1
|
Nguyen TH, Satwani P, Kumar D, Kapoor U, Malik S, Prince C, Montminy T, Smiley K, Martinez M, Goldner D, Marsh R, Remotti HE, Fazlollahi L, Rytting HB, Romero R, Chandrakasan S. Systemic T-cell activation and IFN-γ activity in indeterminate severe hepatitis are reminiscent of hemophagocytic lymphohistiocytosis: Implications for T-cell- and IFN-γ-directed therapies. J Allergy Clin Immunol 2025; 155:199-212. [PMID: 39278359 PMCID: PMC11890196 DOI: 10.1016/j.jaci.2024.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND Severe hepatitis cases in children are increasingly recognized, but the exact etiology remains unknown in a significant proportion of patients. Cases of indeterminate severe hepatitis (iSH) may progress to indeterminate pediatric acute liver failure (iPALF), so understanding its immunobiology is critical to preventing disease progression. Hemophagocytic lymphohistiocytosis (HLH) is a systemic hyperinflammatory disorder associated with T-cell and macrophage activation with liver injury. OBJECTIVES We hypothesized that a high proportion of patients with iSH demonstrate systemic T-cell activation similar to HLH before developing iPALF and that the degree of T-cell activation in iSH might correlate with outcomes. METHODS From 2019 to 2022, 14 patients with iSH and 7 patients with PALF of known, nonimmune etiology were prospectively enrolled. We compared immune signatures of iSH, HLH, known PALF, and healthy controls. RESULTS We found that patients with iSH have increased CD8+ T-cell activation and high IFN-γ activity similar to HLH. The amplitude of CD8+ T-cell activation was predictive of iSH progression to iPALF. We also found that in patients with iSH, ferritin had only modest elevation. However, the ratio of age-normalized plasma soluble IL-2 receptor to ferritin level can distinguish iSH from known PALF and HLH. As proof of concept, we report that in 3 patients with steroid-refractory iSH, emapalumab, an IFN-γ blocking antibody used in combination with steroids, improved liver function and may have prevented progression to PALF. CONCLUSIONS Flow-based T-cell activation markers could help in early identification and risk stratification for targeted intervention in patients with iSH.
Collapse
Affiliation(s)
- Thinh H Nguyen
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Prakash Satwani
- Division of Pediatric Hematology-Oncology, Columbia University, New York, NY
| | - Deepak Kumar
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Urvi Kapoor
- Division of Pediatric Hematology-Oncology, Columbia University, New York, NY
| | - Sakshi Malik
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Chengyu Prince
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Taylor Montminy
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Ga
| | - Kristi Smiley
- Division of Bone Marrow Transplantation and Immune Deficiency, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Mercedes Martinez
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, NewYork-Presbyterian Hospital, Columbia University, New York, NY
| | - Dana Goldner
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, NewYork-Presbyterian Hospital, Columbia University, New York, NY
| | - Rebecca Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Helen E Remotti
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | - Heather B Rytting
- Department of Pediatrics, Division of Pediatric Pathology, Children's Healthcare of Atlanta, Atlanta, Ga
| | - Rene Romero
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Ga
| | - Shanmuganathan Chandrakasan
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga.
| |
Collapse
|
2
|
Mann J, Runge S, Schell C, Gräwe K, Thoulass G, Lao J, Ammann S, Grün S, König C, Berger SA, Hild B, Aichele P, Rosshart SP, Ehl S. The Microbiome Modifies Manifestations of Hemophagocytic Lymphohistiocytosis in Perforin-Deficient Mice. Eur J Immunol 2025; 55:e202451061. [PMID: 39548906 PMCID: PMC11739664 DOI: 10.1002/eji.202451061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/18/2024]
Abstract
Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life-threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin-deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe-immune cell interactions due to specific pathogen-free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a "wild" microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota ('PKO-Wildlings') and monitored them for signs of HLH. PKO-Wildlings survived long-term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO-Wildlings. Interestingly, after infection with LCMV, PKO-Wildlings developed an altered HLH pattern. This included lower IFN-γ serum levels along with improved IFN-γ-driven anemia, but more elevated levels of IL-17 and increased liver inflammation compared with PKO-SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host-microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology.
Collapse
Affiliation(s)
- Jasmin Mann
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
| | - Solveig Runge
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
- Department of Medicine II, Medical Center‐ University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
- Department of Microbiome Research, University Hospital ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenGermany
| | - Christoph Schell
- Institute for Surgical Pathology, Medical Center‐ University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Katja Gräwe
- Institute for Surgical Pathology, Medical Center‐ University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Gudrun Thoulass
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
| | - Jessica Lao
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
| | - Sandra Ammann
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Sarah Grün
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
| | - Christoph König
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
| | - Sarah A. Berger
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
- Faculty of BiologyUniversity of FreiburgFreiburgGermany
| | - Benedikt Hild
- Department of Gastroenterology, Hepatology and Transplantation MedicineMedical Faculty University of Duisburg‐EssenEssenGermany
| | - Peter Aichele
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Stephan P. Rosshart
- Department of Medicine II, Medical Center‐ University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
- Department of Microbiome Research, University Hospital ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenGermany
| | - Stephan Ehl
- Institute for ImmunodeficiencyCenter for Chronic Immunodeficiency (CCI), Medical Center‐ University of FreiburgFaculty of MedicineUniversity of FreiburgFreiburgGermany
| |
Collapse
|
3
|
Kranz LA, Hahn WS, Thompson WS, Hentz R, Kobrinsky NL, Galardy P, Greenmyer JR. Neonatal hemophagocytic lymphohistiocytosis: A meta-analysis of 205 cases. Pediatr Blood Cancer 2024; 71:e30894. [PMID: 38296838 DOI: 10.1002/pbc.30894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/03/2024] [Accepted: 01/16/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH. OBJECTIVES The objective of this study was to perform a meta-analysis of published cases of nHLH. METHODS A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case. RESULTS A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0-11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6-27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time. CONCLUSIONS Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.
Collapse
Affiliation(s)
- Lincoln A Kranz
- University of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - Wyatt S Hahn
- University of North Dakota School of Medicine, Grand Forks, North Dakota, USA
| | - Whitney S Thompson
- Mayo Clinic, Neonatal and Perinatal Medicine, Clinical Genomics, Center for Individualized Medicine, Rochester, Minnesota, USA
| | - Roland Hentz
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Paul Galardy
- Pediatric Hematology and Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jacob R Greenmyer
- Pediatric Hematology and Oncology, Hospice and Palliative Medicine, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
4
|
Lv K, Cheng X, Zhou Y, Yu M, Wang S, Shen H, Li F. Patients with Hemophagocytic Lymphohistiocytosis Who Need Intensive Care Can Be Successfully Rescued by Timely Using Etoposide-Based HLH Regimens. Int J Gen Med 2024; 17:431-446. [PMID: 38333019 PMCID: PMC10850986 DOI: 10.2147/ijgm.s443774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/28/2024] [Indexed: 02/10/2024] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) patients who need intensive care usually have multiple organ failure and poor prognosis. However, the clinical characteristics, therapeutic efficacy and outcome in these critically ill HLH patients have remained unclear. Methods We performed a retrospective study of 50 critically ill HLH patients from September 2013 to October 2022. Patients' information was collected, and the overall survival rate was estimated. Results Fifty HLH patients need intensive care, and the median sequential organ failure assessment (SOFA) score was 8. 66.00% patients had septic shock, 60.00% had disseminated intravascular coagulation (DIC) and 56.00% had acute respiratory distress syndrome (ARDS). 64.00% patients needed vasoactive drugs, 60.00% needed invasive or non-invasive positive pressure mechanical ventilation, and 12.00% needed continuous renal replacement therapy (CRRT). Among 18 patients received the etoposide-based regimens, the median time for 17 patients to remove ECG monitoring was 13 days (4-30 days); the median time to remove respiratory support in 10 patients was 8.5 days (4-21 days); the median time for 5 patient to convert from dominant DIC to non-dominant DIC was 4 days (1-14 days) and the median time for 6 patients to stop using vasoactive drugs was 10 days (2-14 days). After 4 weeks of treatment, 7 patients were evaluated as NR, 6 achieved PR, and 5 could not be evaluated. The ORR was 55.56%. Up to the last follow-up, the OS rate of patients receiving etoposide-based regimens was 66.67%. In contrast, all 32 HLH patients in other groups died. Univariate analysis showed that PCT > 0.5 ug/L, PT prolonged > 6 s, TBil > 25umol/L, respiratory failure, renal failure, liver failure and did not receive etoposide- based regimens were the negative factors affecting survival (P = 0.001, 0.017, 0.043, 0.001, 0.000, 0.029, 0.000). Conclusion HLH patients who need intensive care timely used etoposide-based HLH regimens might rescue critically ill patients successfully.
Collapse
Affiliation(s)
- Kebing Lv
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Xiaoye Cheng
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Hematologic Disease, Nanchang, People’s Republic of China
- Institute of Lymphoma and Myeloma, Nanchang University, Nanchang, People’s Republic of China
| | - Yulan Zhou
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Hematologic Disease, Nanchang, People’s Republic of China
- Institute of Lymphoma and Myeloma, Nanchang University, Nanchang, People’s Republic of China
| | - Min Yu
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Hematologic Disease, Nanchang, People’s Republic of China
- Institute of Lymphoma and Myeloma, Nanchang University, Nanchang, People’s Republic of China
| | - Shixuan Wang
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Hematologic Disease, Nanchang, People’s Republic of China
- Institute of Lymphoma and Myeloma, Nanchang University, Nanchang, People’s Republic of China
| | - Huimin Shen
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Fei Li
- Center of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Clinical Research Center for Hematologic Disease, Nanchang, People’s Republic of China
- Institute of Lymphoma and Myeloma, Nanchang University, Nanchang, People’s Republic of China
| |
Collapse
|
5
|
Verbist K, Nichols KE. Cytokine Storm Syndromes Associated with Epstein-Barr Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:227-248. [PMID: 39117818 DOI: 10.1007/978-3-031-59815-9_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.
Collapse
Affiliation(s)
- Katherine Verbist
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Kim E Nichols
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
| |
Collapse
|
6
|
Rosado FG, Gopal P. Laboratory Features and Pathology of Cytokine Storm Syndromes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:43-58. [PMID: 39117807 DOI: 10.1007/978-3-031-59815-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
The laboratory diagnosis of cytokine storm syndromes (CSSs), i.e., hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), is often challenging. The laboratory features using routinely available tests lack specificity, whereas confirmatory testing is available in only few laboratories in the United States. The disease mechanisms are still largely unclear, particularly in adults. In this chapter, the pathogenesis of CSSs, their associated laboratory findings, and recommended diagnostic strategies are reviewed.
Collapse
Affiliation(s)
- Flavia G Rosado
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Purva Gopal
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| |
Collapse
|
7
|
Desai N, Kudose S, Remotti HE, Del Portillo A, Fazlollahi L, Lee MJ, Xiong Y, Moreira RK, Salomao M, Fiel MI, Gonzalez RS, Misdraji J, Gill RM, Hart J, Kleiner DE, Drebber U, Bellizzi AM, Lagana SM. Erythrophagocytosis is not a reproducible finding in liver biopsies, and is not associated with clinical diagnosis of hemophagocytic lymphohistiocytosis. Virchows Arch 2024; 484:61-69. [PMID: 37924345 DOI: 10.1007/s00428-023-03683-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 11/06/2023]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH. However, there are problems with this approach; in particular, we do not know whether this finding is reproducible or whether it is specific to HLH. Therefore, we conducted a multi-institutional study in which experienced liver pathologists reviewed images taken from liver biopsies from patients with normal liver, acute hepatitis, possible HLH, and clinical HLH to determine if there was agreement about the presence or absence of erythrophagocytosis, and to ascertain whether the finding corresponds to a clinical diagnosis of HLH. Twelve liver pathologists reviewed 141 images in isolation (i.e., no clinical information or diagnosis provided). These came from 32 patients (five normal, 17 acute hepatitis, six HLH, four possible HLH). The pathologists classified each image as negative, equivocal, or positive for erythrophagocytosis. Kappa was .08 (no agreement) for case-level and 0.1 for image-level (1.4% agreement, based on two images which were universally considered negative). There was no difference in the proportion of pathologists who diagnosed erythrophagocytosis among those with different diagnoses at case or image-level (p = 0.82 and p = 0.82, respectively). Thus, erythrophagocytosis is an entirely unreliable histologic parameter in liver, as it is irreproducible and not demonstrably associated with a clinical disease (namely, HLH). Unless and until more reliable guidelines can be established, pathologists should refrain from commenting on the presence or absence of erythrophagocytosis in liver biopsy.
Collapse
Affiliation(s)
- Niyati Desai
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA
| | - Satoru Kudose
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA
| | - Helen E Remotti
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA
| | - Armando Del Portillo
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA
| | - Michael J Lee
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA
| | - Yuqing Xiong
- Department of Pathology, Mass General Brigham, Boston, MA, USA
| | - Roger K Moreira
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Maria Isabel Fiel
- Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA
| | - Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, USA
| | | | - Ryan M Gill
- Department of Pathology, University of California, San Francisco, San Francisco, USA
| | - John Hart
- Department of Pathology, University of Chicago, Chicago, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, USA
| | - Uta Drebber
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | | | - Stephen M Lagana
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St.VC14-209A, New York, NY, 10032, USA.
| |
Collapse
|
8
|
Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
9
|
Wang DD, Wu S, Kong BB, Song LL. Hemophagocytic lymphohistiocytosis with jaundice as first manifestation: A case report. World J Clin Cases 2023; 11:8212-8218. [PMID: 38130789 PMCID: PMC10731184 DOI: 10.12998/wjcc.v11.i34.8212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/11/2023] [Accepted: 11/27/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition. It is an immune-mediated disease that has a wide range of causes, elicits a hyperinflammatory response, and results in multiple organ damage. Clinical presentations vary, and in some cases, jaundice occurs as the first symptom. CASE SUMMARY We report the case of a 71-year-old female patient who presented with jaundice. She was admitted to our hospital because of the occurrence of "jaundice for half a month", and upon examination, obstructive jaundice with choledocholithiasis and gallstones was suggested. Cholecystectomy and choledocholithotomy were performed. However, the jaundice did not improve after surgery. We found splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin. Bone marrow biopsy revealed hemophagocytosis. Later, cardiac arrest occurred when she returned 3 wk after the surgery. We considered that HLH was triggered by septic shock. The patient's condition deteriorated rapidly, with multiple organ dysfunction and severe gastrointestinal bleeding. Corticosteroid therapy and symptomatic treatment failed to save her life. CONCLUSION Jaundice rarely presents as the first symptom in HLH patients. The HLH in this case was triggered by septic shock with jaundice as the first symptom. Clinicians should try hard to reduce missed diagnoses and misdiagnoses.
Collapse
Affiliation(s)
- Dan-Dan Wang
- Department of Emergency Medicine, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing 102218, China
| | - Sheng Wu
- Department of Emergency Medicine, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing 102218, China
| | - Bing-Bing Kong
- Department of Emergency Medicine, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing 102218, China
| | - Lin-Lin Song
- Department of Emergency Medicine, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing 102218, China
| |
Collapse
|
10
|
Diamond T, Bennett AD, Behrens EM. The Liver in Hemophagocytic Lymphohistiocytosis: Not an Innocent Bystander. J Pediatr Gastroenterol Nutr 2023; 77:153-159. [PMID: 37098099 PMCID: PMC10524294 DOI: 10.1097/mpg.0000000000003807] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
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.
Collapse
Affiliation(s)
- Tamir Diamond
- Division of Gastroenterology Hepatology and Nutrition, Children’s Hospital of Philadelphia
- Department of Pediatrics University of Pennsylvania
| | - Aaron D. Bennett
- Division of Gastroenterology Hepatology and Nutrition, Children’s Hospital of Philadelphia
| | - Edward M. Behrens
- Department of Pediatrics University of Pennsylvania
- Division of Rheumatology, Children’s Hospital of Philadelphia
| |
Collapse
|
11
|
Diamond T, Lau M, Morrissette J, Chu N, Behrens EM. CXCL9 inhibition does not ameliorate disease in murine models of both primary and secondary hemophagocytic lymphohistiocytosis. Sci Rep 2023; 13:12298. [PMID: 37516815 PMCID: PMC10387083 DOI: 10.1038/s41598-023-39601-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 07/27/2023] [Indexed: 07/31/2023] Open
Abstract
Hemophagocytic Lymphohistiocytosis (HLH) is a group of disorders culminating in systemic inflammation and multi-organ failure with high incidence of hepatic dysfunction. Overproduction of IFN-γ is the main immunopathological driver in this disorder. Monokine induced by IFN-γ (CXCL9) serves as a biomarker for disease activity and response to treatment in this disorder. However, very little is understood about the actual functional role of CXCL9 in pathogenesis in HLH. In the current study, we sought to determine the role of CXCL9 in pathogenesis in murine models of both Familial HLH (prf1-/-) and Toll Like Receptor (TLR) 9 repeated stimulation induced Macrophage Activation Syndrome (MAS), a form of secondary HLH. FHL and MAS were induced in both CXCL9 genetically deficient mice (cxcl9-/-) and controls as well as using AMG487, a pharmacological antagonist of the CXCL9 receptor, CXCR3. Results showed that CXCL9 genetic deficiency did not improve disease parameters or hepatitis in both models. Consistent with genetic ablation of CXCL9, inhibition of its receptor, CXCR3, by AMG487 did not show any significant effects in the FHL model. Taken together, inhibition of CXCL9-CXCR3 interaction does not ameliorate HLH physiology in general, or hepatitis as a classical target organ of disease.
Collapse
Affiliation(s)
- Tamir Diamond
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
| | - Michelle Lau
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jeremy Morrissette
- Department of Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Niansheng Chu
- Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Edward M Behrens
- Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| |
Collapse
|
12
|
Awan RU, Rashid S, Nabeel A, Samant H. COVID-19 vaccination-related hemophagocytic lymphohistiocytosis presenting as acute liver failure. Proc (Bayl Univ Med Cent) 2022; 36:78-80. [PMID: 36578589 PMCID: PMC9762805 DOI: 10.1080/08998280.2022.2123665] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Acute liver failure following COVID-19 infection and/or vaccination is very rare and can be secondary to hemophagocytic lymphohistiocytosis (HLH). Liver injury in such cases appears to be extrinsic and thus treatment hinges on prompt diagnosis and reversal of the primary disease. We describe a patient who developed acute liver failure secondary to HLH after receiving a second dose of the Pfizer COVID-19 vaccine. Persistently elevated liver function tests, fevers, and cytopenia following COVID-19 vaccination should prompt clinicians to calculate an H-score to evaluate for the presence of HLH.
Collapse
Affiliation(s)
- Rehmat Ullah Awan
- Department of Medicine, Ochsner Rush Health, Meridian, Mississippi,Corresponding author: Rehmat Ullah Awan, MD, Department of Medicine, Ochsner Rush Health, 1314 19th Ave., Meridian, MS39305 (e-mail: )
| | - Shazia Rashid
- Division of Gastroenterology, Department of Medicine, Ochsner Health System, Shreveport, Louisiana
| | - Ambreen Nabeel
- Department of Medicine, Ochsner Rush Health, Meridian, Mississippi
| | - Hrishikesh Samant
- Division of Gastroenterology, Department of Medicine, Ochsner Health System, Gonzales, Louisiana
| |
Collapse
|
13
|
Abstract
Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.
Collapse
Affiliation(s)
- Juan Putra
- Division of Pathology, Department of Paediatric Laboratory Medicine, 7979The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Vicky L Ng
- Division of Gastroenterology, Hepatology, and Nutrition, 7979The Hospital for Sick Children, Toronto, ON, Canada
| | - Antonio R Perez-Atayde
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
14
|
Diamond T, Burn TN, Nishiguchi MA, Minichino D, Chase J, Chu N, Kreiger PA, Behrens EM. Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner. PLoS One 2022; 17:e0269553. [PMID: 35671274 PMCID: PMC9173616 DOI: 10.1371/journal.pone.0269553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/23/2022] [Indexed: 12/03/2022] Open
Abstract
Interferon gamma (IFN-γ) is the main cytokine driving organ dysfunction in Familial Hemophagocytic Lymphohistiocytosis (FHL). Blockade of IFN-γ pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-γ receptor (IFN-γ-R). However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a IFNgR-/- bone marrow chimeric model, this study showed that non-hematopoietic IFN-γ response is critical for development of FHL hepatitis in LCMV-infected Prf1-/- mice. Lack of hepatic IFN-γ responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-γ non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44hi CD62Llo) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-γ response results in increased hepatic transcription of type 1 immune response and oxidative stress response pathways, while decreasing transcription of genes involved in extracellular matrix (ECM) production. In summary, these findings demonstrate that there is a hepatic transcriptional response to IFN-γ, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.
Collapse
Affiliation(s)
- Tamir Diamond
- Division of Gastroenterology Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Thomas N. Burn
- Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Mailyn A. Nishiguchi
- Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Danielle Minichino
- Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Julie Chase
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Niansheng Chu
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Portia A. Kreiger
- Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Edward M. Behrens
- Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| |
Collapse
|
15
|
Kikuchi A, Singh K, Gars E, Ohgami RS. Pathology updates and diagnostic approaches to hemophagocytic lymphohistiocytosis. Histopathology 2021; 80:616-626. [PMID: 34716920 DOI: 10.1111/his.14591] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/29/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a complex, often under-recognized hyperinflammatory immune dysregulation syndrome arising in a diverse range of clinical scenarios and conditions. The accurate and timely diagnosis of HLH is crucial for patient survival, and usually requires a high level of clinical suspicion. The histologic corollary to clinical HLH - hemophagocytosis - is neither necessary nor sufficient for the diagnosis of HLH, as it may be seen in a variety of reactive conditions and may be absent in true HLH. Nevertheless, the finding of hemophagocytosis in specific clinical situations should prompt consideration of HLH and further testing to exclude the condition. While traditionally described in bone marrow, identification of hemophagocytosis in other tissues, including lymphoid, splenic, liver, or neural tissue, can be an important asset to the overall recognition of HLH. In this review we discuss the underlying pathophysiology and etiologies of HLH, morphologic aspects of hemophagocytosis and its associated histologic findings in different tissues, and give a brief overview of diagnostic criteria and clinical evaluation.
Collapse
Affiliation(s)
- Alexander Kikuchi
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Kunwar Singh
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Eric Gars
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Robert S Ohgami
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| |
Collapse
|
16
|
Ponnatt TS, Lilley CM, Mirza KM. Hemophagocytic Lymphohistiocytosis. Arch Pathol Lab Med 2021; 146:507-519. [PMID: 34347856 DOI: 10.5858/arpa.2020-0802-ra] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2021] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can eventually result in end-organ damage and death. HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. The prognosis is generally poor, warranting rapid diagnosis and aggressive management. OBJECTIVE.— To provide a comprehensive review of the pathogenesis, clinical features, diagnosis, and management of HLH. DATA SOURCES.— Peer-reviewed literature. CONCLUSIONS.— HLH is a condition where a complete understanding of the pathogenesis, early diagnosis, and proper management has an important role in determining patient outcome. Genetic mutations causing impairment in the function of cytotoxic T lymphocytes and natural killer cells have been identified as the root cause of familial HLH; however, the specific pathogenesis of acquired HLH is unclear. The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population. The HLH-2004 protocol still forms the basis of the diagnosis of HLH in adults, although its use in adults has not been formally validated yet. Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities.
Collapse
Affiliation(s)
- Tanya Sajan Ponnatt
- From the Department of Pathology, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois
| | - Cullen M Lilley
- From the Department of Pathology, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois
| | - Kamran M Mirza
- From the Department of Pathology, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois
| |
Collapse
|
17
|
Kim YR, Kim DY. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. Blood Res 2021; 56:S17-S25. [PMID: 33935031 PMCID: PMC8094004 DOI: 10.5045/br.2021.2020323] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.
Collapse
Affiliation(s)
- Yu Ri Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dae-Young Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| |
Collapse
|
18
|
Majumder A, Sen D. An autopsy series of an oft-missed ante-mortem diagnosis: hemophagocytic lymphohistiocytosis. AUTOPSY AND CASE REPORTS 2021; 11:e2021243. [PMID: 33968822 PMCID: PMC8087375 DOI: 10.4322/acr.2021.243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome resulting from a hyperactivated immune system. Diverse patient profiles and clinical presentations often result in misdiagnosis. This article describes the varied clinical presentations and autopsy findings in three patients with this entity. The etiopathogenesis of HLH, its disparate and confounding clinical features, the diagnostic criteria, and management principles are also briefly reviewed.
Collapse
Affiliation(s)
- Anusree Majumder
- Armed Forces Medical College and Command Hospital (Southern Command), Department of Pathology and Laboratory Sciences, Pune, India
| | - Debraj Sen
- Armed Forces Medical College and Command Hospital (Southern Command), Department of Radiodiagnosis and Imaging, Pune, India
| |
Collapse
|
19
|
Coppola A, Chey C, O'Donovan E, Rahman M. A rare cause of acute liver failure due to haemophagocytic lymphohistiocytosis secondary to diffuse large B-cell lymphoma. JRSM Open 2021; 12:2054270420983623. [PMID: 33717491 PMCID: PMC7930656 DOI: 10.1177/2054270420983623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Acute liver failure is a life-threatening condition commonly caused by drug-induced hepatotoxicity or viral hepatitides. However, there are a number of rarer causes such as haemophagocytic lymphohistiocytosis. Haemophagocytic lymphohistiocytosis is a syndrome of uncontrolled immune cell activation, triggered by infection or malignancy, which carries a high mortality. Whilst mild to moderate liver injury is commonly seen with haemophagocytic lymphohistiocytosis, acute liver failure has rarely been reported in adults. We present a case of a 74-year-old man with acute liver failure secondary to haemophagocytic lymphohistiocytosis triggered by undiagnosed large B-cell lymphoma. Initially treated for biliary sepsis, there was a delay in the diagnosis of haemophagocytic lymphohistiocytosis and despite initiating chemotherapy, he died soon after. This case highlights the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure, as given the life-threatening potential of haemophagocytic lymphohistiocytosis, a prompt diagnosis may allow early initiation of chemotherapy for any chance of survival.
Collapse
Affiliation(s)
- Andrew Coppola
- Department of Surgery and Cancer, Imperial College London Faculty of Medicine, London SW7 2BU, UK
| | - Chia Chey
- Department of Gastroenterology, Surrey and Sussex Healthcare NHS Trust, Surrey RH1 5RH, UK
| | - Emma O'Donovan
- Department of Haematology, Surrey and Sussex Healthcare NHS Trust, Surrey RH1 5RH, UK
| | - Monira Rahman
- Department of Gastroenterology, Surrey and Sussex Healthcare NHS Trust, Surrey RH1 5RH, UK
| |
Collapse
|
20
|
Bray MA, Sartain SE, Gollamudi J, Rumbaut RE. Microvascular thrombosis: experimental and clinical implications. Transl Res 2020; 225:105-130. [PMID: 32454092 PMCID: PMC7245314 DOI: 10.1016/j.trsl.2020.05.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/12/2020] [Accepted: 05/17/2020] [Indexed: 02/07/2023]
Abstract
A significant amount of clinical and research interest in thrombosis is focused on large vessels (eg, stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis.
Collapse
Key Words
- adamts13, a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13
- ap, alternate pathway
- apc, activated protein c
- aps, antiphospholipid syndrome
- caps, catastrophic aps
- asfa, american society for apheresis
- atp, adenosine triphosphate
- cfh, complement factor h
- con a, concavalin a
- cox, cyclooxygenase
- damp, damage-associated molecular pattern
- dic, disseminated intravascular coagulation
- gbm, glomerular basement membrane
- hellp, hemolysis, elevated liver enzymes, low platelets
- hitt, heparin-induced thrombocytopenia and thrombosis
- hlh, hemophagocytic lymphohistiocytosis
- hus, hemolytic-uremic syndrome
- isth, international society for thrombosis and haemostasis
- ivig, intravenous immunoglobulin
- ldh, lactate nos, nitric oxide synthase
- net, neutrophil extracellular trap
- pai-1, plasminogen activator inhibitor 1
- pf4, platelet factor 4
- prr, pattern recognition receptor
- rbc, red blood cell
- scd, sickle cell disease
- sle, systemic lupus erythematosus
- tlr, toll-like receptor
- tf, tissue factor
- tfpi, tissue factor pathway inhibitor
- tma, thrombotic microangiopathy
- tnf-α, tumor necrosis factor-α
- tpe, therapeutic plasma exchange
- ulc, ultra large heparin-pf4 complexes
- ulvwf, ultra-large von willebrand factor
- vwf, von willebrand factor
Collapse
Affiliation(s)
- Monica A Bray
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas; Baylor College of Medicine, Houston, Texas
| | - Sarah E Sartain
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas; Baylor College of Medicine, Houston, Texas
| | - Jahnavi Gollamudi
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas; Baylor College of Medicine, Houston, Texas
| | - Rolando E Rumbaut
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas; Baylor College of Medicine, Houston, Texas.
| |
Collapse
|
21
|
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. [PMID: 31887162 PMCID: PMC6936840 DOI: 10.1371/journal.pone.0226899] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/PURPOSE Hemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening hyperinflammatory syndrome. Sinusoidal hemophagocytosis is occasionally observed on liver biopsy in patients who do not have clinical suspicion of HLH. We aimed at comparing the clinical characteristics and outcomes of patients with signs of hemophagocytosis on liver biopsy meeting and not meeting the HLH diagnostic criteria. METHODS We reviewed the clinical, laboratory features and outcomes of all adult patients consecutively admitted in our center between 08/2011 and 08/2017 presenting with liver histology showing sinusoidal hemophagocytosis and of critically ill patients presenting with severe liver disease in whom hemophagocytosis was histologically confirmed. The characteristics of patients fulfilling and not fulfilling the diagnostic criteria of HLH were compared. RESULTS We identified 12 cases (58% male, median age 61, 75% with a chronic underlying disease) with liver histology showing sinusoidal hemophagocytosis. All had at least some of the clinical features typically associated with HLH. Six were critical ill patients. In 4 cases with insufficient laboratory and clinical criteria, liver biopsy allowed to confirm the HLH diagnosis. Six patients died, of which four met the diagnostic criteria for HLH. Two patients with chronic liver disease died despite not fulfilling the diagnostic criteria of HLH. CONCLUSION Hemophagocytosis on liver biopsy may contribute to confirming a diagnosis of HLH in suspected cases with indeterminate clinical and laboratory findings. Sinusoidal hemophagocytosis in patients with cirrhosis was associated with bad outcome.
Collapse
Affiliation(s)
- Jacqueline De Gottardi
- Hepatology, University Clinic of Visceral Surgery and Medicine, Inselspital, DBMR, University of Bern, Berne, Switzerland
| | - Matteo Montani
- Institute of Pathology, University of Bern, Berne, Switzerland
| | | | - Alicia Rovo
- Department of Hematology, Inselspital, University of Bern, Berne, Switzerland
| | - Annalisa Berzigotti
- Hepatology, University Clinic of Visceral Surgery and Medicine, Inselspital, DBMR, University of Bern, Berne, Switzerland
- * E-mail:
| |
Collapse
|
22
|
Menêses MOSDC, Etchebehere RM, De Araújo MF, Duque ACDR, Rodrigues DBR, Pereira SADL. Hemophagocytic Lymphohistiocytosis in Autopsied Adults: Clinical, Laboratory and Immunohistochemical Evaluation for CD68 and CD57. Case Report and Literature Review. JOURNAL OF HEALTH SCIENCES 2019. [DOI: 10.17921/2447-8938.2019v21n4p422-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare, usually fatal and underdiagnosed autoimmune-activated disease. The present study aimed to perform a macroscopic, histopathological and immunohistochemical evaluation for CD68 and CD57 in organs of autopsied adults with HLH. A total of 604 autopsy reports were analyzed, and all the patients that filled the diagnostic criteria for HLH (n = 2) were selected. These patients were 18 and 37 years old. Were evaluated both clinical and autopsy reports and performed histopathological and immunohistochemical analysis of the liver and spleen. Both patients filled the diagnostic criteria for HLH, as well as presented common signs and symptoms of this disease, such as chills, abdominal pain, diaphoresis, and jaundice. Hemophagocytosis was observed in the spleen, bone marrow, and lymph nodes of the two patients at autopsy. Immunostaining in the liver and spleen of both patients was mainly severe for CD68, and predominantly mild for CD57, indicating a decrease in NKC numbers and an increase in the number of macrophages, respectively. This was the first study to evaluate CD57 and CD68 in autopsies of adults with HLH. Thus, more studies are required, not only to better elucidate the pathogenetic mechanisms involved in the secondary HLH, but also to disseminate the results in the clinical environment, contributing to the early diagnosis and treatment with consequent reduction of mortality rate. Keywords: Autoimmune Diseases. Histiocytosis. Biomarkers. ResumoA Linfohistiocitose Hemofagocítica (HLH) é uma doença autoimune rara, geralmente fatal e subdiagnosticada. Este estudo tem como objetivo realizar avaliação macroscópica, histopatológica e imunohistoquímica para CD68 e CD57 em órgãos de pacientes adultos com HLH submetidos a autópsia. Um total de 604 laudos de autópsias foram analisados e todos os pacientes que preencheram os critérios diagnósticos para HLH (n = 2) foram selecionados. Esses pacientes tinham 18 e 37 anos de idade. Foram analisados tanto os prontuários quanto os laudos de autópsia, bem como foram realizadas análises histopatológicas e imunohistoquímicas do fígado e baço dos pacientes. Ambos preencheram os critérios diagnósticos para HLH e apresentarem sinais e sintomas comuns da doença, como calafrios, dor abdominal, sudorese e icterícia. A hemofagocitose foi observada no baço, medula óssea e linfonodos dos dois pacientes na autópsia. A imunohistoquímica do fígado e do baço de ambos os pacientes demonstrou imunomarcação acentuada para CD68 e predominantemente discreta para CD57, que indicam diminuição do número de NKC e aumento do número de macrófagos, respectivamente. Este foi o primeiro estudo a avaliar o CD57 e CD68 em autópsias de adultos com HLH. Assim, mais estudos são necessários, não apenas para melhor elucidar os mecanismos patogenéticos envolvidos na HLH secundária, mas também para disseminar os resultados no ambiente clínico, contribuindo para o diagnóstico e tratamento precoces com consequente redução da taxa de mortalidade. Palavras-chave: Doenças Autoimunes. Histiocitose. Biomarcadores.
Collapse
|
23
|
Abstract
OBJECTIVES Describe a single center experience of hemophagocytic lymphohistiocytosis in a PICU over a 10-year period, to identify clinical features that may be associated with worse outcomes, including mortality, hospital and ICU length of stay, and functional and cognitive impairments on discharge. DESIGN Retrospective electronic medical record review, 2007-2017. SETTING PICU located in a large urban academic quaternary care children's hospital. PATIENTS All children admitted with hemophagocytic lymphohistiocytosis to our PICU from 2007 to 2017. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS All patients were identified utilizing International Classification of Diseases, 9th Revision and International Classification of Diseases, 10th Revision codes. Each chart was reviewed for demographic information, hemophagocytic lymphohistiocytosis diagnostic criteria, laboratory data, Pediatric Risk of Mortality Score III, clinical features and events of ICU stay, and PICU and hospital (length of stay). Mortality at 1 year and change in Functional Status Scale from admission to discharge were recorded. There were 42 admissions with 33 unique patients. Median Pediatric Risk of Mortality score at admission was 9 (interquartile range, 7-16). Median PICU length of stay was 7 days (interquartile range, 2-21 d) and hospital length of stay was 24 days (interquartile range, 14-37 d). During their ICU stay, 56% of patients received mechanical ventilation, 43% required vasoactives, 18% required continuous renal replacement therapy, and 5% received extracorporeal life support. Clinical factors related to increased PICU length of stay included Pediatric Risk of Mortality III score (p = 0.019), maximum lactate dehydrogenase (p = 0.017), maximum total bilirubin (p = 0.042), need for mechanical ventilation (p = 0.002), vasoactive use (p = 0.02), and secondary infection (p = 0.007). The most common therapies for hemophagocytic lymphohistiocytosis included steroids (93%), etoposide (55%), and anakinra (48%). Of the 26 patients who survived to hospital discharge, 19% had newly acquired morbidities. Overall 1-year mortality was 42%. CONCLUSIONS Hemophagocytic lymphohistiocytosis diagnosed in the PICU is a disease with high mortality. Patients who survive to discharge had relatively little morbidity, however, the mortality risk in the year following discharge continued to remain high.
Collapse
|
24
|
Gavin AL, Huang D, Huber C, Mårtensson A, Tardif V, Skog PD, Blane TR, Thinnes TC, Osborn K, Chong HS, Kargaran F, Kimm P, Zeitjian A, Sielski RL, Briggs M, Schulz SR, Zarpellon A, Cravatt B, Pang ES, Teijaro J, de la Torre JC, O'Keeffe M, Hochrein H, Damme M, Teyton L, Lawson BR, Nemazee D. PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nat Immunol 2018; 19:942-953. [PMID: 30111894 PMCID: PMC6105523 DOI: 10.1038/s41590-018-0179-y] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/28/2018] [Indexed: 01/06/2023]
Abstract
The sensing of microbial genetic material by leukocytes often elicits beneficial pro-inflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked the gene encoding phospholipase D3 (PLD3) to Alzheimer's disease and have linked PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins whose functions are obscure. Here, PLD4-deficient mice were found to have an inflammatory disease, marked by elevated levels of interferon-γ (IFN-γ) and splenomegaly. These phenotypes were traced to altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA sensor TLR9. Macrophages from PLD3-deficient mice also had exaggerated TLR9 responses. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5' exonucleases, probably identical to spleen phosphodiesterase, that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which indicates that both enzymes are needed to regulate inflammatory cytokine responses via the degradation of nucleic acids.
Collapse
Affiliation(s)
- Amanda L Gavin
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Deli Huang
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Christoph Huber
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
- , Bottmingen, Switzerland
| | - Annica Mårtensson
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
- Sophiris Bio, La Jolla, CA, USA
| | - Virginie Tardif
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University, Philadelphia, PA, USA
| | - Patrick D Skog
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Tanya R Blane
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Therese C Thinnes
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Kent Osborn
- The University of California, San Diego, La Jolla, CA, USA
| | - Hayley S Chong
- The University of California, San Diego, La Jolla, CA, USA
| | | | - Phoebe Kimm
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Armen Zeitjian
- The University of California, San Diego, La Jolla, CA, USA
| | | | - Megan Briggs
- The University of California, San Diego, La Jolla, CA, USA
| | - Sebastian R Schulz
- Division of Molecular Immunology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Alessandro Zarpellon
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Benjamin Cravatt
- The Department of Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Ee Shan Pang
- Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - John Teijaro
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Juan Carlos de la Torre
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Meredith O'Keeffe
- Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | | | - Markus Damme
- Biochemisches Institut, Christian-Albrechts-Universität, Kiel, Germany
| | - Luc Teyton
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Brian R Lawson
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
| | - David Nemazee
- The Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
| |
Collapse
|
25
|
Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
26
|
Liang J, Alfano DN, Squires JE, Riley MM, Parks WT, Kofler J, El-Gharbawy A, Madan-Kheterpal S, Acquaro R, Picarsic J. Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites. Pediatr Dev Pathol 2017; 20:498-505. [PMID: 28403691 DOI: 10.1177/1093526616686890] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of "secondary" HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.
Collapse
Affiliation(s)
- Jiancong Liang
- 1 Department of Pathology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania.,2 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Tennessee
| | - Danielle N Alfano
- 3 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pennsylvania
| | - James E Squires
- 3 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pennsylvania
| | - Melissa M Riley
- 3 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pennsylvania
| | - W Tony Parks
- 4 Department of Pathology, Dartmouth-Hitchcock Medical Center, New Hampshire
| | - Julia Kofler
- 5 University of Pittsburgh School of Medicine, Pennsylvania
| | - Areeg El-Gharbawy
- 6 Department of Pediatrics-Medical Genetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania
| | - Suneeta Madan-Kheterpal
- 6 Department of Pediatrics-Medical Genetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania
| | - Roxanne Acquaro
- 6 Department of Pediatrics-Medical Genetics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania
| | - Jennifer Picarsic
- 1 Department of Pathology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pennsylvania
| |
Collapse
|
27
|
Xing Y, Yang J, Lian G, Chen S, Chen L, Li F. Chronic active Epstein-Barr virus infection associated with hemophagocytic syndrome and extra-nodal natural killer/T-cell lymphoma in an 18-year-old girl: A case report. Medicine (Baltimore) 2017; 96:e6845. [PMID: 28489771 PMCID: PMC5428605 DOI: 10.1097/md.0000000000006845] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/13/2017] [Accepted: 04/17/2017] [Indexed: 12/11/2022] Open
Abstract
RATIONALE Chronic active Epstein-Barr virus infection (CAEBV) associated with hemophagocytic syndrome (HPS) and extra-nodal natural killer (NK)/T-cell lymphoma (ENKL) is a rare life-threatening disorder. This disease is easily misdiagnosed because of its varied presentations. PATIENT CONCERNS An 18-year-old girl was admitted to our hospital with a history of edema in the lower limbs and intermittent fever lasting for more than 1 month. At admission, she had severe liver injury of unknown etiology. Laboratory test results revealed pancytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Results of serologic tests for EBV were positive. Results of a skin biopsy indicated EBV-positive NK/T-cell lymphoma, and bone marrow aspiration revealed focal hemophagocytosis and atypical lymphoid cells. DIAGNOSIS On the basis of these findings, we diagnosed the case as extra-nodal NK/T-cell lymphoma-associated HPS (natural killer/T-cell lymphoma-associated hemophagocytic syndrome), which is commonly induced by CAEBV. INTERVENTIONS Treatment consisted of general management of hepatitis, supplemented with albumin and empirical antibiotic therapy. OUTCOMES The patient died from massive gastrointestinal hemorrhage a week after she was discharged from the hospital. LESSONS ENKL and HPS present with varied features and are generally fatal; therefore, clinicians should proceed with caution in suspected cases. HPS should be considered when the patient presents with fever, hepatosplenomegaly, pancytopenia, and liver failure. When HPS is suspected, clinicians should determine the underlying cause, such as severe infection, including infection with viruses such as EBV; genetic predisposition; or underlying malignancies, especially lymphoma because of its strong association with HPS.
Collapse
|
28
|
Cytomegalovirus-Induced Hemophagocytic Lymphohistiocytosis in an Extreme Preterm Infant: Recognition and Therapy Leading to Recovery. Adv Neonatal Care 2017; 17:91-95. [PMID: 27501069 DOI: 10.1097/anc.0000000000000268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that can be triggered by cytomegalovirus, a relatively common infectious exposure to neonates. The clinical presentation is common to many acute illnesses seen in extreme premature infants; however, there are key clinical and laboratory findings that can lead to the diagnosis. PURPOSE We present a case of an extreme premature infant of 25 weeks' gestation who developed cytomegalovirus-induced HLH. Using the current published protocols that are used in pediatric cancer can be adapted for use in a premature infant, which led to remission of HLH and eventual discharge from the neonatal intensive care unit. IMPLICATIONS FOR PRACTICE There are published treatment protocols used in pediatric oncology that when initiated early can lead to favorable outcomes and remission in even the most fragile neonates. IMPLICATIONS FOR RESEARCH Additional studies are needed on the pharmacokinetics, dosing, and side effects on medications used for treatment of HLH in preterm infants. Additional research is needed to improve the clinician's ability to reach the diagnosis as well as define treatment strategies that provide optimal outcomes.
Collapse
|
29
|
Lin S, Li Y, Long J, Liu Q, Yang F, He Y. Acute liver failure caused by hemophagocytic lymphohistiocytosis in adults: A case report and review of the literature. Medicine (Baltimore) 2016; 95:e5431. [PMID: 27893685 PMCID: PMC5134878 DOI: 10.1097/md.0000000000005431] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 10/13/2016] [Accepted: 10/28/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare condition that can be caused by a primary or acquired disorder of uncontrolled immune response. Liver injury is a common complication of HLH; however, HLH presenting as acute liver failure (ALF) has rarely been reported in adults. CASE SUMMARY A 34-year-old man was admitted to our hospital with nausea and fatigue persisting for 2 weeks and jaundice for 1 week. He had hyperthermia at the onset of disease. At admission, he had severe liver injury with unknown etiology. The laboratory data showed that he had hyperferritinemia, thrombocytopenia, anemia, hypertriglyceridemia, and hypofibrinogenemia. Finally, a bone marrow biopsy revealed hemophagocytic cells, and he was diagnosed with HLH. The patient was treated with prednisone and plasma exchange. However, the liver function of the patient deteriorated, and he finally died of multiorgan failure. CONCLUSIONS Reports of adult patients with ALF caused by HLH have increased, and HLH should be suspected in patients with ALF of indeterminate cause. Although the efficacy of the treatment strategy recommended by the HLH 2004 remains to be confirmed in adult patients with ALF caused by HLH, early diagnosis and prompt combined treatment with steroids and cyclosporin A or etoposide should be emphasized.
Collapse
|
30
|
Álvarez Artero E, Campo Núñez A, Albarrán Severo B, Pardo-Lledias J. Severe liver disease as first sign of a haemophagocytic syndrome. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 40:348-349. [PMID: 27260631 DOI: 10.1016/j.gastrohep.2016.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 04/01/2016] [Accepted: 04/04/2016] [Indexed: 11/28/2022]
Affiliation(s)
- Elisa Álvarez Artero
- Servicio de Medicina Interna, Hospital General Río Carrión, Complejo Asistencial Universitario de Palencia (CAUPA), Palencia, España.
| | - Amaia Campo Núñez
- Servicio de Medicina Interna, Hospital General Río Carrión, Complejo Asistencial Universitario de Palencia (CAUPA), Palencia, España
| | - Beatriz Albarrán Severo
- Servicio de Hematología, Hospital General Río Carrión, Complejo Asistencial Universitario de Palencia (CAUPA), Palencia, España
| | - Javier Pardo-Lledias
- Servicio de Medicina Interna, Hospital General Río Carrión, Complejo Asistencial Universitario de Palencia (CAUPA), Palencia, España
| |
Collapse
|
31
|
Filippone EJ, Farber JL. Hemophagocytic lymphohistiocytosis: an update for nephrologists. Int Urol Nephrol 2016; 48:1291-1304. [DOI: 10.1007/s11255-016-1294-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 04/11/2016] [Indexed: 12/11/2022]
|
32
|
Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases. Am J Surg Pathol 2015; 39:1075-84. [PMID: 26034866 DOI: 10.1097/pas.0000000000000453] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ipilimumab is a monoclonal antibody that inhibits the CTLA4 receptor on cytotoxic T lymphocytes, resulting in immune-mediated tumor cell death. Ipilimumab is most often used in the treatment of metastatic melanoma, and rarely liver toxicity necessitating cessation of treatment occurs. The aim of this study was to characterize the histologic features and clinical course of ipilimumab-associated hepatitis. Eleven patients with clinical suspicion of ipilimumab-induced hepatitis, due to the development of abnormal liver function tests (LFTs) while receiving treatment, and who underwent liver biopsy, were identified over a 6-year period. Ten patients were male and 1 female (median age 58 y), and all received 1 to 4 doses of ipilimumab. None had known preexisting liver disease. Two patients were obese, and another had a history of alcohol abuse. Viral and autoimmune serologies were negative in all patients except 1 who had a mildly elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3. The inflammatory infiltrate was similar in composition in both patterns, composed predominantly of CD8+ T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7 cases and frequently formed loose histiocytic aggregates. Central vein endothelialitis was present in 8 cases. Patients in this group tended to have markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the other showed morphologic features indistinguishable from nonalcoholic steatohepatitis. Discontinuation of ipilimumab and administration of immunosuppressives resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation. Ipilimumab may potentially unmask previously subclinical liver disease, for example, fatty liver disease, and the diagnosis of ipilimumab-induced liver injury may only be recognized with certainty after cessation of the drug leads to normalization of LFTs. Overall, ipilimumab-associated hepatitis most often presents with a panlobular active hepatitis that resembles autoimmune hepatitis. Prominent sinusoidal histiocytic infiltrates and central vein damage with endothelialitis may be helpful histologic clues to the diagnosis of ipilimumab-associated hepatitis.
Collapse
|
33
|
Weinstein JL, Badawy SM, Bush JW, Schafernak KT. Deconstructing the diagnosis of hemophagocytic lymphohistiocytosis using illustrative cases. J Hematop 2015. [DOI: 10.1007/s12308-015-0254-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
|
34
|
Ryu JM, Kim KM, Oh SH, Koh KN, Im HJ, Park CJ, Chi HS, Seo JJ. Differential clinical characteristics of acute liver failure caused by hemophagocytic lymphohistiocytosis in children. Pediatr Int 2013; 55:748-52. [PMID: 23848458 DOI: 10.1111/ped.12181] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 06/17/2013] [Accepted: 07/04/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Children with acute liver failure (ALF) caused by hemophagocytic lymphohistiocytosis (HLH) may be at risk of undergoing unnecessary liver transplantation (LT). The aim of this study was to compare the characteristics of ALF caused by HLH with those of ALF of unknown etiology in children. METHODS The clinical features and laboratory findings for eight children with ALF caused by HLH (ALF-HLH group) and 27 children with ALF of unknown etiology (ALF-UK group) were retrospectively compared by reviewing medical records. RESULTS The ALF-HLH group had a higher incidence of pleural effusion, C-reactive protein elevation (especially >5 mg/dL), thrombocytopenia, anemia, fever, splenomegaly, and hypoalbuminemia (<2.5 mg/dL), and a higher in-hospital mortality rate. No significant differences were found in the white blood cell count, liver enzymes, coagulation profile, or incidence of hepatomegaly. CONCLUSIONS LT should be performed only after it is proven that ALF is not caused by HLH, if a child with ALF shows the differential clinical features of ALF caused by HLH. Further research with larger sample sizes, however, is needed.
Collapse
Affiliation(s)
- Jeong-Min Ryu
- Department of Pediatric Emergency Medicine, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | |
Collapse
|
35
|
Rosado FGN, Kim AS. Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol 2013; 139:713-27. [PMID: 23690113 DOI: 10.1309/ajcp4zdkj4icouat] [Citation(s) in RCA: 224] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a frequently fatal and likely underdiagnosed disease involving a final common pathway of hypercytokinemia, which can result in end-organ damage and death. Although an early diagnosis is crucial to decrease mortality, the definitive diagnosis is often challenging because of the lack of specificity of currently accepted diagnostic criteria and the absence of confirmatory gold standards. Because of the wide range of laboratory assays involved in the diagnosis of HLH, practicing pathologists from a broad spectrum of clinical specialties need to be aware of the disease so that they may appropriately flag results and convey them to their clinical counterparts. Our article summarizes these new advances in the diagnosis of HLH and includes a review of clinical findings, updated understanding of the pathogenesis, and promising new testing methods.
Collapse
|
36
|
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder resulting from immune dysfunction reflecting either primary immune deficiency or acquired failure of normal immune homeostasis. Familial HLH includes autosomal recessive and X-linked disorders characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines, secondary to defects in genes encoding proteins involved in granule-dependent cytolytic pathways. In older children and adults, HLH is associated more often with infections, malignancies, autoimmune diseases, and acquired immune deficiencies. HLH, macrophage activation syndrome, sepsis, and systemic inflammatory response syndrome are different clinical entities that probably represent a common immunopathological state, termed cytokine storm. These conditions may be clinically indistinguishable; all include massive inflammatory response, elevated serum cytokine levels, multi-organ involvement, haemophagocytic macrophages, and often death. Tissues of haematopoietic and lymphoid function are directly involved; other organs are secondarily damaged by circulating cytokines and chemokines. Haemophagocytic disorders are now increasingly diagnosed in the context of severe inflammatory reactions to viruses, malignancies and systemic connective tissue diseases. Many of these cases may reflect underlying genetic predispositions to HLH. The detection of gene defects has contributed considerably to our understanding of HLH, but the mechanisms leading to acquired HLH have yet to be fully determined.
Collapse
Affiliation(s)
- G Naheed Usmani
- Division of Pediatric Hematology and Oncology, University of Massachusetts Medical Center, Worcester, MA, USA
| | - Bruce A Woda
- Department of Pathology, UMass Memorial Medical Center, Worcester, MA, USA
| | - Peter E Newburger
- Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA
| |
Collapse
|
37
|
Chiossone L, Audonnet S, Chetaille B, Chasson L, Farnarier C, Berda-Haddad Y, Jordan S, Koszinowski UH, Dalod M, Mazodier K, Novick D, Dinarello CA, Vivier E, Kaplanski G. Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein. Front Immunol 2012; 3:239. [PMID: 22891066 PMCID: PMC3413989 DOI: 10.3389/fimmu.2012.00239] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 07/17/2012] [Indexed: 01/25/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8(+) T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.
Collapse
Affiliation(s)
- Laura Chiossone
- Centre d'Immunologie de Marseille-Luminy, INSERM, U 1104 Marseille, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
38
|
Abstract
PURPOSE OF REVIEW Recent studies pertaining to the histopathology of the liver and biliary tract are reviewed. RECENT FINDINGS Several studies are reviewed which describe the histologic features and clinical behavior of 'plasma cell hepatitis' in the posttransplant setting. Cytokeratin 7, EMA, and CD68 were found to be useful immunohistochemical stains in fibrolamellar hepatocellular carcinoma and may aid in the distinction between this variant and classic hepatocellular carcinoma. Arginase-1, another immunohistochemical stain, was found to have improved sensitivity over HepPar-1 in the diagnosis of classic hepatocellular carcinoma. Metabolic syndrome is common in children with nonalcoholic fatty liver disease and may be an indicator of more severe disease activity and fibrosis. Histologic features were described that may aid in the distinction between the steroid-responsive IgG4-associated cholangitis and the steroid-nonresponsive primary sclerosing cholangitis. In addition, immunohistochemical stains for IgM and IgG may be helpful in distinguishing between autoimmune liver diseases, with primary biliary cirrhosis and its antimitochondrial-negative variant, autoimmune cholangitis, being the two autoimmune liver diseases with a predominance of IgM-positive plasma cells. SUMMARY Several informative studies pertaining to hepatobiliary pathology were published this year, with topics including posttransplant plasma cell hepatitis, familial hemophagocytic lymphohistiocytosis, pediatric nonalcoholic fatty liver disease, and the use of immunohistochemical stains specific for various immunoglobulin subtypes.
Collapse
|