Hemophagocytic lymphohistiocytosis is a rare and life-threatening systemic disease that can cause hepatic infiltration and present as acute liver failure. Here, we report a case of a 3-year-old pediatric patient who presented with acute liver failure and hepatic encephalopathy secondary to hemophagocytic lymphohistiocytosis. She had left lateral segment liver transplant from her father. After 27 months, she had bone marrow transplant from her sister. At the time of reporting (36 months after liver transplant), she showed normal liver function and blood peripheral counts. We found that liver transplant can be a curative treatment for this type of rare disorder, not only to improve the quality of life but also to prolong survival.
Key words : Acute liver failure, Bone marrow transplant, Living-donor liver transplantation
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening multisystemic syndrome that is characterized by ineffective and uncontrolled immune responses. It is potentially fatal and particularly affects infants and children. Hemophagocytic lymphohistiocytosis is usually triggered by inherited and acquired factors.1 The diagnosis of this syndromic disorder is based on a unique pattern of clinical and laboratory findings. At clinical presentation, patients generally present with unremitting fever, splenomegaly, and cytopenia.2 Patients with HLH almost always have evidence of hepatitis that ranges in severity. Hemophagocytic lymphohistiocytosis can be a rare cause of acute liver failure in children, resulting in poor prognosis and mortality rates of between 67% and 100%.3 In the setting of acute liver failure, diagnosis of HLH can be challenging because of overlapping symptoms and signs from uncontrolled immune activation and dysregulation. Therefore, many of these patients are referred to hospitals with acute liver failure of unknown causes. Here, we report the longest known liver transplant survivor of acute liver failure associated with HLH according to our data search.
A 3-year-old female child was followed for hepatosplenomegaly at another center for 2 years. During the last 6 months of follow-up, she developed pancytopenia. She was admitted to the same center with jaundice, which lasted for 2 weeks, during which time she also had another episode of hepatosplenomegaly. Her laboratory tests revealed negative viral markers and negative liver autoimmune markers. Dysfunctional B cells were seen in her lymphocyte subset. A liver biopsy was conducted, showing hepatocellular injury and necrosis. During follow-up, her total bilirubin and direct bilirubin levels increased and thrombocyte and white blood cell counts decreased.
She was referred to our center with jaundice, lactic acidosis, resistant high-grade fever, and hepatic encephalopathy. Although her vital findings were stable, she was unconscious with positive light reflex, positive clonus, and increased deep tendon reflex. She had multiple ecchymosis all over her body. Her liver was palpable 5 cm below the right costal margin, and her spleen was palpable 8 cm below from the left costal margin.
Laboratory tests showed a hemoglobin level of 14.2 g/dL, white blood cell count of 3570/mm3, thrombocyte count of 84 600/mm3, creatinine level of 0.86 mg/dL, total bilirubin level of 33.1 mg/dL, direct bilirubin level of 23.1 mg/dL, alanine aminotransferase level of 496 mg/dL, aspartate aminotransferase level of 752 mg/dL, and lactate level of 3.9 mmol/L. She had coagulopathy with international normalized ratio of 2.96. Viral markers for cytomegalovirus, herpes simplex, hepatitis A, hepatitis B, hepatitis C, hepatitis E, human immunodeficiency virus, and parvovirus were all negative. All cultures and autoimmune markers were also negative. Serum α1-antitrypsin level was 142 mg/dL (normal range, 110-280 mg/dL), ceruloplasmin was 48.6 mg/dL, and alpha-fetoprotein was 0.7 IU/mL. Niemann-Pick and Gaucher enzymes were negative. The lysosomal acid lipase value was 0.11 nmol/punch/h (normal range, 0.37-2.3 nmol/punch/h). Tandem mass spectrometry results showed no pathologic amino acid or carnitine findings. Urine evaluation showed normal organic acid levels. Hematologic evaluation showed haptoglobin level of 1 mg/dL (normal range, 11-220 mg/dL), negative indirect and direct Coombs tests, glucose-6-phosphate dehydrogenase level of 11.2 U/g (normal range, 4.6-15.5 U/g), and a higher than normal ferritin level (1286 ng/mL).
We also evaluated bone marrow aspirates, which revealed hypocellularity with erythroid series dominancy. There was dysmorphia in all erythroid, monocytic, neutrophilic, and megakaryocyte series. Hemophagocytic histiocytes were seen in the bone marrow aspirate (Figure 1). Immunologic tests showed normal immunoglobulin (Ig) A, IgM, IgG, and IgE values. The lymphocyte subgroup analyses showed 62% lymphocytes, 59% CD3-positive T lymphocytes, 46% CD3/CD4-positive T4 lymphocytes, 12% CD3/CD8-positive T8 lymphocytes, 30% CD19-positive B lymphocytes, and 32% CD20-positive B lymphocytes. Doppler ultrasonography of the liver showed normal vascular anatomy but increased echogenicity of liver parenchyma and splenomegaly. Computed tomography scans showed hepatomegaly and splenomegaly. No brain edema was seen in the cranial computed tomography scans.
The diagnostic tests for the cause of acute liver failure were unrevealing except for HLH. She had hepatosplenomegaly, resistant fever, pancytopenia, and decreased natural killer (NK) cell activity. According to these positive parameters, she was diagnosed with acute liver failure due to HLH.
In March 2015, the patient received a living-donor liver transplant of left lateral segments from her father. Postoperative recovery was uneventful, and the patient regained full consciousness in 3 days. Cyclosporine and mycophenolate mofetil were given as immunosuppression. The pathology of the explanted liver revealed dense mixed inflammatory cell infiltrate and extensive necrosis of the parenchyma (Figure 2). She was discharged from the hospital on day 20 after transplant. Dexamethasone was added to her immunosuppression protocol,and 3 doses of etoposide were given for HLH. She continued HLH therapy with 10 mg/m2 dexamethasone administered every 15 days for 7 months. She was also evaluated for central nervous system involvement of HLH. A lumbar puncture showed normal cerebrospinal fluid cytology; therefore, intrathecal therapy was not given. The genetic results for HLH revealed c.676G>T homozygote mutation on STX11 gene. A hematopoietic stem cell transplant (HSCT) from her fully HLA-matched sister was performed 13 months after liver transplant. Her immunosupression regimen was changed from cyclosporine to everolimus. At 36-month follow-up posttransplant, she continues to have normal liver function.
Hemophagocytic lymphohistiocytosis syndrome was first described by Scott and Robb Smith in 1939, which was known at that time as histolytic medullary reticulosis. The syndrome is characterized by hyperinflammation, which results in increased cytokine production and impaired NK and cytotoxic T-cell production.4 The overproduction of cytokines, such as interferon gamma, tumor necrotic factor α, interleukin (IL) 1, and IL-6, results in widespread hemophagocytosis and host tissue destruction.5 The Histiocyte Society proposed a standard definition of HLH in 1994, which was later revised in 2004.6 Because HLH is rare and presentation is variable, the diagnosis is challenging. Patients with primary or familial hemophagocytic lymphocytosis, an autosomal recessive and fatal disease, have poor survival without treatment. Secondary hemophagocytic syndrome develops due to a strong immunologic activation response that is usually caused by severe infections.7
According to the HLH 2004 criteria, a diagnosis of HLH may be established if a patient demonstrates a molecular diagnosis consistent with HLH, including pathologic mutations or presence of 5 or more of established symptoms (fever ≥ 38.5°C; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in bone marrow, liver, spleen, or lymph nodes; low or absent NK cell activity; ferritin ≥ 500 ng/mL; and soluble IL-2 receptor level ≥ 2400 U/mL).6 Hemophagocytosis in bone marrow, liver, spleen, or lymph nodes is not essential or pathognomonic for HLH diagnosis.8
Management of HLH is aimed at suppressing the underlying inflammatory response. In the HLH 1994 protocol, treatment included dexamethasone, etoposide, cyclosporine, and intrathecal methotrexate. The HLH 2004 guidelines have included early initiation of cyclosporine, antithymocyte globulin, and alemtuzumab-based protocols.9 However, in patients with persistent disease or disease reactivation, HSCT is recommended as a potential cure.2
Liver involvement in HLH is common, and hepatic dysfunction can range from mild elevation of transaminases to liver failure. Hemophagocytic lymphohistiocytosis has been described as a rare cause of acute liver failure in previous studies.3 Case series studies have reported death in 7 of 8 patients due to acute liver failure caused by HLH.9-12 However, HLH is a controversial indication for liver transplant due to the risk of posttransplant HLH recurrence.13 Despite this risk, liver transplant is still the best option of a potentially lifesaving intervention that allows for better quality of life.14
In our patient, the diagnostic work-up regarding cause of acute liver failure was challenging, but the patient’s immune dysregulation and hyperinflammation guided us to reach a final diagnosis of acute liver failure secondary to HLH. Our patient met the HLH 2004 diagnostic criteria, showing persistent fever ≥ 38.5°C, splenomegaly, cytopenia, hypofibrinogenemia (83 mg/dL), hemophagocytosis in bone marrow, low NK cell activity, and hyperferritinemia. Hemophagocytic histiocytes in the bone marrow aspirates and the pathology of the explanted liver confirmed the diagnosis (Figures 1 and 2). Because of rapid progression of the disease, a diagnosis of HLH is sometimes confirmed after liver transplant, although our patient was diagnosed before liver transplant. Despite the concern for recurrent HLH posttransplant, our patient was successfully treated with living-donor liver transplant. In regard to the immunosuppressive protocol, which is still not clear for these patients but should aim to prevent HLH recurrence and graft rejection, our patient first received cyclosporine and mycophenolate mofetil, with dexamethasone added later and 3 doses of etoposide given for HLH. Therapy for HLH continued with 10 mg/m2 dexamethasone every 15 days for 7 months. After genetic results revealed c.676G>T homozygote mutation on the STX11 gene, HSCT was performed, with immunosuppression changed from cyclosporine to everolimus. At 36 months posttransplant, liver functions have remained normal.
Our case suggests that HLH should be kept in mind in the diagnostic work-up of acute liver failure. We showed that, in a patient with familial-type HLH disease, liver transplant combined with posttransplant HLH therapy and HSCT safely led to successful patient outcome. This case is important as it reports the longest liver transplant survivor of acute liver failure associated with HLH.
Volume : 17
Issue : 1
Pages : 226 - 229
DOI : 10.6002/ect.MESOT2018.P80
From the Departments of 1Transplantation, 2Pediatric Hematology,
Gastroenterology, and 4Anesthesiology, Baskent University, Ankara, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Ebru H. Ayvazoğlu Soy, Baskent University Faculty of Medicine, Department of General Surgery, 53.sok No:48 06490 Bahçelievler, Ankara, Turkey
Phone: + 90 312 2036868-1159
Figure 1. Hemophagocytic Histiocytes Are Shown in Bone Marrow Aspirates (×100 Magnification)
Figure 2. Pathology of the Explanted Liver Shows Dense Mixed Inflammatory Cell Infiltrate and Extensive Necrosis of Liver Parenchyma