|
The liver is the principal site of iron storage and as such is susceptible to damage from iron overload. At the cellular level, mitochondria swell, and their membranes rupture, resulting in cell death. Hemosiderotic liver damage produces little inflammation, making its detection by blood tests such as serum transaminase difficult. Patients with advanced hereditary hemochromatosis tend to have large iron deposits in hepatocytes [4], while those with transfusional iron overload often show iron deposition in Kupffer cells, as well as in hepatocytes [5].
The main clinical sequelae of excess iron deposition in the liver are fibrosis/cirrhosis or cancer. In patients receiving regular transfusions, collagen formation and portal fibrosis can occur within 2 years of the first transfusion [5], while liver cirrhosis can develop within the first decade of life if the excess iron is not removed. Patients are also vulnerable to viral infections such as hepatitis C, which synergistically exacerbates hepatic damage [6, 7] and increases the risk of liver failure and hepatocellular carcinoma [8]. 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) [9]. Alcohol can also accelerate liver damage in iron-overloaded patients [10].
Studies have shown there to be a correlation between the development of liver fibrosis and high liver iron [11] and serum ferritin [12] 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.
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.
• 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 [13], the availability of SQUID machines is limited and it is an expensive technique requiring specialized equipment and technicians.
Cardiac failure is a major, life-threatening complication of iron overload and is the most common cause of death in patients with thalassemia major [14]; it is also a common problem in patients with SCD [15, 16] and myelodysplastic syndromes [17]. Cardiac iron accumulation most commonly occurs after other organs such as the liver and spleen have become saturated with iron, although some patients have cardiac iron loading even with apparently adequate control of overall body iron levels. Changes in cardiac function are often absent (ie asymptomatic) or minor until iron levels reach a critical level or duration of loading, after which, systolic function rapidly deteriorates and refractory heart failure and death occur [18]. Once cardiac dysfunction is detected, the prognosis for a patient is extremely poor in the absence of intervention, but can be improved if appropriate therapy is given to address the iron overload.
The severity of the cardiac dysfunction depends upon the amount of iron deposited in individual myocardial fibers and the number of fibers affected. In patients with mild cardiac dysfunction, iron deposition is usually limited to the perinuclear areas, with only a few fibers involved, whereas in patients with significant cardiac dysfunction, iron deposits occupy large areas of the myocardial fibers [18, 19]. The most common form of cardiac hemosiderotic injury is dilated cardiomyopathy (enlargement of one or more of the heart chambers), which generally manifests as systolic or diastolic dysfunction [18]. Signs of myocardial damage due to iron overload generally present as arrhythmia, angina, cardiomegaly, heart failure, and pericarditis. Iron overload can also produce conduction defects when there is iron deposition in the Bundle of His and the Purkinje system [19, 20]. Sudden death due to arrhythmia can therefore occur among patients with advanced iron overload [20].
The most useful noninvasive diagnostic techniques for hemosiderotic cardiomyopathy are left ventricular ejection fraction (LVEF) studies performed with radionuclide ventriculography (in adults) or echocardiography (in children). Recent fast MRI techniques have also shown promise in detecting increased myocardial iron deposition in the heart muscle [15]. In general, the lower the myocardial MRI T2* value the higher the risk of cardiac dysfunction; T2* values <20 ms are associated with a progressive and significant decline in LVEF.
Although the mechanism of cardiac iron uptake is not as well defined as that of hepatocyte uptake, it is known that low-capacity divalent metal and transferrin-bound transporters are critical under normal physiologic conditions [21]. In vitro studies have shown that under iron overload conditions, uptake of NTBI is considerably greater and has the propensity to permeate cells by unregulated mechanisms. DMT1 may play a part in NTBI uptake in the heart, as may the L-type voltage-dependent Ca2+ channel (LVDCC). DMT1 is present at low levels in heart tissue, while LVDCCs are found in abundance and with great activity in cardiomyocytes. Furthermore, LVDCC currents can be increased when ferrous iron concentrations are elevated, creating a potential mechanism for precipitous iron uptake.
It was initially thought that liver iron levels and cardiac iron burden would correlate with one another, however, results have shown that the relationship is complex. The mechanism of iron entry and clearance from the heart and liver differ, which translates into differences in transport kinetics, with cardiac iron clearing six-times more slowly than liver iron [22]. Patients may therefore develop cardiac dysfunction despite low liver iron levels. Some data suggest a critical liver iron concentration (LIC) above which high myocardial iron levels are present [23], although other studies have found no correlation at between cardiac iron and LIC in patients with ß-thalassemia [18, 24].
In one longitudinal study, a LIC of >15 mg/g dry weight was shown to be predictive of increased risk of cardiac disease and early death in patients with ß-thalassemia receiving chelation therapy [25]. Similarly, the maintenance of serum ferritin levels below 2500 ng/mL has been associated with increased cardiac disease-free survival [26].
1 | 2 | 3 | next >
|
Français
Español
Deutsch
Italiano
