Heterozygous Hemochromatosis (HH) and Heterozygous Alpha 1 Antitrypsin Deficiency (AAT) as a Cause of Cirrhosis Requiring Liver Transplant

Abstract

Hereditary hemochromatosis (HH) is an autosomal recessive disease caused by mutations of HFE gene that increases iron absorption in the intestine. It is commonly found in Caucasians. Men have 24 times higher rate of iron overload compared to women. 85-90% of patients with homozygous HFE gene mutation C282Y will be affected. 10% of them will develop clinical symptoms or end organ damage like cirrhosis of liver. Role of heterozygous C282Y or H63D mutations in the development of cirrhosis is still questionable. Alpha 1-Antitrypsin (AAT) deficiency is usually characterized by impaired secretion of α-1 AT from liver cells.This disorder is usually inherited as autosomal co-dominant. AAT deficiency usually is associated with Pi ZZ, Pi SZ, or Pi Null haplotypes and can progress to liver cirrhosis. On the contrary, Pi MZ which is considered the most common heterozygous type often does not lead to liver disease. We are reporting a rare case of both heterozygous HH and AAT deficiency that developed cirrhosis requiring liver transplant. 57 yr old white male who received a liver transplant for end stage liver disease with complications of cirrhosis. Both his father and grandmother had liver disease. Patient was found to have elevated liver enzymes at age 17 during routine physical exam. Lab exam showed elevated iron saturation (83%) and elevated Ferritin (1061) with low α-1 AT. Genetic testing showed HFE heterozygous for C282Y wild type and heterozygous for alpha 1 antitrypsin deficiency MZ phenotype. MRI showed cirrhosis with evidence of portal hypertension. Liver biopsy showed cirrhotic liver with grade 2/4 intra hepatocyte iron deposition. Immunohistochemical stain and PAS- D stains were positive with presence of α-1 AT globule. As Ferritin level continued to rise, patient underwent multiple sessions of phlebotomy. In matter of few years he developed intractable ascites, hepatic encephalopathy, and hepatic hydrothorax. Transjugular intrahepatic portosystemic shunt was not performed due to high MELD score. After thorough workup patient underwent a successful orthotopic liver transplant. Conflicting evidence on the association of the two disorders and on the severity of the condition in patients in whom these disorders coexist have rised from reviewing small numbers of patients. Our case is the first reported case of cirrhosis developed from heterozygous HH C282Y wild type and heterozygous AAT deficiency Pi MZ type which required liver transplant.Figure: Hepatocellular siderosis (Iron stain).Figure: Alpha-1-antitrypsin globules within hepatocytes (Immunostain).Figure: Alpha-1-antitrypsin globules within hepatocytes (PASD stain).