Peripheral and Autonomic Diabetic Neuropathy and Their Additive Risk of Major Adverse Liver Outcomes in Type 2 Diabetes.

INTRODUCTION

Type 2 diabetes (T2D) is a risk factor for the progression of liver disease, particularly relating to metabolic dysfunction-associated steatotic liver disease (MASLD), and consequent major adverse liver outcomes (MALO). Given that diabetic neuropathy reflects advanced metabolic and microvascular injury, we investigated whether somatic and autonomic neuropathy in T2D is associated with MALO.

METHODS

In this retrospective cohort study using a large, federated health research network (TriNetX), adults with T2D were stratified into (i) diabetes alone, without coding of neuropathy, (ii) diabetes with peripheral neuropathy coding, (iii) diabetes with autonomic neuropathy coding, and (iv) diabetes with combined peripheral and autonomic neuropathy coding. Propensity score matching was performed to balance demographic, metabolic, and comorbidity profiles. The primary outcome was incident MALO, defined as hepatic decompensation, portal hypertension/stable varices, hepatocellular carcinoma, liver failure, or liver transplantation. Secondary outcomes included individual MALO endpoints, major adverse cardiovascular events (MACE) and all-cause mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs).

RESULTS

After matching, a clear gradient was evident between the increased risk of MALO and the presence of neuropathy: peripheral neuropathy and risk of MALO (HR 1.95 [95% CI 1.85, 2.05]), autonomic neuropathy (HR 2.62 [2.52, 2.72]) and combined neuropathy (HR 3.21 [3.03, 3.41]). Associations were consistent across individual MALO endpoints, irrespective of obesity status, and remained significant following temporal washout analyses. Neuropathy also conferred greater risk for MALO compared to other microvascular complications (vs. retinopathy; 2.21 [2.05, 2.39]).

CONCLUSION

Diabetic neuropathy is associated with an elevated risk of MALO in T2D. Autonomic, and to a lesser extent peripheral, neuropathy identifies a particularly high-risk phenotype, supporting neuropathic burden as a surrogate marker, and potential driver, of advanced systemic metabolic injury and progressive liver risk.