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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 2  |  Issue : 3  |  Page : 99-102

Hemophagocytic lymphohistiocytosis secondary to classic hodgkin lymphoma in a patient with decompensated chronic liver disease


1 Department of Gastroenterology, Apollo Hospital, Chennai, Tamil Nadu, India
2 Department of Pathology, Apollo Hospital, Chennai, Tamil Nadu, India
3 Department of Haematology, Apollo Hospital, Chennai, Tamil Nadu, India

Date of Submission20-Jun-2021
Date of Decision15-Mar-2022
Date of Acceptance15-May-2022
Date of Web Publication05-Jul-2022

Correspondence Address:
Kartik Natarajan
Flat Number 6, Second Floor, Gopalkunj, Srinivasa Pillai Street, West Mambalam, Chennai - 600 033, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ghep.ghep_33_21

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  Abstract 


Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It is characterized by fever, cytopenias, splenomegaly, jaundice, neurological symptoms, and hemophagocytosis in bone marrow, liver, or lymph nodes. Secondary HLH is commonly associated with hematological malignancies, particularly non-Hodgkin lymphoma. We report a case of a patient with liver decompensation with spontaneous bacterial peritonitis and fever of unknown origin caused by malignant infiltration by classic Hodgkin lymphoma and secondary HLH. The patient was managed with modified dose of adriamycin, bleomycin, vinblastine, and dexamethasone and showed response post two cycles and is planned for two more cycles. The case highlights the importance of investigating persistent fever and accurately diagnosing and promptly treating HLH which can otherwise have a rapidly fatal course.

Keywords: Chronic liver disease, Hodgkin lymphoma of the liver, secondary hemophagocytic lymphohistiocytosis, spontaneous bacterial peritonitis


How to cite this article:
Natarajan K, Jacob S, Prasad S, Pandurangan P, Palaniswamy KR. Hemophagocytic lymphohistiocytosis secondary to classic hodgkin lymphoma in a patient with decompensated chronic liver disease. Gastroenterol Hepatol Endosc Pract 2022;2:99-102

How to cite this URL:
Natarajan K, Jacob S, Prasad S, Pandurangan P, Palaniswamy KR. Hemophagocytic lymphohistiocytosis secondary to classic hodgkin lymphoma in a patient with decompensated chronic liver disease. Gastroenterol Hepatol Endosc Pract [serial online] 2022 [cited 2022 Aug 14];2:99-102. Available from: http://www.ghepjournal.com/text.asp?2022/2/3/99/349951




  Introduction Top


Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. We report a case of a patient with liver decompensation and fever of unknown origin caused by malignant infiltration by classic Hodgkin lymphoma and secondary HLH.


  Case Report Top


A 56-year-old man presented with complaints of fever, jaundice, and abdominal distension for 2 months. Fever was continuous, low grade, and not relieved by antipyretics. There were intermittent high-grade spikes associated with chills which responded transiently to antipyretics, 6 days preceding presentation. Jaundice was insidious in onset and gradually progressive. Abdominal distension was progressive with mild, intermittent flank pain. He had a clinical history of being diagnosed with cryptogenic liver disease (CLD) a year back which was biopsy proven.

Upon admission, he was febrile (39.6°C) and normotensive (110/70 mm/Hg) with a heart rate of 90 beats/min. Physical examination revealed pallor, bilateral pitting pedal edema, and icterus. He had flaps indicating Grade II hepatic encephalopathy and per abdomen examination revealed the presence of Grade II ascites and splenomegaly (3 cm). Initial basic laboratory studies on admission were notable for anemia (hemoglobin: 6.3 g/dL), leukopenia (white cell count: 2.31 × 103/uL), thrombocytopenia (platelet count: 80 × 103/μL), direct hyperbilirubinemia (total bilirubin: 12.2 mg/dl and direct: 9.8 mg/dl), elevated liver enzymes (SGOT: 459 U/L, SGPT: 117 U/L, and alkaline phosphatase: 296 U/L), and an elevated INR (2.35). Viral markers were negative and MELD Na score was 28. Serum AFP was 4 ng/ml and corrected reticulocyte count was 4. Ascitic fluid analysis revealed a high SAAG low protein ascites with evidence of spontaneous bacterial peritonitis (SBP); ascitic fluid polymorphonuclear cell count was 4960/mm3. Ascitic fluid cytology and culture, blood, and urine cultures were unremarkable. Endoscopy revealed small varices. Thus, a provisional diagnosis of decompensated CLD secondary to SBP with features of portal hypertension was made. The patient was treated with intravenous antibiotics, anti-encephalopathy measures, and other liver support medication.

Despite this, low-grade fever persisted. Repeat paracentesis showed resolution of the SBP. A peripheral blood smear showed microcytic hypochromic cells and leukopenia. Transferrin saturation was 8.5%, serum lactate dehydrogenase – 458, serum fibrinogen – 280, serum ferritin – 5113 ng/ml, and serum triglycerides – 70 mg/dl. Serum protein electrophoresis was unremarkable and direct antiglobulin test was negative. Bone marrow aspiration and biopsy revealed a normocellular marrow with increased macrophage activity and hemophagocytosis [Figure 1]. Abdominal computed tomography (CT) scan [Figure 2] revealed caudate lobe hypertrophy with a round hypodense lesion measuring 9 mm × 9 mm in the right lower lobe of the liver. A positron emission tomography scan [Figure 3] was done which showed multifocal fluorodeoxyglucose (FDG)-avid areas in the right lobe of the liver in segment VIII (15 mm × 15 mm, SUV max – 6.34), segment V (37 mm × 20 mm, SUV max – 5.79), and segment VI (48 mm × 40 mm, SUV max – 7.73). Segmental FDG uptake (16 mm, SUV max – 5.01) was noted in the proximal transverse colon, but colonoscopy was normal.
Figure 1: Bone marrow showing hemophagocytosis

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Figure 2: CT scan image showing small hypodense lesion in the right lower lobe of the liver (arrow), splenomegaly with enlarged portal vein. CT: Computed tomography

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Figure 3: PET-CT images showing increased uptake (arrows) in the liver in segments V, VI, and VIII. PET-CT: Positron emission tomography–computed tomography

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A liver biopsy from segment VI revealed portal infiltrate by few large cells with vesicular nuclei and multinucleate cells against a background of lymphocytes and edema with underlying CLD [Figure 4] and [Figure 5]. The large cells were positive for CD30 [Figure 6] and paired box 5 (PAX5) [Figure 7] and negative for leukocyte common antigen [Figure 8], CD15 [Figure 9], CD3, CD20, BOB-1, and anaplastic lymphoma kinase 1, thereby establishing a diagnosis of underlying classical Hodgkin lymphoma causing secondary HLH. There was no features suggestive of HLH in the liver.
Figure 4: Hematoxylin and eosin stain - Liver biopsy showing infiltrate by Hodgkin lymphoma

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Figure 5: Hematoxylin and eosin stain - Liver biopsy showing infiltrate by Hodgkin lymphoma

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Figure 6: CD30 positive liver biopsy

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Figure 7: PAX5 positive. PAX5: Paired box 5

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Figure 8: LCA negative. LCA: Leukocyte common antigen

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Figure 9: CD15 negative

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The patient was given two cycles of adriamycin, bleomycin, vinblastine, and dexamethasone protocol, i.e., adriamycin, bleomycin, vinblastine, and dexamethasone (50% reduction of adriamycin and vinblastine in view of underlying liver disease). Fever subsided and the serum ferritin level came down to 2504 ng/ml. The patient is planned for four further cycles with the abovementioned regimen.


  Discussion Top


HLH is a hyperinflammatory syndrome mediated by the uncontrolled activation of immune cells (macrophages, lymphocytes, and histiocytes) and elevated cytokines such as tumor necrosis factor-α, interleukin-6 (IL-6), interferon-γ, and macrophage inflammatory protein-1α.[1] It is characterized by fever, cytopenias, splenomegaly, jaundice, neurological symptoms, and hemophagocytosis in bone marrow, liver, or lymph nodes.[2] Secondary HLH is commonly associated with hematological malignancies, particularly non-Hodgkin lymphoma (NHL).[3]

In addition to SBP as a cause of decompensation, our patient presented with fever of unknown origin which was due to HLH secondary to classical Hodgkin's lymphoma with liver involvement.

The diagnosis of HLH is based on the criteria used in the HLH-2004 trial:[4],[5]

Heterozygosity of one of the genes together with clinical findings associated with HLH,[6],[7] or five of the following nine findings:

  • Fever ≥38.5°C
  • Splenomegaly
  • Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL (for infants <4 weeks, hemoglobin <10 g/dL), platelets <100,000/microL, and absolute neutrophil count <1000/microL
  • Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 mg/dL)
  • Hemophagocytosis in bone marrow, spleen, lymph node, or liver
  • Low or absent NK cell activity
  • Ferritin >3000 ng/mL[8]
  • Elevated soluble CD25 (soluble IL-2 receptor-alpha) two standard deviations above age-adjusted laboratory-specific norms
  • Elevated CXCL9.[9]


Our patient fulfilled six of the above criteria and responded promptly to steroid therapy. A hemato-oncologist was involved and chemotherapy was dose based on the patient profile.

Liver involvement in HLH, as seen in this patient, is nearly universal and results in elevation of liver enzymes.[10] Increased triglycerides and abnormal coagulation parameters (especially elevated D-dimer) caused by hepatic dysfunction and disseminated intravascular coagulopathy are also frequently seen.[11] There are studies describing various NHL as a cause of HLH and have been associated with a high mortality based on the malignancy and the type of presentation of the liver disease.[10],[12]


  Conclusion Top


Secondary HLH can be masked by signs of decompensation in a patient with underlying chronic liver disease. A high index of suspicion and prompt initiation of therapy can be lifesaving but still carries a high mortality.

Disclosures

Informed consent was obtained from the patient. All identifying information has been removed to protect patient privacy. The patient is still yet to undergo four cycles of chemotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.



 
  References Top

1.
Janka G. Hemophagocytic lymphohistiocytosis: When the immune system runs amok. Klin Padiatr 2009;221:278-85.  Back to cited text no. 1
    
2.
Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009;2009:127-31.  Back to cited text no. 2
    
3.
Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:435-44.  Back to cited text no. 3
    
4.
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.  Back to cited text no. 4
    
5.
Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, 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.  Back to cited text no. 5
    
6.
Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 2011;118:5794-8.  Back to cited text no. 6
    
7.
Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood 2018;132:89-100.  Back to cited text no. 7
    
8.
Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227-35.  Back to cited text no. 8
    
9.
Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med 2020;382:1811-22.  Back to cited text no. 9
    
10.
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.  Back to cited text no. 10
    
11.
Okamoto M, Yamaguchi H, Isobe Y, Yokose N, Mizuki T, Tajika K, et al. Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. Intern Med 2009;48:775-81.  Back to cited text no. 11
    
12.
Takahashi N, Chubachi A, Kume M, Hatano Y, Komatsuda A, Kawabata Y, et al. A clinical analysis of 52 adult patients with hemophagocytic syndrome: The prognostic significance of the underlying diseases. Int J Hematol 2001;74:209-13.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]



 

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