Increased risk of steatotic liver disease, major adverse liver outcomes, cardiovascular events and mortality in pheochromocytoma: a model of chronically elevated sympathetic tone.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally, yet the contribution of autonomic dysfunction to its progression remains incompletely understood. Pheochromocytoma and paraganglioma (PPGL), characterised by excessive catecholamine production, provide a human model to investigate the impact of chronic sympathetic activation on MASLD and major adverse liver outcomes (MALO). METHODS: We conducted a retrospective cohort study using data from the TriNetX Network, including adults with PPGL (exposure) and essential hypertension (controls), defined using ICD-10 codes/anthropometry. Cohorts were propensity score matched (1:1) for demographic, metabolic and blood pressure-related variables and followed for five years from index diagnosis. The primary outcome was time to incident MASLD. Secondary outcomes included MALO, type 2 diabetes (T2D), major adverse cardiovascular events (MACE) and all-cause mortality. Survival analysis generated hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: After matching, 45,595 patients were included in each arm. PPGL was associated with increased risk of incident MASLD (HR 1.48; 95% CI 1.38-1.58) and MALO (1.59; 1.44-1.76), including hepatic decompensation (1.73; 1.53-1.95) and hepatocellular carcinoma (2.18; 1.70-2.80), compared with essential hypertension. A modest increase in MACE was observed (1.13; 1.09-1.16), while incident T2D risk was not significantly different (1.02; 0.98-1.06). Pheochromocytoma and PPGL treated with α-adrenergic blockade demonstrated greatest cardiometabolic risk. CONCLUSION: PPGL was associated with increased risk of MASLD, progressive liver complications, MACE and mortality, supporting a link between chronic catecholamine excess and adverse hepatic outcomes. These findings provide human evidence that sustained sympathetic overactivity may contribute to hepatic steatosis and progression.