Abstract
Hepatic diseases affect approximately 10% of patients with sickle cell disease (SCD), encompassing a spectrum of acute and chronic liver injuries related to ischemia, iron overload, pigment stones, and sequestration. Sickle cell hepatopathy is linked to increased mortality, yet its impact on hematopoietic cell transplant (HCT) outcomes remains poorly understood. While HCT can reverse the SCD phenotype and improve organ function, it carries potential liver-related toxicities. This study aims to evaluate the effect of underlying hepatopathy on HCT outcomes and, conversely, the effect of HCT on sickle cell–associated liver disease.
We conducted a retrospective chart review of 19 patients with SCD who received a nonmyeloablative HCT on an NHLBI protocol (NCT00977691, NCT00061568, NCT02105766) and had pre- and post-HCT liver biopsies. Patients received either a matched related donor or haploidentical HCT. We evaluated HCT outcomes, peri-transplant toxicity, and post-HCT changes in liver pathology. For the purposes of our analyses, we defined sickle hepatopathy as an elevated ferritin level greater than 1000 mcg/L and/ or a direct bilirubin level greater than 0.4 mg/dL. A clinical pathologist evaluated pathology samples for inflammation and fibrosis using the Histologic Activity Index (HAI; range 0–18) and the Deugnier iron scoring system (range 0–60), with higher scores indicating greater disease severity. Pre- and post-HCT Deugnier, HAI fibrosis, and HAI inflammation scores were available for 9, 13 and 12 patients, respectively. The data was analyzed descriptively using measures of frequencies and proportions for categorical variables and medians for continuous variables. The phi coefficient and Fisher's exact test were used as part of the statistical analysis to assess associations between biochemical and histological markers of hepatopathy.
The study population included slightly more males than females (52.6% vs. 47.4%), with a median age of 37 years. Most individuals had HbSS (89.5%), with 5.3% HbSβ0-thalassemia and 5.3% HbSC genotypes. All participants met laboratory criteria for hepatopathy. Pre-HCT histopathology showed nodular regenerative hyperplasia (NRH) in 15.8% of patients, while 10.5% had cirrhosis, 10.5% had bridging fibrosis, and 10.5% had active chronic hepatitis C. The 1-year overall survival and sickle cell free survival was 100%. Long-term follow-up revealed death in 5 patients. Two deaths occurred after re-transplantation and more than 10 years after initial HCT. One death occurred within 5 years of HCT, and 2 deaths occurred between 5 and 10 years of HCT.
Pre-HCT, 47.4% patients had a ferritin level >1000 mcg/L, and only 44.4% of these patients continued to have ferritin levels above this cut off range post-HCT. 68.4% patients had a direct bilirubin >0.4 mg/dL pre-HCT, and 38.5% of these patients continued to have elevated direct bilirubin levels post-HCT. No patients experienced veno-occlusive disease. Ursodiol was used prophylactically in 31.5% of patients, and no patients received defibrotide prophylaxis or treatment.
Among 12 patients with available pre- and post-HCT HAI inflammation scores, 91.7% showed improvement or stability, with the median score decreasing from 2 to 1. Of the 6 patients with elevated pre-HCT HAI fibrosis scores and post-HCT data, 66.6% demonstrated improvement or stability, while the median remained 0; the remaining 7 of 13 patients had normal fibrosis scores pre-HCT. Deugnier scores improved or remained stable in 55.5% of 9 patients, with the median decreasing from 25 to 22. In evaluating changes in hepatopathy from pre- to post-HCT, the relationship between biochemical markers (ferritin and direct bilirubin) and histological markers (Deugnier score, HAI fibrosis, and HAI inflammation) was assessed. A moderate correlation was noted between improvement in both ferritin and HAI inflammation (phi coefficient 0.58). Pairwise comparisons, however, showed no statistically significant associations (all p-values = 1.0, Fisher's exact test). These findings possibly reflect the limited statistical power of this study and small subgroup sizes.
Our data suggest that for this select and limited population of individuals with SCD-associated hepatopathy, non-myeloablative HCT can result in stable to improved liver disease, with HCT outcomes comparable to the population of patients who undergo HCT for SCD without pre-existing sickle cell hepatopathy.
