Case Presentation: 3 years after liver transplantation, a 53-year-old female on tacrolimus had 4 months of jaundice, abdominal pain, and vomiting with transaminitis and hyperbilirubinemia. At an outside transplant center, two liver biopsies showed cholestasis and inflammation; removal of choledocholithiasis and placement of a biliary stent for an anastomotic stricture resulted in no improvement. She was eventually admitted and had pancytopenia, hypertrygliceridemia, hyperferritinemia, positive Parvovirus-B19 nucleic acid testing, and foci of hemophagocytosis on bone marrow biopsy. Citing insufficient fulfillment of HLH-2004 criteria (5/8 required for diagnosis), the outside team favored a diagnosis of unidentified drug-induced liver injury over hemophagocytic lymphohistiocytosis (HLH)[1]. The patient was started on intravenous immunoglobulin for Parvovirus-B19 treatment before being transferred for re-transplant evaluation.At our hospital, she was afebrile without organomegaly, but had worsening pancytopenia, transaminitis, hyperbilirubinemia, and hyperferritinemia. Her soluble IL-2R level was elevated (1100 U/mL) and imaging showed only mild intra-hepatic strictures. Her H-score was 161 (optimal cutoff for diagnosis: 169/337), but high suspicion by our hematology team prompted HLH-directed daily dexamethasone treatment[2]. An in-house liver biopsy showed Kupffer and Ito cell hyperplasia with erythrophagocytosis, a finding described in prior HLH cases[3]. Re-review of her prior biopsies showed sinusoidal lymphohistiocytosis with erythrophagocytosis that was missed on earlier interpretations. All three biopsies showed cholestasis without cellular rejection, ductopenia or fibrosis. During the rest of her hospital course, she had worsening cytopenias (platelets 30K/uL, leukocytes 1.5K/uL, hemoglobin < 9g/dL), hyperferritinemia (16,576ng/mL), transaminitis (AST 1076U/L), and hypofibrinogenemia (158 mg/dL). Her H-score ranged between 176-186, making her clinical picture consistent with a missed diagnosis of HLH. Despite the addition of etoposide to her treatment, she expired from liver failure one month after initial admission.
Discussion: Liver transplant recipients are at high risk of hospital admission for liver dysfunction. Since immunosuppression and infection are triggers for HLH, this is an important diagnosis to consider in transplant recipients with unexplainable liver dysfunction[4]. HLH is rare and most often arises within 1 year post-transplant, which can lead to its under-recognition in those with a more distant transplant history[5]. Despite not meeting 5 of 8 HLH-2004 criteria, our patient had an H-score and biopsies that were consistent with a case of developing HLH. While atypical, her Parvovirus B19 infection likely exacerbated her clinical decline[6,7].
Conclusions: A high degree of early suspicion is important when evaluating HLH in liver transplant recipients. Since the H-score was developed using adult, rather than pediatric, data, it may be a more accurate diagnostic method in adults compared to HLH-2004[4]. Furthermore, while HLH is typically associated with CMV and EBV, transplant recipients should also be screened for less common triggers given their immunosuppressed state. Lastly, careful review of liver biopsy can better characterize unexplainable liver dysfunction, as it can reveal evidence of hemophagocytosis and help rule out common causes of transplant-related liver dysfunction (rejection, ductopenia, fibrosis).
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