Liver disease in shwachman-diamond syndrome: A report from the shwachman-diamond syndrome registry

Abstract

Abstract Background: Shwachman-Diamond Syndrome (SDS) is a ribosomopathy marked by marrow failure, exocrine pancreatic dysfunction, and leukemia predisposition. Hepatic abnormalities are reported but have not been systematically characterized, particularly in adults. As patients increasingly survive into adulthood and face complex treatment decisions—such as hematopoietic stem cell transplantation (HSCT) or oncology therapies—it is critical to understand SDS-associated comorbidities like liver disease across the age spectrum. We aimed to characterize the clinical features, management, and outcomes of liver injury in a large cohort of SBDS-associated SDS patients. Methods: We conducted a retrospective study of 246 patients with biallelic SBDS mutations in the North American SDS Registry (ages 0-38 years). Persistent liver injury (PLI) was defined by AST and ALT above upper limit of normal (ULN) on at least 3 separate occasions ≥1 month apart. Clinical, biochemical, imaging, and histopathologic data were analyzed. Associations with PLI were assessed via univariate and multivariate logistic regression. Results: Of 246 patients, 171 had sufficient liver data; 94 (55%) met criteria for PLI. Onset typically occurred in early childhood (median 1.0-year, range 0.04-37.9 years) and persisted for a median of 6.0 years, with only 36% resolving by last follow-up. Median ALT level at PLI onset was 139 U/mL (4× ULN, IQR 81–228.5 U/mL), and the median AST at onset was also 139 U/mL (2.6× ULN, IQR 81–139 U/mL). The median peak ALT recorded during the disease course was 341 U/mL (8.3× ULN (IQR 190.3–591 U/mL), while the median maximum AST was 247 U/mL (4.1×, ULN IQR 134–247 U/mL). Patients with PLI diagnosed in early childhood had subsequent decline and normalization of liver enzymes as children aged. In contrast, adult patients with PLI exhibited more modest ALT elevations, and no distinct peak was observed, suggesting a different clinical trajectory in older patients with new onset PLI. Liver biopsies (n=30) revealed inflammation (69.5%), fibrosis (65.2%), and steatosis (40%), sometimes in asymptomatic patients. Imaging was frequently normal; elastography results were variable. In multivariate analysis, younger age at SDS diagnosis was associated with lower odds of PLI (OR 0.86, p<0.001). Notably, some cases of liver injury emerged or persisted after HSCT, and two liver-related deaths occurred. Conclusions: Liver involvement in SDS is common, chronic, and often subclinical, with the majority of cases occurring in childhood. As more SDS patients reach adulthood and undergo oncologic interventions, systematic assessment of hepatic comorbidities becomes essential to inform timing, eligibility, and risk mitigation strategies. Additionally, evaluation of hepatic comorbidities should be integrated into transplant planning to better assess eligibility, optimize timing, and individualize risk mitigation in SDS. These findings underscore the importance of age-conscious, multidisciplinary care and the need for prospective, multicenter studies to define the long-term hepatic trajectory in SDS.