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Year : 2018  |  Volume : 61  |  Issue : 2  |  Page : 281-283
Hemophagocytic lymphohistiocytosis presenting with acute liver failure and central nervous system involvement in early infancy

1 Department of Pediatrics, Shri Ram Hospital, Jodhpur, Rajasthan, India
2 Department of Pathology, Super Religare Laboratories Limited, Jodhpur, Rajasthan, India
3 Department of Pediatrics, Dr SN Medical College, Jodhpur, Rajasthan, India
4 Department of Pediatrics, AIIMS, Jodhpur, Rajasthan, India

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Date of Web Publication20-Apr-2018


Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal and likely underdiagnosed disease characterized by unregulated histiocyte proliferation, hypercytokinemia and hemophagocytosis, causing life-threatening tissue damage and organ failure. We report a case of a 56-day-old infant presenting with fever, acute liver failure, and neurological manifestations as presenting features that succumbed to rapidly progressive HLH. Our objective is to emphasize the importance of early diagnosis by high suspicion in varied initial presentation of HLH so that life-saving therapy may be instituted in time.

Keywords: Acute liver failure, familial hemophagocytosis lymphohistiocytosis, infant, neurological manifestations

How to cite this article:
Kumar M, Kothari N, Gupta B D, Gupta N. Hemophagocytic lymphohistiocytosis presenting with acute liver failure and central nervous system involvement in early infancy. Indian J Pathol Microbiol 2018;61:281-3

How to cite this URL:
Kumar M, Kothari N, Gupta B D, Gupta N. Hemophagocytic lymphohistiocytosis presenting with acute liver failure and central nervous system involvement in early infancy. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Oct 19];61:281-3. Available from: https://www.ijpmonline.org/text.asp?2018/61/2/281/230544

   Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is characterized by the impaired function of natural killer cells, hyperactivation of antigen presenting cells and cytotoxic T cells, leading to hypercytokinemia and hyperinflammation, causing life-threatening tissue damage and organ failure. Primary or familial HLH (FHL) is associated with several known genetic mutations and presents usually at an early age (median age 2.9 months). Secondary or acquired HLH (sHLH) is caused by infection, malignancies, autoimmune diseases, metabolic disorders, prolonged intravenous nutrition, and acquired immune deficiency states. Fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, coagulopathy, liver dysfunction, and neurological symptoms are most typical findings of HLH.[1] We report a 56-day-old male infant with rapidly progressive HLH, presented primarily with acute liver failure and central nervous system (CNS) involvement.

   Case Report Top

A 56-day-old male infant was admitted with a complaint of fever, loose motions, vomiting, abdominal distension, increasingly drowsiness and refusal to feed for 3 days. The patient was full term, normal vaginal delivered with birth weight 3.5 kg. Antenatal, perinatal, and early infantile history was unremarkable. Antenatal screening of mother for hepatitis B, syphilis, and HIV was negative. There was no family history of consanguinity, sibling death or abortion.

At the time of admission, patient weighed 5.39 kg, length 58 cm, and head circumference 38.5 cm. Heart rate – 198/min, respiration rate – 100/min, temperature – 101.8°F by axilla and was maintaining 98% oxygen saturation on room air. There were no dysmorphic features, cyanosis, clubbing, edema, rash, petechiae, and significant lymphadenopathy. The patient was having pallor, icterus, and firm hepatosplenomegaly (liver – 6.5 cm and spleen – 5 cm). The patient was encephalopathic with brisk knee reflexes (3+). Rest of examination was unremarkable.

Initial hematological and biochemical values are shown in [Table 1]. Peripheral blood smear showed lymphocytic leukocytosis, thrombocytopenia, and no abnormal/immature cells or hemoparasites. Electrocardiogram showed sinus tachycardia. Chest X-ray cranial ultrasound, echocardiography, and opthalmologic evaluation were normal. Abdominal ultrasound revealed hepatosplenomegaly with hypoechoic liver parenchyma, few periportal lymph nodes, bilateral pleural effusion, and mild ascites. The patient was initially treated as acute liver failure and septicemia. Serum alpha-fetoprotein was 184.59 ng/ml and ANA titer was negative. Later, the patient had multiple episodes of generalized tonic seizures and became comatose. Cerebrospinal fluid (CSF) examination revealed very high protein 955.8 mg/dl and 186 cells/mm 3 with 13% neutrophils, 15% lymphocytes, and 72% histiocytes [Figure 1]c. The patient was evaluated for high suspicion of HLH. Serum lactate dehydrogenase (9440 U/L), ferritin (6866.39 ng/mL), and triglycerides level (1157 mg/dl) were very high. Viral serology for secondary causes of HLH was done, and hepatitis A virus IgM, hepatitis B virus surface antigen, hepatitis C virus IgM, hepatitis E virus IgM, Herpes Simplex virus IgM, HIV, cytomegalovirus IgM (<5 U/mL), and Epstein–Barr virus IgM (1.80 U/mL) were nonreactive. Blood and urine culture were sterile for any growth. The patient was continuously deteriorating with persistence of fever, anemia, and thrombocytopenia despite multiple transfusions of packed red cells and platelets, increasing ascites, deterioration of liver function test (serum glutamic oxaloacetic transaminase 5440 U/L, serum glutamic pyruvic transaminase 5570 U/L, serum bilirubin total/conjugated 11.85/5.1 mg/dl, and international normalized ratio 6.34), renal function impairment (blood urea 136 mg/dl and serum creatinine 0.86 mg/dl), and expired due to multiorgan failure. Bone marrow aspiration showed hypercellular marrow with histiocytic cells showing phagocytosed RBCs, erythroblasts, and neutrophils [Figure 1]a. Liver biopsy showed Kupffer cells hyperplasia with increased lymphocytic infiltrate in portal, periportal, and sinusoidal areas and aggregates of histiocytes showing phagocytosis of RBCs, neutrophils, and lymphocytes [Figure 1]b. No pathology was detected in oral mucosal biopsy. Soluble CD25 level found grossly elevated 3,569.49 IU/ml which confirmed the diagnosis of HLH [Table 2].[1]
Table 1: Initial hematological and biochemical profile

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Figure 1: Microphotograph of (a) bone marrow aspiration showing mononuclear histiocyte with engulfed erythrocyte (arrowhead) (Giemsa stain, ×100), (b) liver biopsy showing Kupffer cell hyperplasia with hemophagocytosis (arrow head) in H and E stain, (c) histiocyte with engulfed erythrocyte in cerebrospinal fluid ( Giemsa stain, ×40)

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Table 2: Diagnostic guidelines for hemophagocytic lymphohistiocytosis-2004

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   Discussion Top

The initial presentation of HLH may vary widely often leading to misdiagnosis, delaying the life-saving therapy. HLH can present as fever of unknown origin, anemia, thrombocytopenia, hepatitis/acute liver failure, coagulopathy, sepsis-like, Kawasaki like, and with neurologic abnormalities.[2]

HLH as a cause of acute liver failure was present in 2% of cases in <3 years of age, 1% in >3 years of age children, and in 2.7% of cases of neonates and infants <90 days.[3],[4] Liver involvement ranges from mild hepatitis to hepatic failure. Autopsy evaluation showed chronic persistent hepatitis.[1],[5]

CNS involvement in HLH, defined as the presence of neurological symptoms or an elevated WBC count in the CSF, reported in 10%–76% of all cases, either at presentation or during the course of the disease. Most common neurological manifestation reported is seizures followed by decrease consciousness, ataxia, irritability, hypotonia or hypertonia, meningismus, intracerebral hemorrhage, signs of increased intracranial pressure, cranial nerve palsies, focal neurological deficit, spastic quadriparesis, encephalopathy, and coma. Histopathological findings are lymphohistiocytic leptomeningitis with hemophagocytosis, parenchymal involvement with perivascular infiltrations, cerebral tissue necrosis, and demyelination. Neuroimaging findings consist of diffuse leptomeningeal and perivascular enhancement, patchy cortical and subcortical T2 signal hyperintensity, ventriculomegaly, hemorrhage, subdural fluid collections, diffuse atrophy, and nodular or ring enhancement of the parenchymal lesion.[6],[7]

In our case, primary HLH triggered by some acute illness is likely diagnosis, presented primarily with acute liver failure along with neurological manifestations possibly due to HLH, supported by CSF finding. However, we were not able to perform familial testing and sHLH may be a possibility secondary to infections (including congenital infection).

FHL is a fatal disease with a median survival of <2 months after diagnosis if untreated.[1] Overall, patients presenting with acute liver failure and with CNS disease achieve poorer outcomes. Neurological sequelae were reported in long-term survivors.[5],[6] Early diagnosis and prompt initiation of the treatment are the main prognostic factors. Treatment is applied according to HLH 2004 protocol.[1]

In conclusion, acute liver failure and neurological manifestations can present early in the course in HLH, leading to poorer outcome if lifesaving therapy is not instituted on time.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Hemophagocytic Lymphohistiocytosis Study Group. Histiocyte Society. Treatment Protocol of the Second International HLH Study 2004. HLH; 2004.  Back to cited text no. 1
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. 2
Squires RH Jr., Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: The first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652-8.  Back to cited text no. 3
Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH; Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure. J Pediatr 2011;159:813-80.  Back to cited text no. 4
Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology 1998;32:310-6.  Back to cited text no. 5
Kim MM, Yum MS, Choi HW, Ko TS, Im HJ, Seo JJ, et al. Central nervous system (CNS) involvement is a critical prognostic factor for hemophagocytic lymphohistiocytosis. Korean J Hematol 2012;47:273-80.  Back to cited text no. 6
Kollias SS, Ball WS Jr., Tzika AA, Harris RE. Familial erythrophagocytic lymphohistiocytosis: Neuroradiologic evaluation with pathologic correlation. Radiology 1994;192:743-54.  Back to cited text no. 7

Correspondence Address:
Mukesh Kumar
51-A, Sector D, Shankar Nagar, Choupasni, Jodhpur, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_264_17

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  [Figure 1]

  [Table 1], [Table 2]

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