Liver Cancer in Methylmalonic and Propionic Acidemias: A Rare Complication? A Clinico-Pathological Study of 24 Livers

Abstract

In methylmalonic (MMA) and propionic acidemias (PA), liver or liver-kidney transplantation (Tx) is indicated for metabolic decompensations, kidney failure (MMA), and to improve quality of life. Liver cancer was reported in five patients with MMA. We characterized the pathology of 23 explanted livers and one cancer to investigate for pre-cancerous changes. We included seven patients with PA, 16 with MMA, and a patient with cancer after kidney Tx for MMA. Liver function tests, alpha-foetoprotein, and liver ultrasound were collected. Routine and special stains were performed. Abnormalities were observed in liver tests or ultrasound in half of the patients. Two had cirrhosis (one MMA, one PA). The maximum alpha-foetoprotein was 28 ng/mL. The key lesion was clusters and nodules of clear cells in 83%: distended hepatocytes with central nuclei, sharply demarcated from the parenchyma, in the periportal area. These cells contained less glycogen than the surrounding liver; macro-vacuolar steatosis was observed in 20%. Fibrosis was present in all but two, mostly stage 1 (67%), and mild lymphocytic inflammation in the portal tracts. Large-cell dysplasia was observed in the three oldest patients (one PA, two MMA). The phenotype of the clusters and nodules highlighted mitochondrial and LFABP loss. Abnormal labelling of glutamine synthetase was seen at distance from the nodules. The liver cancer was a hepatocellular carcinoma. Liver abnormalities were observed in all patients. The clusters and nodules of clear cells likely originate from propionyl-CoA accumulation and mitochondrial dysfunction. This abnormal pathology pleads for early liver Tx. Regular liver monitoring is recommended with alpha-foetoprotein and ultrasound.