Non-invasive assessment of hepatic iron overload: are we finally there?

Abstract

Iron excess in tissues can lead to toxicity and organ disease. The liver, as the primary site of body iron deposition, is also a principal target for its toxicity. Heavy iron overload in humans is usually associated with a genetically determined disturbance of iron homeostasis (i.e. hereditary hemochromatosis, HH) or with intensive transfusion regimens associated with hereditary anemia (i.e. bthalassemia). Liver biopsy is the most accurate method for assessing hepatic iron burden and provides important information on underlying liver damage and diseases. However, it entails the risk for potential complications while accurate iron measurements may be biased by sampling variability in advanced chronic disease. Therefore, at least within a diagnostic workup, costs and benefits of liver biopsy should be carefully considered. In hereditary hemochromatosis, a positive genetic test for HFE or other hemochromatosis gene mutations (transferrin receptor 2, hemojuvelin, hepcidin) may allow to avoid liver biopsy in most symptomatic patients, whereas histology remains essential in homozygotes with abnormal transaminases, hepatomegaly or serum ferritin higher than 1000 ng/ml [1]. In recent years, the potential role of mild iron overload as factor of comorbidity in the progression of several hepatic disorders (e.g. viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, porphyria cutanea tarda) has been increasingly recognized. In fact, accurate evaluation of hepatic iron content is now regarded as an important clinical manoeuvre in the management of chronic non-HH liver disease. Due to safety concerns of liver biopsy, non-invasive methods to measure hepatic iron content have been, therefore, devised. Serum ferritin may be a good surrogate marker for evaluating iron stores but suffers from low specificity. High sensitivity has been reported for the superconducting quantum interference device (SQUID) that measures magnetic susceptibilities [2]. SQUID, however, is not widely available and requires experienced operators. Computed tomography shows attenuation of the liver in the presence of excess iron, but seems to suffer of low sensitivity and specificity particular at mild iron overload grades and in the presence of fat [3]. Magnetic resonance has been intensively exploited, until recently, as a sensitive and specific tool for assessing hepatic iron overload [4‐9]. Due to the paramagnetic properties of iron, its increased hepatic content decreases both the T2 relaxation time and the liver signal’s intensity (SI): this gives the typical dark liver at MRI. Gradient-recalled-echo (GRE) techniques have been shown to be more accurate in quantifying mild iron overload states than spin-echo sequences due to higher sensitivity to field inhomogeneities induced by paramagnetic substances. Most published studies agree on the fact that MRI is accurate in assessing a moderate-severe iron overload but a validated and cost effective method for taking advantage of MRI in quantifying also low grades of iron stores was still missing. In addition, an ideal method should also be simple and easy to be standardized in order to be transferred and applied to different machines. Gandon and coworkers seem to have taken a fundamental step toward this end [7]. They studied 174 patients by both percutaneous liver biopsy with biochemical assessment of hepatic iron concentration and MRI of the liver with various GRE sequences on a 1.5 T magnet. They calculated liver iron concentration by evaluating the correlation between liver to muscle (L/M) signal intensity ratio and developed an algorithm to calculate magnetic resonance hepatic iron concentration. Data obtained in a study group (nZ139) that included patients with suspected iron overload or patients managed for hepatitis C, were then applied to a validation group (nZ35). A highly