2460 A Father-Son Pair With APOB and PNPLA3 Double Heterozygosity Resulting in Advanced Nonalcoholic Fatty Liver Disease

Abstract

INTRODUCTION: Mutations in apolipoprotein (apo) B cripple the machinery and transport needed for lipoprotein export from the liver resulting in familial hypobetalipoproteinemia (FHBL). In heterozygotes, the normal allele allows for sufficient transport and mobilization of fat from the liver, but homozygotes are unable to compensate, leading to elevated intrahepatic triglycerides, NASH, and cirrhosis. We report a father-son pair with heterozygote FHBL who developed advanced NASH which we believe is due to its compound heterozygosity with PNPLA3, a gene important in the pathogenesis of NAFLD and NASH. CASE DESCRIPTION/METHODS: A Caucasian father and son of European ancestry were referred to our hepatology clinic. The son is a 46-year-old male who was evaluated for elevated transaminases and very low LDL-cholesterol. There was no significant alcohol consumption. Family history was significant for a father with cirrhosis and paternal grandmother who died of an unknown liver complication. Physical exam revealed obesity with hepatomegaly and acanthosis nigricans. Laboratory studies were notable for an LDL-cholesterol 15 mg/dL, triglycerides 30 mg/dL, and ALT 109 U/L. Increased liver echogenicity was found on ultrasound. Transient Elastography showed CAP of 327 dB/m (severe steatosis) and liver stiffness of 8.5 kPa (F2 fibrosis). Genetic testing revealed heterozygosity for both APOB (c.1830 -1G >A) and PNPLA3 (p.I148M) genes. The father is a 71-year-old male who was diagnosed with liver disease during evaluation for thrombocytopenia. There was no significant alcohol consumption. Physical examination revealed abdominal obesity and splenomegaly. Laboratory studies were notable for an LDL-cholesterol of 28 mg/dL and platelets of 83 k/mm3. Liver biopsy confirmed cirrhosis due to steatohepatitis and his HVPG was 12 mmHg. Recent imaging identified two small liver lesions with arterial enhancement, concerning for early liver cancer. Genetic testing revealed variants in both APOB and PNPLA3 genes identical to his son's mutations. DISCUSSION: We describe a father-son pair with double heterozygosity for APOB and PNPLA3 genes in the setting of obesity who developed progressive NASH. Neither APOB heterozygosity nor PNPLA3 heterozygosity is associated with advanced NAFLD, but their double heterozygosity may cause progressive NASH and cirrhosis, as illustrated here. A strong family history and very low serum LDL-cholesterol levels were helpful in working up this father-son pair.