Misdiagnosis of Alpha-1 Antitrypsin Phenotype in an Infant with CMV Infection and Liver Failure

A 4-month-old female with a history of neonatal cholestasis was initially evaluated with jaundice, ascites, coagulopathy, and worsening aminotransferase levels. At 5 weeks of age, her parents had noticed ‘‘yellowing’’ of her eyes and skin accompanied by a slightly more pale appearance of her regularly yellow-colored stools. Initially, she was noted to have conjugated hyperbilirubinemia, with total bilirubin 6.5 and conjugated 4.5, aspartate aminotransferase (AST) 163, alanine aminotransferase (ALT) 103, and elevated alkaline phosphatase. Liver ultrasound was normal. A percutaneous liver biopsy, obtained due to her continued unexplained cholestasis, was reported as showing possible large duct obstruction and bile duct proliferation, suggestive of extrahepatic biliary atresia. A subsequent endoscopic retrograde cholangiopancreatography (ERCP) and intraoperative cholangiogram showed no anatomic abnormalities in the intrahepatic and extra hepatic biliary system, inconsistent with the diagnosis of biliary atresia (Fig. 1). During her hospital admission, a serum alpha-1 antitrypsin (A1AT) concentration was 34 mg/dl (normal 100–250 mg/dl), with A1AT MZ phenotype reported. Her conjugated hyperbilirubinemia improved slightly, and her liver numbers stabilized. She was discharged home with a close follow-up outpatient appointment in the pediatric gastroenterology clinic. The remainder of her evaluation for neonatal cholestasis, including an echocardiogram and ophthalmology examination for Alagille’s syndrome, was negative. Infectious studies were negative as well. Hepatosplenomegaly or ascites were not detected by physical examination, with reassuring and age-appropriate biometrics noted. Ongoing outpatient medical care revealed elevated cytomegalovirus (CMV) IgM titers (0.97). Due to persistent cholestasis, a repeat A1AT serum concentration was low level at 32 mg/dl, although a repeat ELISA was now reported as the Z phenotype consistent with the ZZ genotype. Due to conflicting tests of mutant serum A1AT proteins, her liver biopsy was re-analyzed with intrahepatic positive periodic acid–schiff stain (PAS) granules now reported, consistent with the diagnosis of A1AT deficiency (Fig. 2). Concomitantly, CMV viremia was confirmed with an elevated CMV polymerase chain reaction (PCR) assay of 12,800. In the clinic, she exhibited significantly increased abdominal distension and marked ascites. Her bilirubin (total 8.8 mg/dl; conjugated 5.3 mg/dl) and aminotransferases (AST/ALT 500/309 units/l) were elevated. Additionally, a significant coagulopathy was noted with an international normalized ratio (INR) of 2.2 and low fibrinogen of 88. Hyponatremia (119 mg/dl) and metabolic acidosis were also present. She did not have any changes in her mental status, and her venous ammonia concentration was mildly elevated to 68 lmol/l. She was admitted to Lucile Packard Children’s Hospital at Stanford for correction of her electrolyte abnormalities and coagulopathy. She was treated with ganciclovir for CMV viremia. During her first 48 h in the hospital, despite the use of IV phytonadione, her hepatic synthetic liver function deteriorated rapidly, with daily doses of fresh-frozen plasma required to treat her coagulopathy. Due to her P. Arias (&) J. Kerner M. Christofferson W. Berquist K. T. Park Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Lucile Packard Children’s Hospital, Stanford University Medical Center, 750 Welch Road, Suite 116, Palo Alto, CA 94304, USA e-mail: parias@stanford.edu