Childhood onset, indolent progression, and risk of hepatic rupture: the natural history of hereditary lysozyme amyloidosis.

Abstract

Background: Lysozyme amyloidosis (ALys) is a rare systemic amyloidosis caused by pathogenic variants in LYZ. We describe the natural history and outcomes for this disease in the largest cohort yet published.

Methods: All patients diagnosed with ALys at the National Amyloidosis Centre between 1988 and 2025 were included. Diagnosis was established by immunohistochemistry or proteomics with the identification of a variant in LYZ. Trends in data were analysed longitudinally.

Results: Thirty-five patients were included (median age: 45 years). Twenty-five (71%) carried the Asp67His (p.Asp85His) variant. Median age at symptom onset was 23.7 years, and 43% reported childhood symptoms. Sicca syndrome was the commonest presenting manifestation (46%), followed by gastrointestinal (GI) symptoms (23%). Renal involvement occurred in 57%. Eight developed kidney failure requiring renal replacement therapy. Six kidney transplants were performed with no amyloid recurrence. Liver involvement was present in 80%. Spontaneous hepatic rupture or haemorrhage occurred in five patients, necessitating emergency liver transplantation in four. GI bleeding occurred in 31%. Reproductive outcomes were successful in many patients.

Conclusions: ALys is characterised by early symptom onset, indolent systemic progression, and risk of catastrophic hepatic or splenic rupture. These findings provide a framework for surveillance, transplantation planning, and future therapeutic studies.