- Email: [email protected]
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis After Minimal Change Disease
DIAGNOSTIC DILEMMA Thomas J. Marrie, MD, Section Editor
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis After Minimal Change Disease Kai Rou Tey, MD,a Kristen Barrett, MD,b Richa Jain, MD,c Thomas D. Boyer, MD,b Archita Desai, MDb a
Department of Internal Medicine, University of Arizona College of Medicine South Campus, Tucson; bDepartment of Gastroenterology, University of Arizona College of Medicine, Tucson; cDepartment of Pathology, University of Arizona College of Medicine, Tucson.
PRESENTATION Jaundice, dark urine, and pruritus were the symptoms of a healthy 31-year-old woman who presented to our hepatology clinic. The patient was healthy until December 2014 when she presented with generalized edema and proteinuria. Kidney biopsy showed adult-onset minimal change disease, and she was treated with prednisone for 1 month and received ciprofloxacin within this period. Proteinuria resolved, and prednisone was discontinued. She remained well until 1 month later when she presented with pruritus and dark urine. Liver test results were deranged (Table 1). She was referred to the University of Arizona where an extensive workup was negative and she was diagnosed with idiopathic cholestasis. She reported taking a supplement product containing turmeric, bromelain, and cayenne powder for 1 month before developing jaundice and pruritus. She was treated with ursodeoxycholic and cholestyramine. When liver test results failed to improve, prednisone 20 mg/day was added. There was some improvement in symptoms and liver test results, but jaundice persisted. Six months into her present illness, she was found to have sudden worsening liver test results, and she was admitted for evaluation. Other than feeling fatigue and generalized pruritus, she did not have any additional symptoms. Liver biopsy showed marked ductopenia with chronic cholestasis and presence of focal periportal and centrilobular fibrosis (Figures 1 and 2). She was discharged,
Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Kai Rou Tey, MD, Department of Internal Medicine, University of Arizona College of Medicine South Campus, 2800 E Ajo Way, 85713 Tucson, AZ. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.05.029
and evaluation for liver transplantation was initiated. Two weeks later, she presented with intermittent fever up to 39.4 C, associated with cough, generalized headache, and blurring of vision.
ASSESSMENT On admission, she was febrile and hypotensive but alert and oriented. Physical examination was notable for jaundice and new splenomegaly. Infectious workup, which included blood and sputum cultures, and chest radiograph, was unremarkable. Serology for human immunodeficiency virus; hepatitis A, B, and C; and interferon-gamma release assay for tuberculosis was negative. Her antinuclear antibody, mitochondrial antibody, and anti-liver-kidney-microsome antibody were negative. Ebstein-Barr virus immunoglobulin-M and G were negative. Human cytomegalovirus immunoglobulin M was negative, but cytomegalovirus immunoglobulin G was positive with quantitative polymerase chain reaction of 1570 IU/mL. Ferritin was elevated at 2891 ng/mL (normal: 5-204 ng/mL). Cerebrospinal fluid analysis was unremarkable. She became progressively neutropenic on the third day of admission (Table 1). She was also noted to be more lethargic. Magnetic resonance imaging of the brain was remarkable for left frontal and anterior temporal lobe encephalomalacia thought to be due to remote trauma. Magnetic resonance cholangiopancreatography showed a markedly enlarged spleen (Figure 3). Rheumatology was consulted because she had continued dry eyes and blurring of vision. Repeat workup was negative for autoimmune causes (antinuclear antibody, anti-Ro antibody, anti-La antibody), negative for parvovirus B19 immunoglobulin M antibody, but significant for increasing ferritin up to 11,713 ng/mL. Together with the constellation of symptoms of pancytopenia and new splenomegaly, this
2 Table 1
The American Journal of Medicine, Vol -, No -,
-
2016
Selected Laboratory Values
Laboratory Value White blood cells (k/mL) % of neutrophils Hemoglobin (g/L) Platelets (k/mL) ALT (m/L) AST (m/L) Alkaline phosphatase (m/L) Total bilirubin (mg/dL) PT-INR
6 mo Before 5 mo Before 2 wks Before Day of Normal Range Admission Admission Admission Admission Hospital Day 5
Hospital Day 10
4.0-11.0
0.3 8.5 171 91 46 509 38.0 2.2
11.5-15.5 150-450 0-55 5-34 40-150 0.2-1.2
Albumin (g/dL) 3.5-4.9 Blood urea nitrogen (mg/dL) 6-20 Creatinine (mg/dL) 0.5-1.0 Fibrinogen (mg/dL) 200-430
731 417 190 10.7 1.3 3.7 -
41 61 154 17.5 1.7 3.5
9.3 84.0 11.6 293 548 455 2555 41.1 2.5
5.0 88.0 9.3 144 147 105 611 29.2 5.7
2.3 12 0.8
1.7 20 0.9 645
0.6 2.0 7.9 146 133 84 619 31.9 1.1 (patient was given vitamin K and FFP) 1.8 10 0.7 -
2.0 12 1.0 817
ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; PT-INR ¼ prothrombin time-international normalized ratio; FFP ¼ fresh-frozen plasma.
raised concern for hemophagocytic lymphohistiocytosis. Peripheral blood smear showed severe normocytic normochromic anemia with anisopoikilocytosis and leukopenia with absolute neutropenia. Bone marrow biopsy showed hypocellular marrow with prominent hemophagocytosis (Figure 4). Flow cytometry showed no B- or T-cell clonal abnormalities.
DIAGNOSIS A diagnosis of vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis was made. The patient’s initial presentation of cholestatic liver injury was thought to be related to drug-induced liver injury, perhaps turmeric or the contents in the herbal products that she took before the development of symptoms. Initial imaging ruled out biliary obstruction and primary sclerosing cholangitis.
Liver biopsy did not support “overlap” syndromes of autoimmune cholangitis/hepatitis. Drug-related cholestasis will normally resolve after the cessation of the offending drug. In rare cases, persistence of a self-propagating immune response may lead to vanishing bile duct syndrome due to progressive destruction of bile duct.1 Ductopenia can be diagnosed by estimating the percentage of portal tracts that are devoid of interlobular duct or by calculating the ratio of interlobular ducts to the number of portal tracts.2 Liver biopsy in this patient showed significant ductopenia (>50% of portal tracts are devoid of interlobular ducts) supporting the diagnosis of vanishing bile duct syndrome. Our patient’s constellation of symptoms met the criteria for the diagnosis of secondary hemophagocytic lymphohistiocytosis (Table 2),3 which develops as a result of immune-mediated activation associated with infections, malignancies, or autoimmune disorders.4 Persistent
Figure 1 Liver needle biopsy: 200, hematoxylin-eosin (A) and 400, Periodic acideSchiff with diastase (B). The lobules show prominent cholestasis and Kupffer cell hyperplasia with mild inflammation.
Tey et al
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis
3
Figure 2 Liver needle biopsy: (A) 400, hematoxylin-eosin: The portal tracts show the hepatic artery without an accompanying bile duct. There is prominent ductular reaction with neutrophilic infiltrate. The loss of bile ducts is highlighted by trichrome stain (B, 400) and immunohistochemical stain (C, 200) for cytokeratin 19 (200, Clone A53-B/A2.26, Ventana, Roche, Tucson, AZ).
activation of immune system results in high cytokine levels, leading to the hyperinflammatory state.5 Severe cases of drug hypersensitivity may lead to hemophagocytic syndromes; postulated mechanisms include activation of macrophages that produce cytokines.6
To our knowledge, this is the second case report on a patient with vanishing bile duct syndrome with hemophagocytic lymphohistiocytosis. Li et al7 reported a case of immune-mediated intrahepatic duct destruction triggered by amoxicillin-clavulanate in a patient with autoimmune
Figure 3 Magnetic resonance cholangiopancreatography coronal view showing markedly enlarged spleen, measuring 21.5 cm (right) compared with prior imaging 4 months ago (left). The liver appeared normal in size and configuration, there is no intrahepatic or extrahepatic biliary ductal dilation, and the gallbladder is absent.
4
The American Journal of Medicine, Vol -, No -,
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2016
Our case is unique in that the patient was also diagnosed with minimal change disease of the kidney 1 year before this presentation. It is postulated that the increased glomerular permeability in these patients is due to the circulating factor secreted by immature T cells.9 Minimal change in disease has been associated with drugs, infections, and malignancy, particularly hematologic malignancy.10 The coexistence of vanishing bile duct syndrome, hemophagocytic lymphohistiocytosis, and adult-onset minimal change disease suggests that the underlying mechanisms probably are due to the sustained immune activation, leading to persistently high cytokine levels, resulting in multiorgan failure.
Figure 4 Bone marrow biopsy showing hypocellular bone marrow, with prominent hemophagocytosis. There are virtually no myeloid progenitors. Noted: foamy cytoplasm of histocyte.
disorder with coexisting hemophagocytic lymphohistiocytosis. Schneier et al8 described 3 patients who presented with acute liver failure as the initial manifestation of secondary hemophagocytic lymphohistiocytosis. Two of the patients had histiocytes with hemophagocytosis seen within the hepatic sinusoids with a background of portal fibrosis on liver biopsy.8 Our patient’s liver biopsy was reviewed by 2 different groups of pathologists, who concluded that there was no evidence of hemophagocytosis. Although rare, it is important to raise suspicion for hemophagocytic lymphohistiocytosis in a patient who presents with liver decompensation given the overlapping clinical picture. Table 2 Diagnosis Lymphohistiocytosis
Criteria
for
Hemophagocytic
Criteria
Definitions
Fever Splenomegaly Cytopenia (affecting 2 of 3 lineages in the peripheral blood) Hypertriglyceridemia and/or hypofibrinogenemia Hemophagocytosis in bone marrow or spleen or lymph nodes Low or absent Natural Killer cell activity Hyperferritinemia High soluble CD25 (ie, soluble IL-2 receptor)
Temperature >38.5 C Hemoglobin <9 g/dL Platelet <100 k/mL Neutrophils <1.0 k/mL Fasting triglyceride >265 mg/dL, Fibrinogen 150 mg/dL And no evidence of malignancy
Ferritin 500 mg/L 2400 U/mL
Five of the 8 criteria must be present. IL ¼ interleukin. Adapted from Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131.3
MANAGEMENT Management of the coexisting diseases in this patient was challenging. The fundamental principles in the management of hemophagocytic lymphohistiocytosis consist of 2 components: (1) eradication of the underlying inciting agent or trigger and controlling the overactivation of immune system and (2) reducing production of cytokines. The recommended standard protocol for hemophagocytic lymphohistiocytosis consists of etoposide and dexamethasone with or without cyclosporine, according to the established study Hemophagocytic Lymphohistiocytosis 2004.3 However, because of the albumin-bound property of etoposide, the presence of severe impairment of liver and hypoalbuminemia in our patient made the treatment more challenging because hypoalbuminemia may increase the effective dosing of the medications.11 The anticholestatic effect of ursodeoxycholic acid seems to be effective in patients with vanishing bile duct secondary to primary biliary cirrhosis because of its effect on the stimulation of biliary secretions and antiapoptotic effect.12 However, its role in drug-induced vanishing bile duct syndrome remains limited.13 For our patient with progressive liver failure, liver transplantation, the mainstay of treatment, was deemed contraindicated because of her coexisting hemophagocytic lymphohistiocytosis. This complex case was managed through a multidisciplinary team approach: hematology-oncology, rheumatology, infectious disease, and critical. Our patient received the treatment for hemophagocytic lymphohistiocytosis, with dose adjustment of etoposide and dexamethasone in the hopes of achieving clinical remission for hemophagocytic lymphohistiocytosis and providing potentially curative treatment through hematopoietic cell transplantation. Unfortunately, her course of hospitalization was complicated by disseminated Aspergillus infection, and she died of cardiac arrest secondary to septic shock on day 31 of her hospitalization.
References 1. Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced cholestasis. Hepatology. 2011;53:1377-1387. 2. Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease. J Hepatol. 1997;26(Suppl 1):31-35.
Tey et al
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis
3. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131. 4. Chang CS, Wang CH, Su IJ, Chen YC, Shen MC. Hematophagic histiocytosis: a clinicopathologic analysis of 23 cases with special reference to the association with peripheral T-cell lymphoma. J Formos Med Assoc. 1994;93:421-428. 5. Janka GE, Lehmberg K. Hemophagocytic syndromesean update. Blood Rev. 2014;28:135-142. 6. Lambotte O, Costedoat-Chalumeau N, Amoura Z, Piette JC, Cacoub P. Drug-induced hemophagocytosis. Am J Med. 2002;112:592-593. 7. Li H, Li X, Liao XX, et al. Drug associated vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis. World J Gastrointest Endosc. 2012;4:376-378. 8. Schneier A, Stueck AE, Petersen B, Thung SN, Perumalswami P. An unusual cause of acute liver failure: three cases of hemophagocytic
9.
10. 11. 12.
13.
5
lymphohistiocytosis presenting at a transplant center. Semin Liver Dis. 2016;36:99-106. Sellier-Leclerc AL, Duval A, Riveron S, et al. A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J Am Soc Nephrol. 2007;18: 2732-2739. Dabbs DJ, Striker LM, Mignon F, Striker G. Glomerular lesions in lymphomas and leukemias. Am J Med. 1986;80:63-70. Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125:2908-2914. Pusl T, Beuers U. Ursodeoxycholic acid treatment of vanishing bile duct syndromes. World J Gastroenterol. 2006;12: 3487-3495. Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015;62(1 Suppl):S25-S37.
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis After Minimal Change Disease Kai Rou Tey, MD,a Kristen Barrett, MD,b Richa Jain, MD,c Thomas D. Boyer, MD,b Archita Desai, MDb a
Department of Internal Medicine, University of Arizona College of Medicine South Campus, Tucson; bDepartment of Gastroenterology, University of Arizona College of Medicine, Tucson; cDepartment of Pathology, University of Arizona College of Medicine, Tucson.
PRESENTATION Jaundice, dark urine, and pruritus were the symptoms of a healthy 31-year-old woman who presented to our hepatology clinic. The patient was healthy until December 2014 when she presented with generalized edema and proteinuria. Kidney biopsy showed adult-onset minimal change disease, and she was treated with prednisone for 1 month and received ciprofloxacin within this period. Proteinuria resolved, and prednisone was discontinued. She remained well until 1 month later when she presented with pruritus and dark urine. Liver test results were deranged (Table 1). She was referred to the University of Arizona where an extensive workup was negative and she was diagnosed with idiopathic cholestasis. She reported taking a supplement product containing turmeric, bromelain, and cayenne powder for 1 month before developing jaundice and pruritus. She was treated with ursodeoxycholic and cholestyramine. When liver test results failed to improve, prednisone 20 mg/day was added. There was some improvement in symptoms and liver test results, but jaundice persisted. Six months into her present illness, she was found to have sudden worsening liver test results, and she was admitted for evaluation. Other than feeling fatigue and generalized pruritus, she did not have any additional symptoms. Liver biopsy showed marked ductopenia with chronic cholestasis and presence of focal periportal and centrilobular fibrosis (Figures 1 and 2). She was discharged,
Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Kai Rou Tey, MD, Department of Internal Medicine, University of Arizona College of Medicine South Campus, 2800 E Ajo Way, 85713 Tucson, AZ. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.05.029
and evaluation for liver transplantation was initiated. Two weeks later, she presented with intermittent fever up to 39.4 C, associated with cough, generalized headache, and blurring of vision.
ASSESSMENT On admission, she was febrile and hypotensive but alert and oriented. Physical examination was notable for jaundice and new splenomegaly. Infectious workup, which included blood and sputum cultures, and chest radiograph, was unremarkable. Serology for human immunodeficiency virus; hepatitis A, B, and C; and interferon-gamma release assay for tuberculosis was negative. Her antinuclear antibody, mitochondrial antibody, and anti-liver-kidney-microsome antibody were negative. Ebstein-Barr virus immunoglobulin-M and G were negative. Human cytomegalovirus immunoglobulin M was negative, but cytomegalovirus immunoglobulin G was positive with quantitative polymerase chain reaction of 1570 IU/mL. Ferritin was elevated at 2891 ng/mL (normal: 5-204 ng/mL). Cerebrospinal fluid analysis was unremarkable. She became progressively neutropenic on the third day of admission (Table 1). She was also noted to be more lethargic. Magnetic resonance imaging of the brain was remarkable for left frontal and anterior temporal lobe encephalomalacia thought to be due to remote trauma. Magnetic resonance cholangiopancreatography showed a markedly enlarged spleen (Figure 3). Rheumatology was consulted because she had continued dry eyes and blurring of vision. Repeat workup was negative for autoimmune causes (antinuclear antibody, anti-Ro antibody, anti-La antibody), negative for parvovirus B19 immunoglobulin M antibody, but significant for increasing ferritin up to 11,713 ng/mL. Together with the constellation of symptoms of pancytopenia and new splenomegaly, this
2 Table 1
The American Journal of Medicine, Vol -, No -,
-
2016
Selected Laboratory Values
Laboratory Value White blood cells (k/mL) % of neutrophils Hemoglobin (g/L) Platelets (k/mL) ALT (m/L) AST (m/L) Alkaline phosphatase (m/L) Total bilirubin (mg/dL) PT-INR
6 mo Before 5 mo Before 2 wks Before Day of Normal Range Admission Admission Admission Admission Hospital Day 5
Hospital Day 10
4.0-11.0
0.3 8.5 171 91 46 509 38.0 2.2
11.5-15.5 150-450 0-55 5-34 40-150 0.2-1.2
Albumin (g/dL) 3.5-4.9 Blood urea nitrogen (mg/dL) 6-20 Creatinine (mg/dL) 0.5-1.0 Fibrinogen (mg/dL) 200-430
731 417 190 10.7 1.3 3.7 -
41 61 154 17.5 1.7 3.5
9.3 84.0 11.6 293 548 455 2555 41.1 2.5
5.0 88.0 9.3 144 147 105 611 29.2 5.7
2.3 12 0.8
1.7 20 0.9 645
0.6 2.0 7.9 146 133 84 619 31.9 1.1 (patient was given vitamin K and FFP) 1.8 10 0.7 -
2.0 12 1.0 817
ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; PT-INR ¼ prothrombin time-international normalized ratio; FFP ¼ fresh-frozen plasma.
raised concern for hemophagocytic lymphohistiocytosis. Peripheral blood smear showed severe normocytic normochromic anemia with anisopoikilocytosis and leukopenia with absolute neutropenia. Bone marrow biopsy showed hypocellular marrow with prominent hemophagocytosis (Figure 4). Flow cytometry showed no B- or T-cell clonal abnormalities.
DIAGNOSIS A diagnosis of vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis was made. The patient’s initial presentation of cholestatic liver injury was thought to be related to drug-induced liver injury, perhaps turmeric or the contents in the herbal products that she took before the development of symptoms. Initial imaging ruled out biliary obstruction and primary sclerosing cholangitis.
Liver biopsy did not support “overlap” syndromes of autoimmune cholangitis/hepatitis. Drug-related cholestasis will normally resolve after the cessation of the offending drug. In rare cases, persistence of a self-propagating immune response may lead to vanishing bile duct syndrome due to progressive destruction of bile duct.1 Ductopenia can be diagnosed by estimating the percentage of portal tracts that are devoid of interlobular duct or by calculating the ratio of interlobular ducts to the number of portal tracts.2 Liver biopsy in this patient showed significant ductopenia (>50% of portal tracts are devoid of interlobular ducts) supporting the diagnosis of vanishing bile duct syndrome. Our patient’s constellation of symptoms met the criteria for the diagnosis of secondary hemophagocytic lymphohistiocytosis (Table 2),3 which develops as a result of immune-mediated activation associated with infections, malignancies, or autoimmune disorders.4 Persistent
Figure 1 Liver needle biopsy: 200, hematoxylin-eosin (A) and 400, Periodic acideSchiff with diastase (B). The lobules show prominent cholestasis and Kupffer cell hyperplasia with mild inflammation.
Tey et al
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis
3
Figure 2 Liver needle biopsy: (A) 400, hematoxylin-eosin: The portal tracts show the hepatic artery without an accompanying bile duct. There is prominent ductular reaction with neutrophilic infiltrate. The loss of bile ducts is highlighted by trichrome stain (B, 400) and immunohistochemical stain (C, 200) for cytokeratin 19 (200, Clone A53-B/A2.26, Ventana, Roche, Tucson, AZ).
activation of immune system results in high cytokine levels, leading to the hyperinflammatory state.5 Severe cases of drug hypersensitivity may lead to hemophagocytic syndromes; postulated mechanisms include activation of macrophages that produce cytokines.6
To our knowledge, this is the second case report on a patient with vanishing bile duct syndrome with hemophagocytic lymphohistiocytosis. Li et al7 reported a case of immune-mediated intrahepatic duct destruction triggered by amoxicillin-clavulanate in a patient with autoimmune
Figure 3 Magnetic resonance cholangiopancreatography coronal view showing markedly enlarged spleen, measuring 21.5 cm (right) compared with prior imaging 4 months ago (left). The liver appeared normal in size and configuration, there is no intrahepatic or extrahepatic biliary ductal dilation, and the gallbladder is absent.
4
The American Journal of Medicine, Vol -, No -,
-
2016
Our case is unique in that the patient was also diagnosed with minimal change disease of the kidney 1 year before this presentation. It is postulated that the increased glomerular permeability in these patients is due to the circulating factor secreted by immature T cells.9 Minimal change in disease has been associated with drugs, infections, and malignancy, particularly hematologic malignancy.10 The coexistence of vanishing bile duct syndrome, hemophagocytic lymphohistiocytosis, and adult-onset minimal change disease suggests that the underlying mechanisms probably are due to the sustained immune activation, leading to persistently high cytokine levels, resulting in multiorgan failure.
Figure 4 Bone marrow biopsy showing hypocellular bone marrow, with prominent hemophagocytosis. There are virtually no myeloid progenitors. Noted: foamy cytoplasm of histocyte.
disorder with coexisting hemophagocytic lymphohistiocytosis. Schneier et al8 described 3 patients who presented with acute liver failure as the initial manifestation of secondary hemophagocytic lymphohistiocytosis. Two of the patients had histiocytes with hemophagocytosis seen within the hepatic sinusoids with a background of portal fibrosis on liver biopsy.8 Our patient’s liver biopsy was reviewed by 2 different groups of pathologists, who concluded that there was no evidence of hemophagocytosis. Although rare, it is important to raise suspicion for hemophagocytic lymphohistiocytosis in a patient who presents with liver decompensation given the overlapping clinical picture. Table 2 Diagnosis Lymphohistiocytosis
Criteria
for
Hemophagocytic
Criteria
Definitions
Fever Splenomegaly Cytopenia (affecting 2 of 3 lineages in the peripheral blood) Hypertriglyceridemia and/or hypofibrinogenemia Hemophagocytosis in bone marrow or spleen or lymph nodes Low or absent Natural Killer cell activity Hyperferritinemia High soluble CD25 (ie, soluble IL-2 receptor)
Temperature >38.5 C Hemoglobin <9 g/dL Platelet <100 k/mL Neutrophils <1.0 k/mL Fasting triglyceride >265 mg/dL, Fibrinogen 150 mg/dL And no evidence of malignancy
Ferritin 500 mg/L 2400 U/mL
Five of the 8 criteria must be present. IL ¼ interleukin. Adapted from Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131.3
MANAGEMENT Management of the coexisting diseases in this patient was challenging. The fundamental principles in the management of hemophagocytic lymphohistiocytosis consist of 2 components: (1) eradication of the underlying inciting agent or trigger and controlling the overactivation of immune system and (2) reducing production of cytokines. The recommended standard protocol for hemophagocytic lymphohistiocytosis consists of etoposide and dexamethasone with or without cyclosporine, according to the established study Hemophagocytic Lymphohistiocytosis 2004.3 However, because of the albumin-bound property of etoposide, the presence of severe impairment of liver and hypoalbuminemia in our patient made the treatment more challenging because hypoalbuminemia may increase the effective dosing of the medications.11 The anticholestatic effect of ursodeoxycholic acid seems to be effective in patients with vanishing bile duct secondary to primary biliary cirrhosis because of its effect on the stimulation of biliary secretions and antiapoptotic effect.12 However, its role in drug-induced vanishing bile duct syndrome remains limited.13 For our patient with progressive liver failure, liver transplantation, the mainstay of treatment, was deemed contraindicated because of her coexisting hemophagocytic lymphohistiocytosis. This complex case was managed through a multidisciplinary team approach: hematology-oncology, rheumatology, infectious disease, and critical. Our patient received the treatment for hemophagocytic lymphohistiocytosis, with dose adjustment of etoposide and dexamethasone in the hopes of achieving clinical remission for hemophagocytic lymphohistiocytosis and providing potentially curative treatment through hematopoietic cell transplantation. Unfortunately, her course of hospitalization was complicated by disseminated Aspergillus infection, and she died of cardiac arrest secondary to septic shock on day 31 of her hospitalization.
References 1. Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced cholestasis. Hepatology. 2011;53:1377-1387. 2. Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease. J Hepatol. 1997;26(Suppl 1):31-35.
Tey et al
Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis
3. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131. 4. Chang CS, Wang CH, Su IJ, Chen YC, Shen MC. Hematophagic histiocytosis: a clinicopathologic analysis of 23 cases with special reference to the association with peripheral T-cell lymphoma. J Formos Med Assoc. 1994;93:421-428. 5. Janka GE, Lehmberg K. Hemophagocytic syndromesean update. Blood Rev. 2014;28:135-142. 6. Lambotte O, Costedoat-Chalumeau N, Amoura Z, Piette JC, Cacoub P. Drug-induced hemophagocytosis. Am J Med. 2002;112:592-593. 7. Li H, Li X, Liao XX, et al. Drug associated vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis. World J Gastrointest Endosc. 2012;4:376-378. 8. Schneier A, Stueck AE, Petersen B, Thung SN, Perumalswami P. An unusual cause of acute liver failure: three cases of hemophagocytic
9.
10. 11. 12.
13.
5
lymphohistiocytosis presenting at a transplant center. Semin Liver Dis. 2016;36:99-106. Sellier-Leclerc AL, Duval A, Riveron S, et al. A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J Am Soc Nephrol. 2007;18: 2732-2739. Dabbs DJ, Striker LM, Mignon F, Striker G. Glomerular lesions in lymphomas and leukemias. Am J Med. 1986;80:63-70. Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125:2908-2914. Pusl T, Beuers U. Ursodeoxycholic acid treatment of vanishing bile duct syndromes. World J Gastroenterol. 2006;12: 3487-3495. Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015;62(1 Suppl):S25-S37.