Recurrent Sickle Cell Hepatopathy After Liver Transplantation Despite Guideline-Directed Red Blood Cell Exchange

ABSTRACT

Sickle cell hepatopathy is an uncommon but severe cause of liver dysfunction after transplantation. We present a case of a 37-year-old man who developed recurrent sickle cell hepatopathy 12 months postliver transplant despite maintaining hemoglobin S (HbS) levels below 30% per American Society of Hematology recommendations. Liver biopsy demonstrated sinusoidal sickling without rejection. Liver tests improved after intensifying red cell exchange to achieve HbS below 20%. This case illustrates that standard posttransplant HbS targets may be insufficient in high-risk patients and highlights the need for individualized HbS goals.

INTRODUCTION

Sickle cell disease (SCD) is caused by a beta-globin mutation that increases the production of hemoglobin S (HbS) relative to hemoglobin A, transforming red blood cells into sickle-shaped forms that cause vascular occlusion and multiorgan ischemia. Sickle cell hepatopathy, affecting an estimated 10%–40% of SCD patients and accounting for ∼7% of disease-related mortality, may present acutely (hepatic crisis, sequestration, intrahepatic cholestasis, acute liver failure) or chronically (viral hepatitis from transfusions, iron overload, cholelithiasis, sickle cell cholangiopathy).^1,2 Liver transplantation is rarely required but may be necessary for refractory liver failure. We report a case of recurrent hepatic sickling 1 year after transplantation despite guideline-directed HbS management, highlighting that standard targets may be insufficient in select posttransplant patients.

CASE REPORT

A 37-year-old African American man with SCD, status post-orthotopic liver transplantation 1 year before for vaso-occlusive acute liver failure, splenectomy, epilepsy on oral antiepileptics, and stage 3a chronic kidney disease, presented as a direct admission from transplant hepatology clinic for elevated liver tests first noted on routine follow-up approximately 12 months posttransplant. The posttransplant course was complicated by a right frontal subarachnoid hemorrhage and seizures. Brain magnetic resonance imaging demonstrated tacrolimus neurotoxicity/encephalopathy; immunosuppression was therefore transitioned from tacrolimus to cyclosporine (target trough 50–100 ng/mL) and mycophenolate mofetil. Hydroxyurea had been discontinued by his outpatient hematologist due to pancytopenia. The patient was maintained on red cell exchange every 6 weeks, targeting hemoglobin (Hb) 6–9 g/dL and HbS <30%.

On admission, the patient was hemodynamically stable and adherent to all medications. An initial cyclosporine level of 25 ng/mL was a nontrough draw; a repeat trough the next day was 68 ng/mL (therapeutic). Key laboratory test results included Hb 6.8 g/dL, mean corpuscular volume 88.1 fL, mean corpuscular volume 88.1 fL, white blood cell count 9.2 × 10³/μL, platelets 178 × 10³/μL, international normalized ratio 1.4, prothrombin time 17.1 seconds, partial thromboplastin time 27 seconds, albumin 3.1 g/dL, lactate dehydrogenase 514 U/L, haptoglobin <20 mg/dL, transferrin saturation 58.7%, and HbS 21%. Epstein-Barr virus and cytomegalovirus polymerase chain reaction were negative. Donor-specific antibodies were not detected, and there was no previous rejection history. Abdominal magnetic resonance imaging (Figure 1) demonstrated hepatomegaly with hepatic iron deposition; hepatic vasculature was patent on Doppler ultrasound. Liver test trends are shown in Figure 2.

Figure 1.

Arrow indicates hepatic iron deposition in the setting of hepatomegaly.

Figure 2.

Longitudinal liver test trends (ALP, AST, ALT, total bilirubin as separate-colored lines) from 1 month before admission through outpatient follow-up. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Acute cellular rejection was initially suspected, and prednisone 40 mg daily was started; however, liver tests continued to rise. Given that corticosteroids are known to precipitate sickle crises and may have contributed to the early worsening, a transjugular liver biopsy was performed promptly and demonstrated sinusoidal sickling, consistent with sickle cell hepatopathy, without evidence of acute cellular or antibody-mediated rejection (Figure 3). Prednisone was discontinued. Hematology recommended a more stringent HbS target of <20%; the patient underwent red cell exchange, achieving an HbS of 8%, with rapid improvement in liver tests within days (Figure 2).

Figure 3.

Arrow points out sickled cells in hepatic sinusoids; no evidence of cellular rejection (hematoxylin and eosin stain, original magnification 40×). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

At outpatient follow-up, transplant hepatology and hematology jointly restarted hydroxyurea, increased red cell exchange frequency to every 4 weeks, maintained the HbS goal <20%, and discontinued mycophenolate mofetil to allow hydroxyurea reintroduction. Liver tests continued to normalize on this intensified regimen (Figure 2).

DISCUSSION

This case demonstrates that sickle cell hepatopathy can recur after liver transplantation even at guideline-directed HbS levels. The differential in this setting is broad, including acute cellular rejection, antibody-mediated rejection, calcineurin inhibitor toxicity, and viral hepatitis, making liver biopsy essential before escalating immunosuppression. Notably, steroids administered for presumed rejection may have transiently worsened sickling, reinforcing the value of early tissue diagnosis.

The pathophysiology likely involves hepatic sinusoidal hypoxia/acidosis from infection, dehydration, or congestion, compounded by posttransplant microvascular vulnerability and calcineurin inhibitor-associated endothelial dysfunction. Our institutional protocol involves close hematology–hepatology collaboration with individualized HbS targets; in this patient, achieving HbS <20% (and acutely <10% at the time of exchange) produced rapid and sustained improvement.

Regarding therapeutic alternatives: crizanlizumab remains controversial; voxelotor was withdrawn due to increased sickling events; gene therapies (Casgevy, Lyfgenia) carry significant toxicity and accessibility barriers; and allogeneic stem cell transplantation was not feasible given the transplanted liver.^3–6 Therefore, intensified red cell exchange with hydroxyurea reintroduction was the most appropriate and practical strategy for this patient.

In conclusion, posttransplant sickle cell hepatopathy can occur at HbS levels below standard thresholds. Individualized, potentially more aggressive HbS goals set collaboratively by hematology and transplant hepatology may be necessary to prevent recurrent hepatic sickling in high-risk patients.

DISCLOSURES

Author contributions: MN Aslam and M. Weber: design of the work; acquisition, analysis, and interpretation of clinical and laboratory data for the study. M.N. Aslam: drafting and reviewing intellectual content, including formation of text and figures; submission of final text and figures. G. Maddineni, A. Al-Hindawi, and S. Park: design of the work; acquisition of histopathology and imaging data. A. Pillai: acquisition of imaging studies and clinical evaluations; improving text and figures; draft revision and review of final text and figures. M.N. Aslam is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

ABBREVIATIONS:

ALP

alkaline phosphatase

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CMV

cytomegalovirus

EBV

Epstein-Barr virus

Hb

hemoglobin

HbS

hemoglobin S

INR

international normalized ratio

LDH

lactate dehydrogenase

MRI

magnetic resonance imaging

PCR

polymerase chain reaction

SCD

sickle cell disease.