Tests
1st tests to order
serum transferrin saturation
Test
First laboratory test to become abnormal.
There is substantial biologic variability in transferrin saturation, which is not mitigated by fasting.[28] 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.
Result
>50% in men; >45% in women
serum ferritin
Test
Ferritin levels are used to estimate the magnitude of iron overload.[4][7][8]
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]
Serum ferritin is elevated in inflammation, alcoholism, chronic viral hepatitis, nonalcoholic fatty liver disease, and the dysmetabolic syndrome.[29] If a patient has elevated serum ferritin level and one of the above confounding factors, liver biopsy should be considered; alternatively, estimation of visceral iron deposition can be done by hepatic MRI.[4][7][8]
Result
elevated; >300 micrograms/L in men; >200 micrograms/L in women. The likelihood of severe clinical complications increases with ferritin levels >1000 micrograms/L.
Tests to consider
HFE mutation analysis
Test
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 usually also requires other acquired risk factors. 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]
Result
C282Y mutation homozygosity (p.Cys282Tyr); less commonly compound heterozygosity (C282Y/H63D) and rare mutations.
serum-based fibrosis tests/transient elastography
Test
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]
Result
serum-based fibrosis tests - may be normal or elevated; transient elastography - may be normal or show increased liver stiffness.
MRI liver
Test
A noninvasive way to measure liver iron content with good sensitivity and specificity.[31]
Result
liver to muscle signal intensity <0.88
liver biopsy
Test
A sensitive and specific test for measuring liver iron content, that also allows the pathologist to assess liver damage due to iron overload, specifically fibrosis and 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]
Result
iron content elevated
LFTs
Test
Transaminases may be increased at the time of diagnosis but are usually not greater than twice normal.
Patients with hemochromatosis and an additional cause of chronic liver disease (e.g., viral hepatitis, alcoholic liver disease, hepatic steatosis) are more likely to have elevated aminotransferase levels.[34]
Liver biopsy should be considered in patients with elevated transaminases as this may be an indicator of advanced fibrosis, signaling the need for hepatocellular carcinoma screening.[19][20]
Result
aminotransferase levels above normal
fasting blood sugar
Test
Should be checked in all patients with an elevated ferritin level.
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]
Result
elevated
echocardiogram
Test
Should be performed in patients with an elevated ferritin level as hemochromatosis can lead to cardiomyopathy and conduction abnormalities, leading to arrhythmias.[36]
Result
mixed dilated-restrictive or dilated cardiomyopathy
ECG
Test
ECG changes can be seen in hemochromatosis, but an ECG is not considered part of the routine screening procedures.
Result
decreased QRS amplitude and T-wave flattening or inversion
MRI heart and other organs
Test
Patients with severe hemochromatosis and signs or symptoms of heart disease, and patients with juvenile hemochromatosis, should undergo cardiac MRI.[8]
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]
Result
suggestive of iron loading: tissue-specific values of T2* (or its reciprocal, R2*) indicative of iron loading have been determined for liver, heart, pancreas, and pituitary gland
testosterone, FSH, and LH assays
Test
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.
Result
lower than normal levels
bone densitometry
Test
Should be performed in patients with an elevated ferritin level who have concomitant predisposing factors to osteoporosis.[38]
Result
osteopenia (T score <-1 SD) or osteoporosis (T score <-2.5 SD)
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