Role of ABCG2 in liver injury associated with erythropoietic protoporphyria

Dear Editor,

We argue against the opinion in the article by Hagiwara et al that decreased ABCG2 expression might be associated with severe liver damage in erythropoietic protoporphyria (EPP) ⁽¹⁾. Cholestasis is the major type of liver injury in EPP patients, and is dependent on protoporphyrin IX (PPIX)-mediated bile duct blockage ⁽²⁾. The authors documented cholestatic injury in the elder brother by observing high levels of alkaline phosphatase (690 U/L) and total bilirubin (7 mg/dL) in serum ⁽¹⁾. The authors also observed PPIX accumulation in hepatocytes, but not in the biliary system, in the same patient ⁽¹⁾. These observations do not match each other, because less PPIX in bile ducts should cause fewer bile duct blockage and less cholestatic injury. Actually, the data in this study contradict a previous study using genetically engineered EPP mouse models, in which PPIX accumulation in hepatocytes attenuates liver damage ⁽³⁾.

The current study determined PPIX location together with ABCG2 expression using the same fluorescence method ⁽¹⁾. It is unknown whether this fluorescence method is specific for PPIX detection. In addition, liver biopsy of the elder brother showed bile thrombi ⁽¹⁾, which should be the PPIX plugs, because PPIX is highly hydrophobic and is the cause of bile duct blockage ⁽²⁾. We suggest that the authors reevaluate PPIX distribution in the liver by using the standard methods for PPIX analysis ⁽⁴⁾. Furthermore, because the authors reported ABCG2 downregulation in only one EPP patient and measured ABCG2 expression after liver injury ⁽¹⁾, it is difficult to determine whether ABCG2 downregulation is a cause or an effect of EPP-associated liver injury. Finally, the risk of liver injury increases in EPP patients with increased age ⁽⁵⁾. The current study showed liver injury in the elder brother but did not provide the age of the younger brother ⁽¹⁾. In summary, the facts do not support the assertion that decreased ABCG2 expression is the cause of liver damage in EPP.