The Iron Overload Syndromes
The Iron Overload Syndromes
(Enlarge Image)
Figure 2.
Algorithm for management of iron overload.
The initial approach to diagnosis in patients with suspected iron overload should include indirect markers of iron stores which include TS, SF and unsaturated iron binding capacity (UIBC). TS is considered the initial screening test and elevated initial TS should be confirmed with a second test. The earlier recommendation of fasting TS to exclude circadian and postprandial variation of TS is no longer necessary; a recent study has shown no improvement in sensitivity or specificity of fasting over random TS tests. A TS of ≥45% identifies 97.9–100% of C282Y homozygotes.
A small proportion of patients with HH, especially younger individuals at an early stage of disease may have TS < 45%, necessitating close follow-up. SF is an excellent predictor of advanced fibrosis and cirrhosis, but lacks specificity as a screening test when used alone. Hyperferritinaemia is present in a number of other conditions including ALD, HCV, neoplastic disease and NAFLD among others. Irrespective of age and gender, a SF > 1000 μg/L is associated with a greater risk of cirrhosis. In C282Y homozygotes, a SF over > 1000 μg/L, elevated aminotransferase level and a low platelet count predicts cirrhosis in over 80% of patients. A normal SF (less than 200 μg/L in premenopausal women and 300 μg/L in men and postmenopausal women) in combination with a TS < 45%, has a negative predictive value of 97% for excluding iron overload.
A recent study by Gurrin et al. demonstrated that male C282Y homozygotes with a baseline SF between 300 and 1000 μg/L had a 25% chance of progressing to SF > 1000 μg/L on an average after 12 years with the greatest risk of progression among men with a baseline TS > 95%. In contrast, women with SF 200–1000 μg/L had only an 18% chance of progressing to SF > 1000 μg/L during the same time period. However, iron overload may be present with an elevated SF level and a normal TS level, particularly in non-HFE-related iron overload. Therefore, a significant elevation in SF with no obvious explanation, especially if greater than 1000 μg/L, may require a liver biopsy to determine whether iron overload is present.
The UIBC is the inverse of TS and can be obtained as a one-step automated test. In large-scale population screening studies, UIBC has been shown to be comparable or slightly better than TS and maybe used as a low cost alternative screening test for detecting HH.
The HFE mutation analysis should be performed in individuals with abnormal iron studies. Genotype testing involves determination of the common HFE gene mutations C282Y and H63D. S65C occurs in less than 1% of clinically significant HH and is not routinely tested. Presence of TS > 45% and C282Y homozygosity or C282Y/H63D compound heterozygosity may be considered diagnostic of HH. The genetic tests available include targeted mutation analysis and sequence analysis. Although targeted mutation analysis tests for the two common C282Y and H63D mutations, sequence analysis identifies less common mutant alleles and is available only in a few clinical and research laboratories. Evidence of increased hepatic iron concentration based on either a liver biopsy or MRI imaging in the absence of C282Y homozygosity or C282Y/H63D compound heterozygosity may indicate iron overload from non-HFE related haemochromatosis or secondary iron overload. Testing for Non-HFE gene mutations in HJV, TfR2, FPN and hepcidin are not generally commercially available.
Liver biopsy was considered the gold standard for the diagnosis of HH prior to the availability of genetic testing and continues to have a role in diagnosis and prognosis. A liver biopsy should be considered in the following situations among patients with HH: (i) a SF > 1000 μg/L for assessment of degree of fibrosis in HFE-HH. (ii) Elevated liver enzymes and/or increased alcohol consumption (>60 gm/day) to evaluate for other concomitant liver diseases, such as NAFLD, alcoholic liver disease or HCV in patients with iron overload. (iii) Diagnosis of non-HFE-related haemochromatosis, as genetic testing in these conditions are not widely available.
In HFE-HH, liver histology shows a characteristic pattern with iron accumulation predominantly in the periportal hepatocytes with absent or minimal iron in the reticuloendothelial cells. In contrast, predominant reticuloendothelial cell iron maybe present in patients with ferroportin disease and secondary iron overload (Figure 3). Liver tissue is also used to measure hepatic iron concentration (HIC) and calculation of hepatic iron index (HII). The normal HIC is less than 1800 mg/g dry weight (equivalent to 32 μg/g). A threshold HIC of >71 μ/g dry weight along with a HII 1.9 μmol/g/year was previously suggested to be helpful in identifying phenotypic HH vs. 'secondary iron overload'. However, it is now evident that phenotypic HH can occur at a lower HII and certain secondary iron overload states, such as thalassaemia may have a HII comparable to HH, and therefore HII is no longer routinely used.
(Enlarge Image)
Figure 3.
Liver histology in iron overload. (a) Periportal iron deposition in patient with hereditary hemochromatosis, (b) Extensive Iron in Kupffer cells in a patient with Thalassemia.
Considerable effort is being made to develop non-invasive markers for detecting cirrhosis in HH. Serum type IV collagen concentration is elevated in HH and a level >115 ng/mL is sensitive, although less specific in detection of cirrhosis. A recent study has shown that serum concentration of Hyaluronic acid >46.5 ng/mL showed 100% sensitivity and specificity in detecting cirrhosis in HH. Other fibrosis markers, such as serum laminin and tissue inhibitor of metalloproteinase (TIMP-I) levels, seem to be of little value for fibrosis prediction.
Transient elastography (FibroScan) is a non-invasive, rapid method, allowing assessment of liver fibrosis by measuring liver rigidity. However, this technique to measure liver stiffness is often difficult especially in the presence of obesity. Non-invasive imaging tests, CT and MRI, are useful for diagnosis, determination of severity and for monitoring therapy. CT noncontrast imaging demonstrates diffuse increased attenuation of the liver, usually greater than 75 Hounsfield units. However, MRI is more sensitive and specific for the detection of abnormal hepatic iron. MRI T2* is now gaining popularity as a non-invasive method for liver iron estimation. The iron in the liver causes local distortion in the magnetic fields and relaxation of the spins resulting in loss of signal intensity in the liver. The loss of signal intensity is proportional to the iron deposition(Figure 4). The hepatic iron deposition is then quantified by measuring the ratio of the signal intensity of the liver and of a reference tissue (e.g. paraspinous muscle). In addition, MRI can also detect complications of iron overload, such as cirrhosis and HCC. Patients with thalassaemia and other anaemias requiring multiple transfusions demonstrate abnormal iron overload in both liver and the spleen, unlike patients with HH who usually do not have splenic iron. Patients with thalassaemia may also exhibit cardiac iron overload; there is no direct correlation between liver and cardiac iron overload. Therefore, in these individuals MRI of both the liver and heart should be obtained. Low values of cardiac T2* reflect high cardiac iron levels and predict heart failure and arrhythmia.
(Enlarge Image)
Figure 4.
Magnetic resonance imaging of the liver in iron overload. T1-weighted out of phase sequence (left) consistent with focal fatty infiltration. Low signal on T2-weighted sequences compatible with iron deposition from hemochromatosis. Small islands of low signal in the spleen secondary to iron deposition. Nodularity of liver capsule consistent with cirrhosis.
Diagnosis of Iron Overload (Figure 2)
Serological Tests for Iron Overload
(Enlarge Image)
Figure 2.
Algorithm for management of iron overload.
The initial approach to diagnosis in patients with suspected iron overload should include indirect markers of iron stores which include TS, SF and unsaturated iron binding capacity (UIBC). TS is considered the initial screening test and elevated initial TS should be confirmed with a second test. The earlier recommendation of fasting TS to exclude circadian and postprandial variation of TS is no longer necessary; a recent study has shown no improvement in sensitivity or specificity of fasting over random TS tests. A TS of ≥45% identifies 97.9–100% of C282Y homozygotes.
A small proportion of patients with HH, especially younger individuals at an early stage of disease may have TS < 45%, necessitating close follow-up. SF is an excellent predictor of advanced fibrosis and cirrhosis, but lacks specificity as a screening test when used alone. Hyperferritinaemia is present in a number of other conditions including ALD, HCV, neoplastic disease and NAFLD among others. Irrespective of age and gender, a SF > 1000 μg/L is associated with a greater risk of cirrhosis. In C282Y homozygotes, a SF over > 1000 μg/L, elevated aminotransferase level and a low platelet count predicts cirrhosis in over 80% of patients. A normal SF (less than 200 μg/L in premenopausal women and 300 μg/L in men and postmenopausal women) in combination with a TS < 45%, has a negative predictive value of 97% for excluding iron overload.
A recent study by Gurrin et al. demonstrated that male C282Y homozygotes with a baseline SF between 300 and 1000 μg/L had a 25% chance of progressing to SF > 1000 μg/L on an average after 12 years with the greatest risk of progression among men with a baseline TS > 95%. In contrast, women with SF 200–1000 μg/L had only an 18% chance of progressing to SF > 1000 μg/L during the same time period. However, iron overload may be present with an elevated SF level and a normal TS level, particularly in non-HFE-related iron overload. Therefore, a significant elevation in SF with no obvious explanation, especially if greater than 1000 μg/L, may require a liver biopsy to determine whether iron overload is present.
The UIBC is the inverse of TS and can be obtained as a one-step automated test. In large-scale population screening studies, UIBC has been shown to be comparable or slightly better than TS and maybe used as a low cost alternative screening test for detecting HH.
Genetic Testing
The HFE mutation analysis should be performed in individuals with abnormal iron studies. Genotype testing involves determination of the common HFE gene mutations C282Y and H63D. S65C occurs in less than 1% of clinically significant HH and is not routinely tested. Presence of TS > 45% and C282Y homozygosity or C282Y/H63D compound heterozygosity may be considered diagnostic of HH. The genetic tests available include targeted mutation analysis and sequence analysis. Although targeted mutation analysis tests for the two common C282Y and H63D mutations, sequence analysis identifies less common mutant alleles and is available only in a few clinical and research laboratories. Evidence of increased hepatic iron concentration based on either a liver biopsy or MRI imaging in the absence of C282Y homozygosity or C282Y/H63D compound heterozygosity may indicate iron overload from non-HFE related haemochromatosis or secondary iron overload. Testing for Non-HFE gene mutations in HJV, TfR2, FPN and hepcidin are not generally commercially available.
Liver Biopsy
Liver biopsy was considered the gold standard for the diagnosis of HH prior to the availability of genetic testing and continues to have a role in diagnosis and prognosis. A liver biopsy should be considered in the following situations among patients with HH: (i) a SF > 1000 μg/L for assessment of degree of fibrosis in HFE-HH. (ii) Elevated liver enzymes and/or increased alcohol consumption (>60 gm/day) to evaluate for other concomitant liver diseases, such as NAFLD, alcoholic liver disease or HCV in patients with iron overload. (iii) Diagnosis of non-HFE-related haemochromatosis, as genetic testing in these conditions are not widely available.
In HFE-HH, liver histology shows a characteristic pattern with iron accumulation predominantly in the periportal hepatocytes with absent or minimal iron in the reticuloendothelial cells. In contrast, predominant reticuloendothelial cell iron maybe present in patients with ferroportin disease and secondary iron overload (Figure 3). Liver tissue is also used to measure hepatic iron concentration (HIC) and calculation of hepatic iron index (HII). The normal HIC is less than 1800 mg/g dry weight (equivalent to 32 μg/g). A threshold HIC of >71 μ/g dry weight along with a HII 1.9 μmol/g/year was previously suggested to be helpful in identifying phenotypic HH vs. 'secondary iron overload'. However, it is now evident that phenotypic HH can occur at a lower HII and certain secondary iron overload states, such as thalassaemia may have a HII comparable to HH, and therefore HII is no longer routinely used.
(Enlarge Image)
Figure 3.
Liver histology in iron overload. (a) Periportal iron deposition in patient with hereditary hemochromatosis, (b) Extensive Iron in Kupffer cells in a patient with Thalassemia.
Considerable effort is being made to develop non-invasive markers for detecting cirrhosis in HH. Serum type IV collagen concentration is elevated in HH and a level >115 ng/mL is sensitive, although less specific in detection of cirrhosis. A recent study has shown that serum concentration of Hyaluronic acid >46.5 ng/mL showed 100% sensitivity and specificity in detecting cirrhosis in HH. Other fibrosis markers, such as serum laminin and tissue inhibitor of metalloproteinase (TIMP-I) levels, seem to be of little value for fibrosis prediction.
Imaging
Transient elastography (FibroScan) is a non-invasive, rapid method, allowing assessment of liver fibrosis by measuring liver rigidity. However, this technique to measure liver stiffness is often difficult especially in the presence of obesity. Non-invasive imaging tests, CT and MRI, are useful for diagnosis, determination of severity and for monitoring therapy. CT noncontrast imaging demonstrates diffuse increased attenuation of the liver, usually greater than 75 Hounsfield units. However, MRI is more sensitive and specific for the detection of abnormal hepatic iron. MRI T2* is now gaining popularity as a non-invasive method for liver iron estimation. The iron in the liver causes local distortion in the magnetic fields and relaxation of the spins resulting in loss of signal intensity in the liver. The loss of signal intensity is proportional to the iron deposition(Figure 4). The hepatic iron deposition is then quantified by measuring the ratio of the signal intensity of the liver and of a reference tissue (e.g. paraspinous muscle). In addition, MRI can also detect complications of iron overload, such as cirrhosis and HCC. Patients with thalassaemia and other anaemias requiring multiple transfusions demonstrate abnormal iron overload in both liver and the spleen, unlike patients with HH who usually do not have splenic iron. Patients with thalassaemia may also exhibit cardiac iron overload; there is no direct correlation between liver and cardiac iron overload. Therefore, in these individuals MRI of both the liver and heart should be obtained. Low values of cardiac T2* reflect high cardiac iron levels and predict heart failure and arrhythmia.
(Enlarge Image)
Figure 4.
Magnetic resonance imaging of the liver in iron overload. T1-weighted out of phase sequence (left) consistent with focal fatty infiltration. Low signal on T2-weighted sequences compatible with iron deposition from hemochromatosis. Small islands of low signal in the spleen secondary to iron deposition. Nodularity of liver capsule consistent with cirrhosis.
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