Title: Clinical significance of Hepcidin inducer Laennec and Porcine in the treatment of Hereditary Hemochromatosis, NASH, and other iron loading chronic liver diseases complicating with Type2 DM

Abstract

Introduction: The disturbance of iron metabolism is one of the characteristic feature of NASH, however as for the mechanisms of the iron deposition in the liver, the precise pathophysiology is still uncertain. In many NASH cases, remarkable decline of serum ferritin as well as the improvement of T2DM were observed after treating with Laennec (Placenta derived drug) in accordance with the improvement of the liver dysfunction. We examined whether Laennec can restore the pathological background through regulating iron and glucose metabolism in NASH and Hereditary Hemochromatosis (H.H.) by the action of “hepcidin inducer”. Background and Aims: We have previously shown that hepcidin-m-RNA could be induced in dose dependent manner on applying with Laennec using primary hepatocytes and HepG2 cell. Here we show that the treatment with Laennec which contains ‘hepcidin inducer’ improves not only H.H. without repeated phlebotomy, but also NASH and other iron loading chronic liver diseases complicating with T2DM. Clinical Implications and Suggestions: NASH: We divided 68 NASH cases (all liver biopsied) into two groups retrospectively. Non-Laennec-treated 30cases were cared with ordinary liver supporting therapy. Laennec-treated 38cases were treated with the infusion of 2 ampules(224mg) of Laennec 1-2 times /W, in addition to the ordinary liver supporting. Serum ferritin, ALT and HbA1c were measured, and liver biopsy was carried out to evaluate changes of fibrosis and iron deposition. H. Hemochromatosis: 47years-old male patient that developed type 2 diabetes mellitus had elevated serum ferritin level (10,191ng/ml) and a decreased hepcidin-25 level (0.5-1.6ng/ml). Liver biopsy revealed remarkable iron deposition and severe fibrosis. As the substitute for the repeated phlebotomy, the infusion with Laennec (672mg/d, 3times/w) has been done for 84 months. At the end of the treatment, the serum ferritin level was decreased to 506ng/ml. HbA1c also improved with the same dose of insulin (8.86.8%). The results suggest that Laennec　may take the place of phlebotomy for H.H. and other hepcidin-deficient diseases. Conclusion: The placenta-derived Laennec which contains “hepcidin inducer” actually improved iron overload of H.H. patient without repeated phlebotomy, and it also ameliorated glucose metabolism complicating with H.H. The decline of serum ferritin levels by infusing with Laennec observed in NASH was simultaneously accompanied by the improvement of the liver fibrosis and inflammation as well as the glucose metabolism. It is possible that Laennec containing hepcidin-inducing material can bring about the improvement of NASH, H.H and other iron loading chronic liver diseases by suppressing ROS-production of iron-origin.