# Elevated Transaminases: Does It Always Warrant a Liver Biopsy? Lessons Learned From Pompe Disease

## TL;DR

Elevated liver enzymes in late-onset Pompe disease are due to muscle injury, not liver disease, highlighting the need for careful diagnosis before liver biopsy.

## Contribution

The paper demonstrates that elevated transaminases in late-onset Pompe disease are muscle-derived, avoiding unnecessary liver biopsies.

## Key findings

- Elevated AST and CK levels in LOPD patients indicate muscle injury rather than liver disease.
- Liver biopsies in LOPD cases showed non-specific glycogen accumulation but no liver pathology.
- Neuromuscular gene panels and GAA testing can non-invasively diagnose LOPD.

## Abstract

Pompe disease (PD) is an autosomal recessive disorder caused by pathogenic variants in GAA, resulting in acid alpha‐glucosidase (GAA) deficiency and lysosomal glycogen accumulation. PD is classified into infantile‐onset (IOPD), characterized by cardiomyopathy and death within the first year if untreated, and late‐onset (LOPD), which presents with gradual muscle weakness at variable ages. Incidentally elevated transaminase levels are common in LOPD and reflect muscle injury rather than liver damage. Creatine kinase (CK) levels are often elevated too, further indicating a myopathic origin. However, these elevated transaminases may be misattributed to liver disease, prompting a liver biopsy. Three charts of patients who underwent liver biopsies prior to a LOPD diagnosis were reviewed, including clinical presentations and diagnostic workups. Liver histology from these biopsies was evaluated and compared to liver pathology in a GAA knockout mouse model. All cases had elevated transaminases and underwent a liver biopsy. One biopsy was normal, while two showed non‐specific hepatocyte glycogen accumulation. In all cases, aspartate transaminase (AST) levels were higher than alanine transaminase (ALT) levels and CK levels were elevated. Enzyme testing demonstrated GAA deficiency, and genetic testing identified biallelic variants in GAA, confirming the diagnosis. These cases highlight the importance of meticulous phenotyping before liver biopsy. A muscle origin should be considered when AST:ALT > 1 with elevated CK levels. Neuromuscular gene panels and GAA enzyme testing offer a non‐invasive diagnostic approach in LOPD. Notably, even when glycogen accumulation is observed in the liver histologically, liver disease is not associated with PD.

LOPD is a neuromuscular glycogen storage and lysosomal disorder. In the setting of elevated transaminases with AST:ALT ratio > 1 and elevated CK levels without other signs of liver involvement, a muscle rather than liver origin is likely, supporting the need for careful phenotyping and consideration of genetic testing before pursuing an invasive liver biopsy.