Prognostic significance of low alanine aminotransferase in patients with transthyretin amyloid cardiomyopathy

Introduction Sarcopenia is prevalent in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and contributes to the development of frailty. Low alanine aminotransferase (ALT) levels serve as a surrogate marker for sarcopenia and have been linked to increased mortality across multiple chronic diseases. Although ALT is inexpensive and widely available, its prognostic value has not yet been evaluated in ATTR-CM. Aim To assess the prognostic significance of ALT levels in patients with ATTR-CM. Methods This was a retrospective cohort study of consecutive patients diagnosed with ATTR-CM between 2013 and 2025 at a regional amyloidosis network centre. A diagnosis of ATTR-CM was achieved on the basis of heart failure symptoms, characteristic echocardiography or cardiac magnetic resonance imaging, and Perugini grade 2–3 uptake on 99mTc-DPD in the absence of a monoclonal dyscrasia on serum and urine immunofixation. Conversely, tissue biopsy was performed in all patients with biochemical evidence of a monoclonal gammopathy. In line with previous studies, a low ALT level was defined as ALT <12 IU/L. Frailty was quantitated using the Clinical Frailty Scale (CFS) at baseline, and National Amyloidosis Centre (NAC) disease staging was performed using N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). The primary outcome was all-cause mortality. Kaplan-Meier survival plots were constructed with analysis dichotomised according to ALT level. Follow-up was restricted to ≤5 years as most events occur within this period, with low numbers at risk thereafter. Results Of the 292 patients diagnosed with ATTR-CM (age 81yr [IQR 77-86]; male 83%; wild-type 90%), 31 (11%) had a low ALT level. Low ALT was associated with older age (83yr [IQR 81-88] vs 81yr [IQR 76-85]; p=0.006), female sex (42% vs 14%; p<0.001), lower albumin (39g/L [IQR 34-41] vs 41g/L [IQR 38-43]; p=0.001), increased frailty (CFS 6-9: 26% vs 14%; p<0.001) and more advanced disease (NAC stages 3–4: 42% vs 23%; p=0.03). There was no difference in body mass index (BMI) between patients with low and normal ALT levels (25.7kg/m2 vs 26.4kg/m2; p=0.42). Kaplan-Meier analysis demonstrated a low ALT at diagnosis was associated with a twofold increased risk of mortality at a median follow up of 1.8 years (hazard ratio (HR) 2.32; 95% CI [1.24–4.36]; p<0.001; Figure). This association remained significant in a multivariable Cox proportional hazards model after adjusting for age, sex, BMI and NAC stage, using disease-modifying therapy as a time-varying exposure (HR 1.83; 95% CI [1.06–3.04]; p=0.03). Conclusions Low ALT levels are an independent predictor of mortality in patients with ATTR-CM. Incorporating ALT measurement into frailty assessment may help improve risk stratification in this population. Future studies are needed to explore whether this biomarker could also help predict the response to disease-modifying TTR therapies.