Liver Disease in Shwachman Diamond Syndrome: Implications for Hematopoietic Stem Cell Transplantation

Although Shwachman Diamond syndrome (SDS) is rare, up to one-third of patients undergo HSCT, offering a unique lens on transplant-related liver risk. The liver is central to conditioning tolerance and post-HSCT outcomes, yet injury may remain silent until stress-tested by transplantation. What was once considered transient liver disease now appears persistent and clinically significant, raising broad implications for evaluation of hepatic risk in transplant populations. We systematically characterized prevalence, features, and outcomes of liver injury in SDS, defining chronic hepatitis (CH) as persistent AST/ALT elevation above the upper limit of normal on ≥3 blood draws ≥1 month apart. To isolate SDS-associated disease, aminotransferase values within 6 months of chemotherapy or HSCT were excluded. Of 246 patients with biallelic SBDS mutations in the North American SDS Registry, 171 were evaluable; 94 (55%) developed CH. CH occurred almost exclusively in childhood and was linked to younger age at SDS diagnosis (median 1.1 vs. 7.0 years, p<0.00001). Most CH cases (71%) had ALT ≥2×ULN (median 183.5 U/mL), nearly all before HSCT, and one child died of liver failure (Figure 1). The remainder (29%) had ALT <2×ULN, including 5 adults with milder disease; 80% of these adults ultimately underwent HSCT. Transplant exposure was comparable between CH and no-CH cohorts (28% vs. 35.5%, p=0.34), and notably one patient without biochemical CH also died of liver failure. Among 26 HSCT patients, 19 (73%) had unresolved CH at transplant while only 7 (27%) achieved biochemical resolution (Figure 2A). Median age at HSCT was 9.0 years (IQR 2.5–20). Five died, including 4 with unresolved CH; only one death was directly liver related. Longitudinal ALT data showed persistent abnormalities leading up to HSCT (median 90–250 U/L), with some >1000 U/L (Figure 2B). Imaging underestimated pathology: 92% had normal imaging prior to biopsy, yet histology revealed fibrosis (58%), inflammation (58%), steatosis (33%), bile duct changes (25%), and iron deposition in a minority (Figure 3A–B). In SDS, chronic hepatitis is common, often unresolved at HSCT, and poorly detected by imaging. Despite reassuring imaging, most biopsies demonstrated significant pathology, underscoring occult hepatic vulnerability at transplant. Nonetheless, patients with CH generally tolerated conditioning without major added toxicity. These findings support routine biochemical surveillance, suggest that normal imaging does not exclude risk, and highlight the need for larger studies to define how liver pathology modifies transplant outcomes.