Brain Iron Deposition And Its Relation With Body Iron Status In HBV-related Cirrhotic Patients

Liver dysfunction complicates with various neurological deficits. The pathogenesis of these neurological complications needs further study. Recent studies indicated that excessive accumulation of paramagnetic substances in the brain, due to the liver failure, may partially explained for the neurological symptoms. Increased brain iron deposition was involved in many neurological disorders, such as Parkinson’s Disese (PD), Alzheimer’s Disease (AD), and Multiple Sclerosis (MS), etc. Liver is a major regulator of body iron metabolism. Hepcidin, a promising peptide synthesized by hepatocytes, was the dominator of body iron regulation by liver. Some studies reported body iron repletion in patients with hepatitis B virus infection-related cirrhosis (HBV-related cirrhosis). However, so far, there has been no study on brain iron content in HBV-related cirrhotic patients, let alone its relation with body iron status.Susceptibility Weighted Imaging (SWI) is sensitive and specific for iron. It was widely used in detections of brain iron accumulation in vivo.We aimed to quantify brain iron content in patients with HBV-related cirrhosis using SWI. We also tested serum Hepcidin, serum iron-related indices, and correlated those serum results with regional brain iron concentration, afterwards. Moreover, We observed changes of brain iron content, serum Hepcidin and serum iron-related indices in patients undergoing liver transplantation. This follow-up study enabled us to further investigate the alterations of brain iron status, as body iron status restored after removal of diseased liver.Part Ⅰ Brain Iron Deposition in HBV-related Cirrhotic PaitientsObjective:To quantify and compare brain iron concentrations between HBV-related cirrhotic patients and healthy controls. To investigate the extent of brain iron accumulation affected by different degree of liver dysfunction in patients.Methods:We enrolled seventy HBV-related cirrhotic patients and forty healthy controls. We quantified brain iron content by phase value which was derived from corrected-phase imaging (CPI) based on SWI technique. The regions of interest (ROIs) included the bilateral red nucleus, substantia nigra, globus pallidus, putamen, caudate, and thalamus. Liver function was graded by Child-Pugh classification and serum albumin level.Results:HBV-related cirrhotic patients had significantly increased iron accumulation in the left red nuclear (P<0.01), the bilateral substantia nigra (right:P<0.01; left:P<0.01) and thalamus (right:P<0.01; left:P<0.01), the right caudate(P<0.01) and putamen (P<0.05), when compared to controls. We did not find significant difference in regional brain iron content between patients divided by their Child-Pugh classification or serum albumin level.Conclusion:HBV-related cirrhotic patients had excessive regional brain iron accumulation. The extent of regional brain iron accumulaiton was not affected by liver dysfunction in patients. Part II Correlation Between Brain Iron Content and Serum Hepcidin, Serum Iron-Related Indices in HBV-related Cirrhotic PatientsObjective:To investigate body iron status and its relation with regional brain iron concentrations in HBV-related cirrhotic patients.Methods:We enrolled thirty HBV-related cirrhotic patients and nineteen healthy controls. Serum Hepcidin and serum iron-related parameters were tested. Serum iron-related parameters included serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation. Brain iron content was quantified by phase value derived from CPI based on SWI technique. The ROIs included the bilateral red nucleus, substantia nigra, globus pallidus, putamen, caudate, and thalamus. Pearson correlation analysis was performed to correlate brain iron concentrations with serum iron-related indices.Results:Cirrhotic patients had significant lower serum transferrin level (P<0.001), total iron binding capacity (P<0.001); and higher transferrin saturation (P<0.01), as well as lower serum Hepcidin concentration (P<0.001) than controls. HBV-related cirrhotic patients had significantly increased iron accumulation in the bilateral red nucleus (right:P <0.05; left:P<0.05); the right substantia nigra (P<0.05), and the bilateral caudate (right:P<0.01; left:P<0.05). Serum ferritin was positively correlated with brain iron concentrations in the bilateral putamen (right:R=0.475, P=0.008; left:R=0.425, P=0.019), while serum Hepcidin concentration negatively related with iron content in the right caudate (R=-0.455, P=0.012).Conclusion:HBV-related cirrhotic patients had body iron dysregulation, and serum iron repletion. The excessive brain iron accumulation was correlated with body iron dysregulation and increased body iron status in patients with HBV-related cirrhosis. Part Ⅲ Brain Iron Accumulation and Body Iron Status in HBV-related Cirrhotic Patients after Liver TransplantationObjective:To observe changes of brain iron concentration, serum hepcidin level, and body iron status in HBV-related cirrhotic patients after liver liver transplantation.Methods:We enrolled forty-four patients awaiting liver transplantation. Patients were diagnosed of either HBV-related cirrhosis or hepatocellular carcinoma comorbid to HBV-related cirrhosis. Liver function was graded by Child-Pugh classification and serum albumin level. Serum iron-related indices included serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation. Liver function, as well as serum Hepcidin and serum iron-related indices were evaluated on admission, and3weeks after transplantation, respectively. Brain iron content was quantified by phase value derived from CPI based on SWI technique. The ROIs included the bilateral red nucleus, substantia nigra, globus pallidus, putamen, caudate, and thalamus. Brain scan was given at admission,9months, and2years after liver transplantation, respectively.Results:We conducted a2-year follow-up study in twenty-four patients. Three weeks after transplantation, patients had significant decreased Child-Pugh score (P<0.01), and increased serum albumin level (P<0.01), compared to those before surgery. We tested serum Hepcidin and serum iron-related indices in9patients at3weeks after transplantation. Patients had significant elevated serum Hepcidin level (P<0.01), and reduced serum iron and transferrin saturation (P<0.05). Twenty patients underwent follow-up study of MR scan after9months after liver transplantation. Patients had significant lower iron concentrations in the right caudate (P<0.01), the right putamen (P<0.05), the left red nucleus (P<0.05), and the left substantia nigra (P<0.05) than those before surgery. Up to March2012, we had conducted2-year follow-up study in twelve patients after liver transplantation. Patients had decreased brain iron concentration in all ROIs. Specifically, the reduction of iron concentratons in the right caudate (P<0.05), putamen (P<0.01), and the left substantia nigra (P<0.05) after liver transplantation reached statistically significance.Conclusion:HBV-related cirrhotic patients had lower level of brain iron content and higher serum Hepcidin level than those before transplantaion, as liver function restored as removal of diseased liver. Together with the downwards trend of regional brain iron accumulation of, this result further indicated that brain iron accumulation was related with body iron metabolism in HBV-related cirrhotic patients.