Review Articles
The Liver in Hemophagocytic Lymphohistiocytosis
Not an Innocent Bystander
Tamir Diamond MD,
Aaron D. Bennett MD,
Edward M. Behrens MD,
Corresponding Author
Tamir Diamond MD
Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA
Address correspondence and reprint requests to Tamir Diamond, MD, Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA 19104 (e-mail: [email protected]).Search for more papers by this authorAaron D. Bennett MD
Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorEdward M. Behrens MD
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA
Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorTamir Diamond MD,
Aaron D. Bennett MD,
Edward M. Behrens MD,
Corresponding Author
Tamir Diamond MD
Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA
Address correspondence and reprint requests to Tamir Diamond, MD, Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA 19104 (e-mail: [email protected]).Search for more papers by this authorAaron D. Bennett MD
Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorEdward M. Behrens MD
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA
Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorT.D. was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. T.D. and A.D.B. were supported by the Fred and Suzanne Biesecker Pediatric Liver Center at Children’s Hospital of Philadelphia. The remaining authors report no conflicts of interest.
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystemic hyperinflammatory disease commonly associated with hepatic dysfunction. Liver injury is mediated by unchecked antigen presentation, hypercytokinemia, dysregulated cytotoxicity by natural killer and CD8 T cells, and disruption of intrinsic hepatic metabolic pathways. Over the past decade, there have been significant advances in diagnostics and expansion in therapeutic armamentarium for this disorder allowing for improved morbidity and mortality. This review discusses the clinical manifestations and pathogenesis of HLH hepatitis in both familial and secondary forms. It will review growing evidence that the intrinsic hepatic response to hypercytokinemia in HLH perpetuates disease progression and the novel therapeutic approaches for patients with HLH-hepatitis/liver failure.
REFERENCES
- 1.Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124–31.
- 2.Niece JA, Rogers ZR, Ahmad N, Langevin A-M, McClain KL. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer 2010; 54: 424–8.
- 3.Otrock ZK, Daver N, Kantarjian HM, Eby CS. Diagnostic challenges of hemophagocytic lymphohistiocytosis. Clin Lymphoma Myeloma Leuk 2017; 17S: S105–10.
- 4.Abdullatif H, Mohsen N, El-Sayed R, et al. Haemophagocytic lymphohistiocytosis presenting as neonatal liver failure: a case series. Arab J Gastroenterol 2016; 17: 105–9.
- 5.Najib K, Moghtaderi M, Bordbar M, Monabati A. Awareness of hemophagocytic lymphohistiocytosis as an unusual cause of liver failure in the neonatal period. J Pediatr Hematol Oncol 2020; 42: e479–82.
- 6.Hadzic N, Molnar E, Height S, et al. High prevalence of hemophagocytic lymphohistiocytosis in acute liver failure of infancy. J Pediatr 2022; 250: 67–74.e1.
- 7.Squires JE, Alonso EM, Ibrahim SH, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition position paper on the diagnosis and management of pediatric acute liver failure. J Pediatr Gastroenterol Nutr 2022; 74: 138–58.
- 8.Alonso EM, Horslen SP, Behrens EM, Doo E. Pediatric acute liver failure of undetermined cause: a research workshop. Hepatology 2017; 65: 1026–37.
- 9.Ryu JM, Kim KM, Oh SH, et al. Differential clinical characteristics of acute liver failure caused by hemophagocytic lymphohistiocytosis in children. Pediatr Int 2013; 55: 748–52.
- 10.Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood 2020; 135: 1332–43.
- 11.Gloude NJ, Dandoy CE, Davies SM, et al. Thinking beyond HLH: clinical features of patients with concurrent presentation of hemophagocytic lymphohistiocytosis and thrombotic microangiopathy. J Clin Immunol 2020; 40: 699–707.
- 12.Parizhskaya M, Reyes J, Jaffe R. Hemophagocytic syndrome presenting as acute hepatic failure in two infants: clinical overlap with neonatal hemochromatosis. Pediatr Dev Pathol 1999; 2: 360–6.
- 13.Leonis MA, Miethke AG, Fei L, et al. Four biomarkers linked to activation of cluster of differentiation 8-positive lymphocytes predict clinical outcomes in pediatric acute liver failure. Hepatology 2021; 73: 233–46.
- 14.Amir AZ, Ling SC, Naqvi A, et al. Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis. Liver Transpl 2016; 22: 1245–53.
- 15.De Gottardi J, Montani M, Angelillo-Scherrer A, Rovo A, Berzigotti A. Hepatic sinusoidal hemophagocytosis with and without hemophagocytic lymphohistiocytosis. PLoS One 2019; 14: e0226899.
- 16.Chen JH, Fleming MD, Pinkus GS, et al. Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Am J Surg Pathol 2010; 34: 852–67.
- 17.Diamond T, Burn TN, Nishiguchi MA, et al. Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-gamma in a predominantly hepatic-intrinsic manner. PLoS One 2022; 17: e0269553.
- 18.Crispe IN. Hepatocytes as immunological agents. J Immunol 2016; 196: 17–21.
- 19.Knolle PA, Wohlleber D. Immunological functions of liver sinusoidal endothelial cells. Cell Mol Immunol 2016; 13: 347–53.
- 20.He Y, Hwang S, Ahmed YA, et al. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol 2021; 18: 18–37.
- 21.Horras CJ, Lamb CL, Mitchell KA. Regulation of hepatocyte fate by interferon-gamma. Cytokine Growth Factor Rev 2011; 22: 35–43.
- 22.Prencipe G, Bracaglia C, Caiello I, et al. The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis. PLoS One 2019; 14: e0226043.
- 23.Shen Y, Cingolani F, Malik SA, Wen J, Liu Y, Czaja MJ. Sex-specific regulation of interferon-gamma cytotoxicity in mouse liver by autophagy. Hepatology 2021; 74: 2745–58.
- 24.Chapin CA, Taylor SA, Malladi P, et al. Transcriptional analysis of liver tissue identifies distinct phenotypes of indeterminate pediatric acute liver failure. Hepatol Commun 2021; 5: 1373–84.
- 25.Xiang X, Feng D, Hwang S, et al. Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice. J Hepatol 2020; 72: 736–45.
- 26.Basset L, Chevalier S, Danger Y, et al. Interleukin-27 and IFNgamma regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis. J Mol Med (Berl) 2015; 93: 1355–67.
- 27.Buatois V, Chatel L, Cons L, et al. Use of a mouse model to identify a blood biomarker for IFNgamma activity in pediatric secondary hemophagocytic lymphohistiocytosis. Transl Res 2017; 180: 37–52.e2.
- 28.Schrage A, Wechsung K, Neumann K, et al. Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines. Hepatology 2008; 48: 1262–72.
- 29.Gola A, Dorrington MG, Speranza E, et al. Commensal-driven immune zonation of the liver promotes host defence. Nature 2021; 589: 131–6.
- 30.Prencipe G, Caiello I, Pascarella A, et al. Neutralization of IFN-gamma reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. J Allergy Clin Immunol 2018; 141: 1439–49.
- 31.De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-gamma in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol 2021; 17: 678–91.
- 32.Barbier L, Ferhat M, Salame E, et al. Interleukin-1 family cytokines: keystones in liver inflammatory diseases. Front Immunol 2019; 10: 2014.
- 33.Yumoto E, Higashi T, Nouso K, et al. Serum gamma-interferon-inducing factor (IL-18) and IL-10 levels in patients with acute hepatitis and fulminant hepatic failure. J Gastroenterol Hepatol 2002; 17: 285–94.
- 34.Belkaya S, Michailidis E, Korol CB, et al. Inherited IL-18BP deficiency in human fulminant viral hepatitis. J Exp Med 2019; 216: 1777–90.
- 35.Weiss ES, Girard-Guyonvarc’h C, Holzinger D, et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood 2018; 131: 1442–55.
- 36.Canna SW, Girard C, Malle L, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol 2017; 139: 1698–701.
- 37.Wegehaupt O, Wustrau K, Lehmberg K, Ehl S. Cell versus cytokine-directed therapies for hemophagocytic lymphohistiocytosis (HLH) in inborn errors of immunity. Front Immunol 2020; 11: 808.
- 38.Ayvazoglu Soy EH, Alam H, Olcay L, et al. Liver transplant in a patient with hemophagocytic lymphohistiocytosis. Exp Clin Transplant 2019; 17(suppl 1): 226–9.
- 39.Ehl S, Astigarraga I, von Bahr Greenwood T, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society. J Allergy Clin Immunol Pract 2018; 6: 1508–17.
- 40.Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 2004; 104: 735–43.
- 41.Bergsten E, Horne A, Arico M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood 2017; 130: 2728–38.
- 42.Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol 2014; 192: 84–91.
- 43. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Etoposide. [Updated February 25, 2018]. 2012.
- 44.Mahlaoui N, Ouachee-Chardin M, de Saint Basile G, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics 2007; 120: e622–8.
- 45.Moshous D, Briand C, Castelle M, et al. Alemtuzumab as first line treatment in children with familial lymphohistiocytosis. Blood 2019; 134(suppl 1: 80.
10.1182/blood-2019-124477 Google Scholar
- 46.Das R, Guan P, Sprague L, et al. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood 2016; 127: 1666–75.
- 47.Albeituni S, Verbist K, Tedrick P, Tillman H, Nichols KE. Combined treatment with ruxolitinib and dexamethasone curtails inflammation and lessens disease in preclinical studies of hemophagocytic lymphohistiocytosis. Blood 2016; 128: 4894.
- 48.Weaver LK, Chu N, Behrens EM. Brief report: interferon-gamma-mediated immunopathology potentiated by toll-like receptor 9 activation in a murine model of macrophage activation syndrome. Arthritis Rheumatol 2019; 71: 161–8.
- 49.Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med 2020; 382: 1811–22.
- 50.Keenan C, Nichols KE, Albeituni S. Use of the JAK inhibitor ruxolitinib in the treatment of hemophagocytic lymphohistiocytosis. Front Immunol 2021; 12: 614704.
- 51.Zhang Q, Zhao YZ, Ma HH, et al. A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis. Blood 2022; 139: 3493–504.
- 52.Chiossone L, Audonnet S, Chetaille B, et al. Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein. Front Immunol 2012; 3: 1–10.
Citing Literature
