Approach Considerations
The diagnosis of hemochromatosis is based on clinical features of the disease; these features include diffuse hyperpigmentation, hepatomegaly, and diabetes mellitus accompanied with biochemical abnormalities of iron metabolism and genotypic investigation.[73] Perform early genetic testing or liver biopsy to avoid the complications of hemochromatosis.
Examination of HFE mutations is pivotal for diagnosis of hemochromatosis; the discovery of the HFE gene allows easy differentiation of hereditary hemochromatosis from other forms of hepatic iron overload, including dysmetabolic hepatosiderosis. Liver biopsy and histologic evaluation of tissue iron accumulation was believed to be the criterion standard for diagnosis of hereditary hemochromatosis until testing of the HFE gene was introduced.[34]
The prevalence of the C282Y and H63D mutations in patients with alcoholic liver disease and in those with chronic hepatitic C (HCV) is the same as in the control population, whereas, in patients with nonalcoholic steatohepatitis (NASH), the prevalence of HFE mutations is higher. Moreover, 40% of patients with porphyria cutanea tarda are homozygous or heterozygous for the C282Y mutation (shown in patients from the United States, the United Kingdom, and Australia but not in Italian patients).
Measuring serum iron has no value in the diagnosis, but measuring transferrin saturation is necessary. The American College of Physicians found insufficient evidence to recommend for or against the use of transferrin saturation and serum ferritin levels to help identify the early stages of hereditary hemochromatosis.[74]
Serum abnormalities of iron metabolism can be seen in 50% of patients with alcoholic liver disease, NASH, or chronic viral hepatitis.[75] These abnormalities comprise an increased ferritin level, which is sometimes accompanied with elevated transferrin saturation. Hepatic iron concentration (HIC) could be slightly elevated, but the level of HIC in patients with hereditary hemochromatosis is much higher. Patients with chronic hepatitis C virus infection (HCV) who do not respond to interferon therapy usually have higher HIC than responders.
Development of noninvasive measures of hepatic iron content has generated significant interest. Many studies are focusing on the role of computed tomography (CT) scanning or magnetic resonance imaging (MRI) in the evaluation of total iron body stores.
Supraventricular arrhythmias are often revealed on electrocardiograms (ECGs).
All patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk of variceal hemorrhage. Patients at risk for variceal hemorrhage should be considered for primary prophylaxis with propranolol or nadolol.
Transferrin Saturation
Transferrin saturation corresponds to the ratio of serum iron and total iron-binding capacity (TIBC). The screening threshold for hemochromatosis is a fasting transferrin saturation of 45-50%. If transferrin saturation is greater than 45%, the presence of the C282Y or H63D mutation may be evaluated to confirm the diagnosis of hemochromatosis.
Hemochromatosis is suggested by a persistently elevated transferrin saturation in the absence of other causes of iron overload. This is the initial test of choice. However, similar to iron studies, transferrin saturation is influenced by liver disease (other than hemochromatosis) and inflammation; therefore, it has limitations in the diagnostic workup.
High transferrin saturation is the earliest evidence of hemochromatosis; a value greater than 60% in men and 50% in women is highly specific. However, approximately 30% of women younger than 30 years who have hemochromatosis do not have elevated transferrin saturation.
Serum iron concentration in patients with hereditary hemochromatosis is greater than 150 mcg/dL. TIBC ranges from 200 to 300 mcg/dL in hemochromatosis-affected patients (normal range, 250-400 mcg/dL). Hepatic iron concentration in hemochromatosis-affected patients ranges from 5000 to 30000 mcg/g (normal values, 100-2200 mcg/g).[76]
Serum Ferritin Studies
Ferritin levels are less sensitive than transferrin saturation in screening tests for hemochromatosis. Ferritin concentration can also be high in other conditions, such as infections, inflammations, and liver disease. Ferritin concentration higher than 1000 mcg/L suggests liver damage with fibrosis or cirrhosis.[77]
Recognize that a high ferritin level may be an indicator of iron overload, not just a sign of nonspecific inflammation, especially if accompanied with elevated liver enzymes.
Serum ferritin levels elevated higher than 200 mcg/L in premenopausal women and 300 mcg/L in men and postmenopausal women indicate primary iron overload due to hemochromatosis, especially when associated with high transferrin saturation and evidence of liver disease.
Genetic Testing
Genetic tests for the C282Y and H63D mutations are widely available. Detection of hemochromatosis-associated mutations is conducted to confirm the diagnosis or to discover asymptomatic patients.
Genetic testing for the HFE mutation is indicated in all first-degree relatives of patients with hemochromatosis and also in patients with evidence of iron overload[78] (eg, elevated transferrin saturation, high serum ferritin levels, excess iron staining or iron concentration on liver biopsy samples). This is particularly indicated in patients with known liver disease and evidence of iron overload, even if other causes of liver disease are present.[79]
Such testing is accomplished by searching for the 2 HFE gene mutations, C282Y and H63D. This is the next step in diagnosis after increased biochemical iron indices are present and other causes of iron overload have been excluded.
The finding of heterozygosity for C282Y is expected in 10% or more of subjects with hemochromatosis of northern European extraction and in approximately 15-20% of patients for the H63D mutation; thus, this finding is common in any white population studied.
At present, only homozygosity for C282Y and compound heterozygosity for C282Y/H63D should be considered indicative of hereditary hemochromatosis. C282Y heterozygosity may contribute to iron overload due to other conditions, but it should not be considered the sole cause of iron overload and it should not be considered diagnostic of hereditary hemochromatosis.
HFE genotyping cannot provide information about the degree of increased body iron stores or organ damage. DNA-based testing cannot replace liver biopsy to confirm the presence of end-stage liver damage.[80] The use of DNA-based tests alone may fail to identify 20-40% of white patients and most black patients with clinical evidence of hemochromatosis but without the C282Y mutation.
Imaging Studies
Radiographs demonstrate cardiomegaly and increased pulmonary vascular markings in patients with hemochromatosis. On echocardiograms, features of restrictive cardiomyopathy are visible.
Heart diseases are associated with hereditary hemochromatosis in one third of patients. Cardiac disease is mainly manifested by congestive heart failure accompanied by supraventricular arrhythmias. On radiographs, cardiomegaly with increased pulmonary vascular markings are seen. Echocardiography reveals the features of the restrictive type of cardiomyopathy.
Computed tomography (CT) scanning is neither sensitive nor specific for the detection of mild hepatic iron overload. Magnetic resonance imaging (MRI) may be more sensitive, but this modality has not been validated as a diagnostic test to help confirm hemochromatosis. However, in cases of elevated ferritin levels in the absence of homozygosity for C282Y/compound heterozygosity for C282Y/H63Asp, hepatic iron quantification with MRI might be helpful.[81] Nonetheless, consensus has not yet been reached regarding the technique or the possibility to reproduce the same method of calculus in different machines.
Biopsies and Histologic Features
A skin biopsy specimen may confirm the diagnosis of hereditary hemochromatosis. Any cutaneous site, hyperpigmented or not, may be selected for biopsy, but avoid performing cutaneous skin biopsies on the legs, because iron deposition in that area may be due to stasis. In healthy people, iron deposition may be evident only around apocrine glands and not around eccrine glands.
Liver biopsy with biochemical determination of hepatic iron concentration and calculation of the hepatic iron index (HII) as well as histologic evaluation with iron staining (Perls Prussian blue) was previously considered the criterion standard for diagnosis. The HII is calculated by dividing body weight in pounds by the hepatic iron concentration (HIC) in micromoles per gram of dry weight. An HII of greater than 1.9 can accurately differentiate homozygous hemochromatosis from heterozygous hemochromatosis, alcoholism, and normal controls. When the HII is 1.5-1.9, the diagnosis of hemochromatosis is equivocal.
Currently, the diagnosis can be confidently based on genetic testing for the C282Y mutation; thus, liver biopsy is no longer essential for diagnosis in many cases. However, liver biopsy may not only be useful to identify liver disease and to determine the presence or absence of cirrhosis, which directly affects prognosis, but it may also be helpful in patients with cirrhosis, which is the primary risk factor for hepatocellular carcinoma.
Indications for liver biopsy
According to guidelines that were developed for the diagnosis and management of hereditary hemochromatosis (on behalf of the Dutch Institute for Healthcare Improvement) (which is mainly expert opinion based), a liver biopsy is indicated in the following cases[81] : (1) elevated liver enzymes in combination with hereditary hemochromatosis, and (2) serum ferritin levels greater than 1000 mcg/L.
According to guidelines from AASLD: "Liver biopsy is recommended in all homozygotes with clinical evidence of liver disease, serum ferritin greater than 1,000 ng/mL, and particularly in those greater than 40 years of age with other risk factors for liver disease. Liver biopsy should also be considered in compound or C282Y heterozygotes with elevated TS, particularly those who have had abnormal liver enzyme levels or clinical evidence of liver disease."[61]
The use of liver biopsy in hereditary hemochromatosis can be restricted to those patients with a high probability of severe fibrosis or cirrhosis. A ferritin level of greater than 1000 mcg/L is a strong and independent predictor of fibrosis, but when alcohol intake exceeds 60 g/d, a significant proportion of patients may have severe fibrosis or cirrhosis, even if their ferritin levels are less than 60 g/d. Liver biopsy should be considered in these patients.
Histologic findings
Histologic evaluation liver and gallbladder biopsies with Perls Prussian blue staining shows a characteristic pattern of hepatic accumulation. In hemochromatosis, iron accumulates predominantly in hepatocytes and biliary epithelial cells, with relative sparing of Kupffer cells. Typically, a gradient of hepatocyte iron accumulation is present, with prominent involvement of periportal hepatocytes (zone 1) and decreasing intensity near the central vein (zone 3). By contrast, iron accumulation in parenteral iron overload occurs predominantly in Kupffer cells.[82]
Primary liver cancer in patients with hemochromatosis may have a wide histologic spectrum.[83] Some tumors show frequent biliary differentiation. Others arise on a nonfibrotic or cirrhotic liver and are often associated with von Meyenburg complexes and, to a lesser extent, with bile duct adenomas.
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