EASL Clinical Practice Guidelines

Which strategy should be used to diagnose HFE-HC?

To outline a diagnostic strategy in patients with suspected HC, several clinical scenarios for patients who should be investigated for HFE-HC have been selected. The following section will discuss a practical diagnostic approach to patients with suspected iron overload.

In contrast to the previous sections, where evidence based recommendations were made, this section is based on the expert opinion of the EASL CPG panelists (Y.D., J.D., A.E., A.P., R.S., H.Z.).

Suggestive symptoms and signs

In patients with symptoms or signs suggestive of HC (unexplained liver disease, chondrocalcinosis, type 1 diabetes, arthralgia, HCC, cardiomyopathy, or porphyria cutanea tarda) serum iron parameters should be determined. If any of these symptoms is related to HC or iron overload, they will be associated with increased serum ferritin concentrations and diagnostic work-up should be carried out as described below.

Hyperferritinemia

In patients presenting with increased serum ferritin concentrations, it is mandatory to search for common causes of hyperferritinemia before genetic tests are carried out (Fig. 3). It is estimated that in over 90% of outpatients with hyperferritinemia, one of the following causes can be identified: chronic alcohol consumption, inflammation (check for CRP), cell necrosis (check for AST, ALT and CK), tumors (ESR, CT scan), and non-alcoholic fatty liver disease (NAFLD) and/or the metabolic syndrome (check for blood pressure, BMI, cholesterol, triglycerides, and serum glucose). In the absence of such conditions or when hyperferritinemia persists despite treatment of another potential underlying cause, transferrin saturation (TS) should be determined. After confirmation of TS elevation, HFE genotyping should be done.


Fig. 3 Proposed algorithm for the diagnosis of genetic causes of hyperferritinemia.
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If the patient is a C282Y homozygote, the diagnosis of HFE-HC can be established. For all other genotypes, confounding cofactors, compensated iron loading anemia, or non-HFE hemochromatosis should be considered. If other factors are suspected, molecular analysis for rare HFE, HJV, HAMP, and TFR2 mutations can be undertaken, with the genetic focus selected according to the clinical, laboratory, and pathological features. Patients with compound heterozygosity for the C282Y and the H63D usually present with mild iron overload, which is associated with comorbid factors such as obesity, NAFLD, chronic alcohol consumption, and end-stage cirrhosis.

If the transferrin saturation is either normal or low, the presence or absence of iron overload will guide further diagnostic work-up. Assessment of liver iron stores by direct means (i.e. MRI or liver biopsy) is recommended. If liver iron concentration is increased, iron overload related to alcohol consumption or to metabolic abnormalities should be considered before genetic testing for non-hemochromatotic genetic iron overload diseases is carried out (ferroportin disease, aceruloplasminemia).

If liver iron concentration is normal, the common causes of hyperferritinemia should be reconsidered before genetic testing for l-ferritin gene mutations (to investigate the hyperferritinemia-cataract syndrome).

In patients with an unclear presentation, family members should be evaluated for the evidence of iron overload, and/or the exact amount of iron removed by phlebotomy should be calculated before rare genetic disorders are tested for by candidate gene sequencing and linkage analysis by a research laboratory.

C282Y homozygosity

If an individual is found to be homozygous for C282Y, management is guided by the serum ferritin concentration (Fig. 4). If the serum ferritin concentration is normal, follow-up once a year is proposed. If the serum ferritin is elevated, initial evaluation should include fasting blood glucose, serum AST, and ALT activity. Further tests should be ordered according to the clinical features (liver scanning, ECG, echocardiography, gonadotropic hormones). For the staging of liver fibrosis, liver biopsy should be considered in patients with serum ferritin >1000 μg/L, unless cirrhosis is obvious upon scanning.


Fig. 4 Proposed algorithm for the diagnostic management of patients with C282Y homozygosity.
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Documented tissue iron overload (liver biopsy or MRI)

In patients displaying hepatic iron deposition in their liver biopsy, further diagnostic considerations depend on the cellular and lobular distribution of iron and on the presence or absence of associated findings including fibrosis, steatosis, steatohepatitis, abnormal crystal inclusions, and chronic hepatitis (Fig. 5). In patients with pure parenchymal (i.e. hepatocellular) iron overload, the two main differential diagnoses are: (i) early HC in the absence of cirrhosis after excluding compensated iron loading anemia; and (ii) end-stage cirrhosis in which iron distribution is heterogeneous from one nodule to the next, and there are no iron deposits in fibrous tissues, biliary walls, or vascular walls. In patients with mesenchymal or mixed iron overload, the correct diagnosis can be suggested according to the type of associated lesions.


Fig. 5 Proposed algorithm for the diagnostic management of tissue iron overload.
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