Reply

Potential conflict of interest: Nothing to report. We read with great interest the correspondence from Sachar and Ma and appreciate their pointing out the important issues regarding cholestasis. As suggested, cholestasis could be one of the main causes of hepatic disorders in patients with erythropoietic protoporphyria.1 Indeed, the liver biopsy from the older brother also showed protoporphyrin (PP) deposition in the bile system. However, PP was predominantly observed in the hepatocytes with hepatocyte swelling and necrosis accompanied. Therefore, based on the histological findings and immunohistochemistry, we concluded that the liver damage should be mainly attributed to hepatocyte necrosis, primarily caused by PP deposition in the hepatocytes. Although an increase of the alkaline phosphatase level reflects cholestasis, elevated total bilirubin may reflect damage to hepatocytes as well as cholestasis. On the contrary, the liver biopsy from the younger brother, who had not suffered from liver dysfunction, showed more PP in the biliary system than the liver from the older brother but no PP in the hepatocytes. This evidence also supports the idea that PP deposition in hepatocytes is unique to liver damage, at least in the presented cases, and that the expression of ABCG2, a PP efflux transporter, should be involved in the pathogenesis. For PP detection in pathological specimens, we applied a polarized light microscope; a Maltese cross was confirmed during the observation, indicating that PP deposits were present in hepatocytes. The author also argued that down‐regulation of ABCG2 might be a consequence of liver injury because severe inflammation could affect the expression of proteins. We also addressed this issue; we analyzed the expression of other membrane transporters, ABCG6 and PEPT1. We did not find any differences in the expression of these transporters between the two brothers. Therefore, the difference in ABCG2 expression is specific among transporters; it is conceivable that the reduction of ABCG2 is not a result of liver injury. We already discussed this issue in a previous reply.3 Concerning age as a risk factor for liver damage, both brothers reported in our study were young, showing only a 2‐year difference in age. In addition, the older brother had developed hepatic disorders when he was 16 years old, suggesting that the difference in age should not primarily affect the pathogenesis of the cases.