mutations in other genes are rare and there are no other available noninvasive tests to confirm the diagnosis. Phlebotomy remains the mainstay of therapy also for non-HFE hemochromatosis. However, phlebotomy may not be well tolerated in certain forms of non-HFE hemochromatosis such as "ferroportin disease."

MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients

AbstractMeasurements of hepatic iron concentration (HIC) are important predictors of transfusional iron burden and long-term outcome in patients with transfusion-dependent anemias. The goal of this work was to develop a readily available, noninvasive method for clinical HIC measurement. The relaxation rates R2 (1/T2) and R2* (1/T2*) measured by magnetic resonance imaging (MRI) have different advantages for HIC estimation. This article compares noninvasive iron estimates using both optimized R2 and R2* methods in 102 patients with iron overload and 13 controls. In the iron-overloaded group, 22 patients had concurrent liver biopsy. R2 and R2* correlated closely with HIC (r2 ≥ .95) for HICs between 1.33 and 32.9 mg/g, but R2 had a curvilinear relationship to HIC. Of importance, the R2 calibration curve was similar to the curve generated by other researchers, despite significant differences in technique and instrumentation. Combined R2 and R2* measurements did not yield more accurate results than either alone. Both R2 and R2* can accurately measure hepatic iron concentration throughout the clinically relevant range of HIC with appropriate MRI acquisition techniques. (Blood. 2005;106:1460-1465)

Urine pregnancy test and intrauterine inseminations

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Comparison of Bathophenanthroline Sulfonate and Ferene as Chromogens in Colorimetric Measurement of Low Hepatic Iron Concentration

Sensitive and accurate measurement of hepatic iron concentration (HIC) is required to investigate liver fibrogenesis (1) and its influence on the outcome of interferon therapy for chronic viral hepatitis C (2)(3). Hepatic iron content can be measured by a quantitative chemical method and/or evaluated by semiquantitative histologic scoring. Quantitative chemical methods assess all liver iron forms, whereas histologic scoring evaluates only the hemosiderin form. A colorimetric method using bathophenanthroline sulfonate as chromogen was recommended in 1978 by the International Committee for Standardization in Hematology (ICSH) for determination of serum iron (4)(5). It was adapted by Barry and Sherlock (6) to the determination of HIC, and we recently evaluated it for measurement of low HIC (7). In 1990, the ICSH replaced bathophenanthroline sulfonate with ferene, a more sensitive chromogen, in the determination of serum iron (8). The aim of the present study was to evaluate the replacement of bathophenanthroline sulfonate with ferene to improve the sensitivity of the colorimetric determination of low HIC. We used samples of a frozen Wistar rat liver for quality control and determination of reliability criteria of both assays. We compared the results obtained with the two chromogens on 66 liver biopsies from patients with chronic liver diseases hospitalized in the Department of Hepatogastroenterology of the Pitie-Salpetriere Hospital. The clinical diagnoses of these patients are summarized in Table 1⇓ . We determined the CV for HIC measurements on two separate samples from the same liver specimen for each chromogen on 38 human liver biopsies. Histologic iron scoring was according to the method of Deugnier et al. (9); among the 66 biopsies, 20 had no stainable iron (score of 0), and the 46 others exhibited iron overload (score ≥6). Biopsies were fixed in 40 g/L formaldehyde and embedded in paraffin as part of …

HFE genotype in patients with hemochromatosis and other liver diseases.

Hereditary hemochromatosis is a common inherited disorder of iron metabolism. The gene HFE, which contains two missense mutations (C282Y and H63D), was recently identified. To determine how HFE genotyping for the C282Y and H63D mutations contributes to the diagnosis of hemochromatosis and to determine the prevalence of HFE mutations in a group of patients with liver disease. Cross-sectional study. Academic medical center. 66 patients with hereditary hemochromatosis and 132 referred patients with other liver diseases. At initial diagnosis, fasting transferrin saturation, ferritin level, routine chemistry panel, and complete blood count were determined. Percutaneous liver biopsy was done on all patients for histologic analysis and measurement of hepatic iron concentration and hepatic iron index. HFE genotyping for the C282Y and H63D mutations was done on all patients by using genomic DNA samples. Of the 66 patients with hemochromatosis diagnosed on the basis of serum iron studies and liver biopsy findings, 60 (91%) were C282Y homozygotes, 2 (3%) were compound heterozygotes, 1 (1.5%) was a C282Y heterozygote, 2 (3%) were H63D heterozygotes, and 1 (1.5%) was negative for both mutations. Of the 132 patients with liver disease, 6 (5%) were C282Y homozygotes, 8 (6%) were compound heterozygotes, 6 (5%) were C282Y heterozygotes, 5 (4%) were H63D homozygotes, 20 (15%) were H63D heterozygotes, and 87 (66%) were negative for both mutations. All 66 C282Y homozygotes had an elevated hepatic iron concentration, and 65 of the 66 patients (98%) had a transferrin saturation of at least 45%. Ten of the 66 patients (15% [95% CI, 7.5% to 26%]) had a hepatic iron index less than 1.9 mmol/kg per year; hemochromatosis was not suspected in 6 of the 10 patients before genotyping. Cirrhosis or substantial hepatic fibrosis was not seen in any (0% [CI, 0% to 18%]) of the 19 patients younger than 40 years of age who were homozygous for the C282Y mutation. All 66 patients homozygous for the C282Y mutation of HFE had an elevated hepatic iron concentration, but approximately 15% of these patients did not meet a previous diagnostic criterion for hemochromatosis (hepatic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is clinically useful in patients with liver disease and suspected iron overload and may lead to identification of otherwise unsuspected C282Y homozygotes.

A technique for obtaining repeated liver biopsies from rats

Many morphological, pharmacological and toxicological studies of hepatotoxicity require frequent sampling of liver over time. In the past this has been achieved by including large numbers of animals in the study and killing subgroups at different times. In this paper we describe a technique for repeated liver biopsy that procures sufficient liver tissue for histopathological assessment and for additional studies, for example measurement of hepatic iron concentration or vitamin A measurement. The advantages and disadvantages of this technique are discussed.

Variability in hepatic iron concentration measurement from needle-biopsy specimens

Background/Aim: Quantitative measurement of hepatic iron by biochemical analysis of liver biopsy samples is required to assess hepatic iron stores accurately. Cirrhotic livers, however, contain variable amounts of fibrous tissue and the distribution of iron within the hepatic parenchyma is not always uniform. The aim of this study was to assess the variability in hepatic iron concentration measurement from needle-biopsy specimens. Methods: The livers from eight patients with cirrhosis selected because of elevated serum ferritin were obtained at the time of liver transplantation ( n=6) or at autopsy ( n=2). Multiple needle biopsies were done, and hepatic iron concentration was measured by atomic absorption spectroscopy. The hepatic iron index was calculated as iron concentration divided by age. Results: Four cases had a mean hepatic iron index above 2.0, in the range of that reported in patients with homozygous genetic hemochromatosis, whereas the other four had an hepatic iron index of less than 2.0. The intra-individual coefficient of variation for hepatic iron concentration ranged from 11.3 to 43.7%, averaging 24.9%. The coefficient of variation was smaller in biopsy samples > 4 mg dry weight than in samples <4 mg (19.8% vs 28.6%, p<0.05). Histological examination of surgical biopsies from these livers showed large amounts of fibrous tissue, and inhomogeneous distribution of iron in the hepatic parenchyma. Conclusions: This study demonstrates an important variability in the measurement of hepatic iron content from needle biopsy speciments in patients with severe cirrhosis.

Was Beethoven's Cirrhosis Due to Hemochromatosis?

Dr. Wagner's description of an advanced macronodular cirrhosis is compatible with end-stage liver disease due to a variety of causes. An alcoholic etiology seems more probable than chronic viral hepatitis since such a diagnosis might also account for the chronic pancreatitis, unless it was related to the cholelithiasis. However, Dr. Wagner's description favors a diagnosis of biliary pigment sludge related to hemolysis. Furthermore, the controversy over the extent of Beethoven's alcohol consumption and the absence of mention of pancreatic calcification weakens the case for an alcoholic etiology. On the other hand, Dr. Wagner's emphasis of bluish-green pigmentation of the liver, blackish pigmentation of the spleen, and an arteropathy of the hepatic vessels suggests the probability of hemochromatosis, which diagnosis is also in keeping with Beethoven's medical history. In this regard the composer's history of recurrent obscure abdominal pain, commencing in his third decade, is especially in keeping with hemochromatosis. As many as a third of patients present with recurrent abdominal pain, and eventually up to 40% of cases develop significant abdominal pain in the course of their disease. While some of these cases of abdominal pain have been attributed to hepatoma, ascites, pancreatitis, perisplenitis, or diabetic neuropathy, the majority remain ill-defined (32). Even so, the diagnosis of hemochromatosis remains unproved in the absence of a histological examination and measurement of hepatic iron concentration. It is proposed that the combined additive, toxic effects of alcohol and iron were the most likely cause of Beethoven's cirrhosis.

Hereditary hemochromatosis.

Preview Hereditary hemochromatosis, once believed to be rare, is now known to affect 1 in 250 to 300 people of northern European descent. Untreated, the disorder can have serious complications, but for patients in whom it is discovered and treated early, the prognosis is good. In this guide to diagnosis and management, Drs Olynyk and Bacon discuss, among other things, which patients to screen, what tests to order, length of treatment, effect of treatment on complications, and prognosis.

Determination of hepatic iron concentration in fresh and paraffin-embedded tissue: Diagnostic implications

Background/Aims: Determination of hepatic iron concentration (HIC) is essential for the evaluation of hereditary hemochromatosis. Occasionally, only paraffin-embedded liver biopsy specimens are available, or fresh biopsy specimens have been placed in saline for transport. This study aimed to describe a method for extraction of liver tissue from paraffin blocks, determine the accuracy of measurement of HIC in recovered tissue compared with fresh tissue, and determine the effect of immersion in saline on HIC. Methods: HIC was measured in both fresh and deparaffinized liver specimens (n = 41). Accurate measurements were defined as either a normal result in both specimens or a result in the deparaffinized specimen that was within 30% of the fresh measurement. Results: Measurements of HIC in fresh and deparaffinized tissue showed an excellent linear relationship (r = 0.95). In deparaffinized samples ≥0.4 mg, accurate measurements were seen in 24 out of 29 specimens, compared with 6 out of 12 specimens weighing <0.4 mg (P < 0.01). The hepatic iron index calculated from results in deparaffinized samples ≥0.4 mg correctly classified all patients. Immersion of fresh biopsy specimens in saline for 1 hour resulted in up to 50% iron loss (P < 0.05). Conclusions: Accurate measurement of HIC in deparaffinized liver biopsy specimens is possible. Calculation of the hepatic iron index from deparaffinized liver tissue can facilitate diagnosis of hemochromatosis when fresh tissue is not available. Samples should not be transported in saline.

Measurement of hepatic iron concentration (HIC) in fresh and paraffin-embedded tissue

Measurement of hepatic iron concentration (HIC) in fresh and paraffin-embedded tissue

Fine-needle aspiration biopsy for the measurement of hepatic iron concentration.

The potential application of fine-needle aspiration liver biopsy in the documentation of hepatic iron overload has been assessed in iron-loaded rats. Fine-needle aspiration and standard liver biopsy specimens were obtained from three groups of animals supplemented with oral and parenteral iron for 2 to 6 mo. The mean dry weights of standard and fine-needle biopsy specimens were 7.41 +/- 0.77 (+/- S.E.M.) and 0.57 +/- 0.54 mg, respectively. Hepatic iron in fine-needle aspiration biopsy specimens correlated significantly with hepatic iron in standard liver biopsy specimens as measured by biochemical determination, computerized image analysis and histological grading (r greater than 0.9, p less than 0.001). In conclusion, we have shown that fine-needle aspiration biopsy of the liver can obtain sufficient tissue for biochemical measurement of the hepatic iron concentration in an animal model of iron overload. The clinical applications of fine-needle aspiration liver biopsy in human beings with iron overload is currently being investigated.

Usefulness and limitations of laboratory and hepatic imaging studies in iron-storage disease

Liver biopsy with measurement of hepatic iron concentration is the most certain procedure for evaluation of iron-storage disease, although use of computed tomography and magnetic resonance imaging procedures recently have been proposed as alternative, noninvasive methods for estimating the degree of iron overload. The results of these imaging procedures were compared with those of other noninvasive techniques and liver biopsies in 48 patients. Final diagnoses, based on synthesis of clinical and laboratory data, included (a) primary hemochromatosis (n = 25; 19 homozygous, 6 heterozygous); (b) secondary hemochromatosis (n = 7); (c) alcoholic liver disease (n = 11); (d) chronic active hepatitis (n = 3); and (e) other (n = 2). Serum ferritin and computed tomography or magnetic resonance scanning had 100% sensitivity in detecting hepatic iron overload more than fivefold above the upper limit of normal (>10.7 μmol Fe/100 mg dry liver) but did not detect lesser degrees of iron overload reliably, including those found in 6 of 13 patients with untreated homozygous primary hemochromatosis and 3 of 7 with secondary hemochromatosis. Computed tomography and magnetic resonance imaging were more specific than ferritin (64% and 92% vs. 21%) in the detection of iron excess, more than five times the upper limit of normal. Among magnetic resonance imaging measures, the ratio of the second echo signal intensities of liver to paraspinous muscle was the most sensitive and most specific for detection of this degree of iron overload. The degree of correlation between hepatic iron concentration and results of noninvasive laboratory or imaging studies were insufficient to permit prediction of hepatic iron content by noninvasive studies alone. It is concluded that computed tomography or magnetic resonance scanning as currently usually used is not cost-effective in routine evaluation of iron overload, although these imaging procedures may play a role in patients in whom liver biopsy is contraindicated. Because of their low cost and ready availability, serum ferritin and transferrin saturation tests remain the preferred screening studies for iron overload. Liver biopsy with quantitative iron measurement remains the study of choice for the definitive diagnosis of hemochromatosis.

Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index

The value of measurement of hepatic iron concentration and determination of the hepatic iron index in distinguishing homozygotes from heterozygotes for hemochromatosis was examined. The study group included 42 homozygotes with an unequivocal diagnosis of hemochromatosis and six individuals who had initial equivocal results but were established as homozygous after extensive follow-up. These were compared with 15 heterozygotes with no sign of increasing body iron stores who had undergone liver biopsy because of an initial suspicion of raised iron levels. In these subjects a hepatic iron concentration of greater than 75 mumol/gm dry weight was clearly indicative of homozygous hemochromatosis. Body iron accumulation was age-related both in homozygotes and in these heterozygotes with mild biochemical abnormalities (r = 0.476; p = 0.001 and r = 0.689; p = 0.01, respectively), with a rate of accretion of approximately 5 mumol/gm dry weight/year in homozygotes and 0.9 mumol/gm dry weight/year in heterozygotes. Thus, lower values in young subjects may be consistent with homozygosity, and higher values in older individuals are consistent with heterozygosity. To overcome this problem, the hepatic iron index (hepatic iron concentration divided by age in years) was analyzed and found to separate the two groups effectively, with no homozygote having an index of less than 1.9 and no heterozygote having an index of greater than 1.5. These results in a series of patients who have been followed for a median of 3 yr (range = 1 to 30 yr) validate the use of the hepatic iron index to discriminate hemochromatosis homozygotes from heterozygotes with raised levels of serum ferritin, transferrin saturation or both.