Approach
In many cases, the diagnosis is made incidentally or following screening prompted by diagnosis of hemochromatosis in a family member. In such cases, the patient may not have any symptoms or complications of the disease. Hemochromatosis should be considered in patients with unexplained chronic asthenia, arthropathy, impotence, hyperpigmentation, liver test abnormalities or cirrhosis, diabetes, cardiomyopathy, porphyria cutanea tarda (characterized by skin disease such as fragile skin, blisters, bullae, and mild liver dysfunction), chondrocalcinosis (radiographic calcification in hyaline and/or fibrocartilage), hepatocellular carcinoma, and hyperferritinemia. Patients with increased liver iron (evident on liver biopsy or magnetic resonance imaging [MRI]) should also be assessed for hemochromatosis.[8]
Clinical assessment
Although lethargy, fatigue, loss of libido, and skin bronzing are regarded as cardinal symptoms of hemochromatosis, a population-based study indicated that these symptoms and signs are no more common in C282Y homozygotes than in subjects without HFE mutations.[18]
C282Y homozygotes with chronic blood loss for any reason (e.g., gastrointestinal source, menses, regular blood donation) may have delayed onset of symptoms.
Laboratory blood tests
The first step in diagnosis is to check serum transferrin saturation and serum ferritin levels.[4][7][8] An elevated transferrin saturation is a common phenotypic marker of hemochromatosis that may be present prior to expansion of body iron stores (indicated by increased serum ferritin). There is substantial biologic variability in transferrin saturation, which is not mitigated by fasting.[28] Transferrin saturation is generally considered to be elevated if it is >45%. The European Association for the Study of the Liver is more specific, stating that transferrin saturation is elevated if it is >45% in females and >50% in males.[8][13] If there is a strong suspicion of hemochromatosis and the initial transferrin saturation is within the normal range, it is reasonable to recheck it and/or proceed with additional testing.
Ferritin levels are used to estimate the magnitude of iron overload; levels >300 micrograms/L in men and >200 micrograms/L in women are considered to be elevated.[8][13] The likelihood of severe clinical complications increases with ferritin levels >1000 micrograms/L.[19][20][21] Elevated ferritin on incidental testing may lead to a suspicion of hemochromatosis. Ferritin is, however, an acute-phase reactant; isolated elevations in serum ferritin may, therefore, lead to unnecessary testing for hemochromatosis.[29]
Next, genetic testing for hemochromatosis should be considered.[4][7][8] C282Y mutation homozygosity is the most common genetic abnormality associated with the disease. A compound mutation heterozygosity (C282Y/H63D) can lead to a mild phenotypic variant, but this usually also requires other acquired risk factors.[4][7] H63D homozygosity is very rarely associated with the clinical phenotype of hemochromatosis and is only evident in the setting of comorbidity. A simple heterozygous mutation (i.e., C282Y/WT) virtually never causes clinical disease.
Genotyping for C282Y should be carried out in people of European origin with biochemical evidence of iron overload (females with transferrin saturation >45% and serum ferritin >200 micrograms/L, and males with transferrin saturation >50% and serum ferritin >300 micrograms/L, or otherwise unexplained persistently elevated transferrin saturation) whether or not they have clinical signs or symptoms indicative of hemochromatosis.[8] In current practice, the demonstration of C282Y homozygosity along with elevated transferrin saturation and serum ferritin is considered sufficient to make the diagnosis of hemochromatosis.[5][8]
Genotyping for H63D can be performed in certain situations, although its value is controversial as it is not necessary for the diagnosis of hemochromatosis and is not generally used to guide treatment.[8] However, most genetic laboratories test for C282Y and H63D genotypes together.[4][7][8] Rare hemochromatosis variants should be investigated in patients with evidence of significant, unexplained iron overload who are not C282Y homozygous, as well as in young individuals with biochemical and clinical evidence of hemochromatosis.[8]
Genotyping is also recommended in adult first-degree relatives of patients with hemochromatosis.[4][7][8] Do not order HFE genotyping for a patient without iron overload or a family history of HFE-associated hereditary hemochromatosis.[7][8][30]
If there are existing genetic test results, do not perform repeat testing unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[30]
Subsequent tests
The following tests can be ordered to assess the degree of iron deposition and/or damage in the tissues:
All patients with hemochromatosis should be assessed for liver fibrosis at diagnosis, using noninvasive techniques, to guide appropriate treatment and follow-up.[8] Tests may include serum-based fibrosis test (e.g., aspartate aminotransferase-to-platelet ratio index [APRI] and FIB-4 (patient age, platelet count, aspartate aminotransferase and alanine aminotransferase) and transient elastography, although few studies have validated their use.[8]
Liver MRI: a noninvasive way to estimate liver iron content with good sensitivity and specificity.[31]
Liver biopsy: this is a sensitive and specific test for measuring liver iron content that also allows the pathologist to evaluate for injury related to iron overload, specifically fibrosis or cirrhosis. However, with the development of noninvasive methods to quantify iron levels and fibrosis, liver biopsy is now less frequently performed to assess iron overload or liver fibrosis, but it is often reserved for the detection of cirrhosis.[4][7][8]
LFTs: transferrin saturation and ferritin are commonly obtained during the course of evaluation of elevated aminotransferases. However, hemochromatosis does not routinely cause elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), including in patients with advanced hepatic fibrosis.[32][33] The presence of mild aminotransferase elevations may suggest an additional cause of chronic liver disease (e.g., viral hepatitis, hepatic steatosis).[34]
Fasting blood sugar: should be checked in all patients with an elevated ferritin level to assess damage to the pancreas from iron overload. Studies suggest that glycosylated hemoglobin may not be as reliable a marker of glucose control in patients undergoing phlebotomy because red cell turnover is faster.[35]
ECG and echocardiogram: should be performed in patients with an elevated ferritin level as hemochromatosis can lead to cardiomyopathy and conduction abnormalities, leading to arrhythmias.[36]
Cardiac MRI: patients with severe hemochromatosis and signs or symptoms of heart disease, and patients with juvenile hemochromatosis, should undergo cardiac MRI.[8]
Other MRI: MRI may also be useful to investigate iron levels/distribution in the spleen, pancreas, and brain in patients with suspected or diagnosed iron overload disorder.[8]
Sex hormones: should be checked in patients with an elevated ferritin level. Hypogonadism is the second most common endocrine disorder associated with the disease, after diabetes.[37] Hypogonadism is usually secondary, associated with low, rather than high, gonadotropins.
Bone densitometry: should be performed in patients with an elevated ferritin level who have concomitant predisposing factors to osteoporosis. Up to one quarter of patients with hemochromatosis have osteoporosis, which is related to both hypogonadism and severity of iron overload.[38]
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