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The liver is the major site of iron storage, and as such it is susceptible to damage from iron overload. At the cellular level, mitochondria swell and their membranes rupture, resulting in cell death (1).

Clinical manifestations

The main clinical manifestations of excess iron deposition in the liver are fibrosis/cirrhosis and hepatocellular carcinoma. In patients receiving regular transfusions, collagen formation and portal fibrosis can occur within 2 years of the first transfusion (2), while liver cirrhosis may develop within the first decade of life if the excess iron is not removed.

Hepatic collagen formation due to iron overloading Iron overload typically manifests with mild-to-moderate hepatomegaly and collagen formation visible in liver biopsy.

Association of fibrosis with LIC and serum ferritin

Studies have shown a correlation between the development of liver fibrosis and high liver iron (3) and serum ferritin (4) levels. The study evaluating liver iron found that the fibrosis score was higher in patients with greater baseline liver iron levels, as well as in those patients who were hepatitis C positive.

Assessing hepatic iron burden

Hepatic iron burden can be assessed noninvasively through regular monitoring of serum ferritin levels. Cirrhosis is more prevalent in those with serum ferritin >1000 mcg/L than in those below this level (5).

Liver iron stores can be measured by several different methods:

• Liver biopsy is the validated standard method for assessing liver iron levels. It is a direct measurement of liver iron, being quantitative, specific, and sensitive, and has been shown to be positively correlated with morbidity and mortality. The invasive nature of this approach means that it can be painful, and may result in internal hemorrhage and infection with transfusional iron overload.
• Magnetic resonance imaging (MRI) provides an indirect but noninvasive, quantitative method of estimating liver iron levels. MRI can be used to quantify iron throughout the liver, and is becoming increasingly available worldwide.
• Superconducting quantum interference device (SQUID) is a non-invasive imaging method that uses a very low-power magnetic field with sensitive detectors to indirectly measure the interference of iron within the field. Although linear correlations have been demonstrated between SQUID measurements and liver biopsy levels (6,7), the availability of SQUID machines is limited, and it is an expensive technique requiring specialized equipment and technicians.

See more about diagnosing iron overload

Transfusional vs. metabolic hepatic iron overload

Liver biopsies of patients with advanced transfusional iron overload often show iron deposition in Kupffer cells as well as hepatocytes (1), whereas similarly iron overloaded patients with hereditary hemochromatosis typically show iron deposits in hepatocytes only (2). This may reflect the rapid influx of iron into the reticuloendothelial system following the senescence of transfused red blood cells.

Factors that may accelerate liver damage

Patients are also vulnerable to viral infections such as hepatitis C, which synergistically exacerbate hepatic damage (8) and increase the risk of liver failure and hepatocellular carcinoma (9). After the introduction of sensitive screening tests and stringent donor selection procedures, the incidence of hepatitis C infection has been significantly reduced. However, there is still a serious risk for hepatitis C and a minor risk for hepatitis B infection in patients with thalassemia and sickle cell disease (SCD) (10). Alcohol can also accelerate liver damage in iron-overloaded patients (11).