Systematic Reviews
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Sep 27, 2018; 10(9): 629-636
Published online Sep 27, 2018. doi: 10.4254/wjh.v10.i9.629
Acute liver failure secondary to severe systemic disease from fatal hemophagocytic lymphohistiocytosis: Case report and systematic literature review
Mitchell S Cappell, Ismail Hader, Mitual Amin
Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States
Mitchell S Cappell, Department of Medicine, Oakland University William Beaumont School of Medicine, Royal Oak, MI 48073, United States
Ismail Hader, Department of Medicine, William Beaumont Hospital, Royal Oak, MI 48073, United States
Mitual Amin, Department of Pathology, William Beaumont Hospital, Royal Oak, MI 48073, United States
Mitual Amin, Department of Pathology, Oakland University William Beaumont School of Medicine, Royal Oak, MI 48073, United States
Author contributions: Cappell MS and Hader I are equal primary authors of this work; Hader I wrote drafts of the case report and results sections; and provided medical care for this patient; Cappell MS as mentor edited the case report section, and wrote most of the other sections; Amin M performed all the microscopic pathology, and wrote the pathologic sections of the paper.
Conflict-of-interest statement: None for all authors. In particular, Dr. Cappell, as a consultant of the United States Food and Drug Administration (FDA) Advisory Committee for Gastrointestinal Drugs, affirms that this paper does not discuss any proprietary confidential pharmaceutical data submitted to the FDA. Dr. Cappell is also a member of the speaker’s bureau for Astra Zeneca and Daiichi Sankyo, co-marketers of Movantik, and has received one-time consulting fees from Mallinckrodt and from Shire. This work does not discuss any drug manufactured or marketed by Astra Zeneca, Daiichi Sankyo, Mallinckrodt or Shire.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Mitchell S Cappell, FACG, MD, PhD, Chief Doctor, Professor, Division of Gastroenterology and Hepatology, William Beaumont Hospital, MOB #602, 3535 W. Thirteen Mile Rd, Royal Oak, MI 48073, United States.
Telephone: +1-732-9911227 Fax: +1-248-5517581
Received: April 28, 2018
Peer-review started: May 3, 2018
First decision: May 24, 2018
Revised: July 20, 2018
Accepted: August 28, 2018
Article in press: August 28, 2018
Published online: September 27, 2018

To systematically review liver disease associated with hemophagocytic lymphohistiocytosis (HLH), propose reasonable contraindications for liver transplantation for liver failure in HLH, and report an illustrative case.


Systematic review according to PRISMA guidelines of hepatic manifestations of HLH using computerized literature search via PubMed of articles published since 1980 with keywords (“hemophagocytic lymphohistiocytosis” or “HLH”) AND (“liver” or “hepatic”). Two authors independently performed literature search and incorporated articles into this review by consensus. Illustrative case report presented based on review of medical chart, and expert re-review of endoscopic photographs, radiologic images, and pathologic slides.


A 47-year-old Caucasian male, was hospitalized with high-grade pyrexia, rash, total bilirubin = 45 g/dL, moderately elevated hepatic transaminases, ferritin of 3300 ng/dL, leukopenia, and profound neutropenia (absolute neutrophil count < 100 cells/mm³). Viral serologies for hepatitis A, B, and C were negative. Abdominal computed tomography scan and magnetic resonance imaging revealed no hepatic or biliary abnormalities. Pathologic analysis of liver biopsy revealed relatively well-preserved hepatic parenchyma without lymphocytic infiltrates or macrophage invasion, except for sparse, focal hepatocyte necrosis. Bone marrow biopsy and aspirate revealed foamy macrophages engulfing mature and precursor erythrocytes, consistent with HLH. Interleukin-2 receptor (CD25) was highly elevated, confirming diagnosis of HLH according to Histiocytic Society criteria. Patient initially improved after high-dose prednisone therapy. Patient was judged not to be a liver transplant candidate despite model for end stage liver disease (MELD) score = 33 because liver failure was secondary to severe systemic disease from HLH, including septic shock, focal centrilobular hepatocyte necrosis from hypotension, bone marrow failure, and explosive immune activation from HLH. The patient eventually succumbed to overwhelming sepsis, progressive liver failure, and disseminated intravascular coagulopathy. Systematic review reveals liver injury is very common in HLH, and liver failure can sometimes occur. Data on liver transplantation for patients with HLH are very limited, and so far the results have shown a generally much worse prognosis than for other liver transplant indications. Liver transplantation should not be guided solely by MELD score, but should include liver biopsy results and determination whether liver failure is from intrinsic liver injury vs multisystem (extrahepatic) organ failure from HLH.


This case report illustrates that liver transplantation may not be warranted when liver failure associated with HLH is primarily from multisystem failure from HLH. Liver biopsy may be very helpful in determining the severity and pathophysiology of the liver disease.

Keywords: Hemophagocytic lymphohistiocytosis, Acute liver failure, Liver injury, Liver transplantation, Acquired immune hyperactivation, Pancytopenia

Core tip: This work systematically reviews liver disease in hemophagocytic lymphohistiocytosis (HLH), proposes contraindications for liver-transplantation in such patients, and reports an illustrative case. A 47-year-old-man was hospitalized with high-grade pyrexia, total-bilirubin = 45 g/dL, and profound neutropenia. Bone marrow biopsy/aspirate revealed hemophagocytic histiocytes. The patient had HLH, satisfying 6 Histiocytic Society criteria. Liver-biopsy histopathology revealed relatively well-preserved hepatic parenchyma, except for sparse hepatocytic necrosis. The patient was not a liver-transplant-candidate, despite model for end stage liver disease-score = 33, due to multi-organ failure from HLH. He expired from multi-organ failure despite receiving corticosteroids. This case and systematic review reveals patients with HLH may not be liver transplant candidates because of liver failure from multisystem failure.