Case Report Open Access
Copyright ©2012 Baishideng. All rights reserved.
World J Gastrointest Endosc. Aug 16, 2012; 4(8): 376-378
Published online Aug 16, 2012. doi: 10.4253/wjge.v4.i8.376
Drug associated vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis
Hui Li, Xin Li, Xiao-Xing Liao, Hong Zhan, Yan Xiong, Chun-Lin Hu, Hong-Yan Wei, Xiao-Li Jing, Department of Emergency, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
Author contributions: Li H, Hu CL, Wei HY and Jing XL collected the data from the case; Li H and Jing XL wrote the manuscript; Liao XX and Zhan H supervised the project; Li X and Xiong Y edited the manuscript; all authors discussed the results and implications and commented on the manuscript at all stages.
Correspondence to: Xiao-Li Jing, Professor, Department of Emergency, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong Province, China. jing-xl@163.com
Telephone: +86-20-87755766-8500 Fax: +86-20-87755766-8773
Received: May 18, 2011
Revised: March 2, 2012
Accepted: August 8, 2012
Published online: August 16, 2012

Abstract

A 28-year-old woman with untreated autoimmune disorder, demonstrated skin rash and fever after taking Amoxicillin-clavulanate and developed progressive jaundice. A bone marrow aspiration indicated an increased number of macrophages with hemophagocytosis and liver biopsy showed pure centrilobular cholestasis with necrosis and some absence of portal bile ducts. Furthermore, a serological test for Epstein-Barr virus was positive. Under treatment by liver dialysis and administration of steroids led to rapidly defervescence and clinical improvement. However, liver enzymes were still markedly elevated with persistent anemia, even after immunosuppressive treatment. The patient is currently waiting for liver transplantation. This is the first description of vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis, with underlying causes including infection, drug-induced factors and untreated autoimmune disorder.

Key Words: Vanishing bile duct syndrome; Hemophagocytic lymphohistiocytosis; Epstein-Barr virus; Amoxicillin-clavulanate



INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a group of disorders of the mononuclear phagocyte system that are characterized by histiocyte proliferation and hemophagocytosis, resulting in fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, liver dysfunction, and coagulopathy. Vanishing bile duct syndrome (VBDS) is another severe cholestatic disease characterized by progressive loss of small intrahepatic ducts, caused by a variety of diseases and leading to chronic cholestasis, cirrhosis, and premature death from liver failure. Multiple similar etiologies of these two types of disease have been described including neoplastic, infectious, autoimmune, and medication/toxin mediated routes. However, concurrent diagnoses of HLH and VBDS have not previously been reported. Here, we describe a case of HLH combined with VBDS, with underlying causes including infection, drug-induced factor and untreated autoimmune disorder.

CASE REPORT

A 28-year-old Chinese woman was transferred to our hospital with persistent fever and progressive jaundice. The presentations were preceded by mild upper respiratory tract infection 2 wk earlier. She took a single dose of Amoxicillin-clavulanate for the upper respiratory tract infection, after which a skin rash developed on her back, arms and thighs and jaundice appeared gradually. After admission to hospital, the patient suddenly developed high fever, marked by remittent fever up to 40.5 °C, as well as progressive obstructive jaundice. Physical examination showed no signs of infection or hematological disease, and was only notable for hepatosplenomegaly. Laboratory studies showed normal white blood cell levels, but progressive decline of hemoglobin and platelets; elevated liver enzymes (alanine aminotransferase 408 U/L, normal 0-37 U/L; aspartate aminotransferase 608 U/L, normal 0-40 U/L); elevated bilirubin (839 μmol/L, normal 0-22.6 μmol/L); elevated ferritin level (> 40 000 μg/L, normal 16-313 ug/L); hypertriglyceridemia (4.58 mmol/L, normal 0.33-1.77 mmol/L); prolonged prothrombin time and activated partial thromboplastin time; normal complement level; ANA > 1:5120; Anti-dsDNA antibody, ENA, anti-SSA antibody, ribonuclear protein antibody and Epstein-Barr virus (EBV)-IgG were positive. Serology for human immunodeficiency virus, hepatitis A, B, and C, tubercle bacillus, and hemococcidium were negative. Computed tomography (CT) scan and magnetic resonance cholangiopancreatography of the upper abdomen revealed a normal extrahepatic biliary tree. Skin biopsies were non-specific and immunohistochemical staining was negative. Liver biopsy showed pure centrilobular cholestasis with necrosis and some absence of portal bile ducts. Repeat bone marrow aspirations revealed hemophagocytosis by macrophages, without any evidence of hematologic malignancy. Positron emission tomography-CT indicated non-cancerous proliferative. The patient had a 2-year history of ANA 1:1280, without any clinic manifestation and a history of immunodeficiency, and denied allergies to previously used medications including antibiotics.

The patient’s combination of clinical features (fever, hepatosplenomegaly) and laboratory evaluation (cytopenia in peripheral blood, hypertriglyceridemia, elevated ferritin, and hemophagocytosis in bone marrow without any obvious evidence of malignancy) fulfilled the diagnosis criteria for HLH. A diagnosis of VBDS, combined with drug-associated HLH was made. She was treated with pulsed methylprednisolone (1000 mg/d for 3 d), intravenous immunoglobulins (0.4 g/kg per day for 3 d), ursodeoxycholic acid and immediate blood transfusion. In addition, although methylprednisolone was followed by oral prednisolone 50 mg/d, the fever and symptoms still persisted. Considering the patient’s desire for fertility, further immunosuppressive treatment was not administered immediately. Later, the patient was put on the artificial liver support system treatment and given 3 rounds of immunoadsorption therapy, after which she rapidly defervesced and improved clinically. However, bilirubin levels were elevated soon after liver dialysis and the patient therefore agreed to immunosuppressive therapy. In addition to methylprednisolone, the combination therapy of cyclophosphamide (400 mg once weekly) and mycophenolate mofetil (1.5 g/d) were continued for approximately 6 wk, with the addition of closporine A. This was eventually suspended because of repeated gastrointestinal bleeding. Thereafter, 6 mo after presentation, liver enzymes were still markedly elevated with persistent anemia. The patient is currently waiting for liver transplantation.

DISCUSSION

HLH is a life threatening clinic and pathologic disorder, in which impaired or ineffective T cells and natural killer lymphocyte cells are activated. This results in hypercytokinemia leading to uncontrolled activation of benign scavenger macrophages and development of hemophagocytosis in the reticuloendothelial system[1]. In most cases, HLH is not a single disease but is frequently associated with infections, malignancies or rheumatological disorders[2]. HLH has been associated with various infections, of which EBV appears to be the most commonly associated triggering infection[3-5]. Associated rheumatic disorders have included rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, mixed connective tissue disease[4-6]. Drug induced hypersensitivity reaction may include hemophagocytic syndromes, with or without reactivation of EBV[7-9]. Regardless of the etiology, the cardinal clinical signs are prolonged fever, which is unresponsive to antibiotics, and hepatosplenomegaly. A third of the patients’ neurological signs, such as irritability, altered consciousness, seizures, and signs of increased intracranial pressure, can be present[10,11]. On histological examination, erythrophagocytosis in HLH is commonly present in lymphoid tissues (liver, spleen, and bone marrow), but rarely evident in skin biopsy specimens. However, phagocytic activity in liver, spleen and marrow biopsy specimens is not universally present. Only one third of initial bone marrow biopsy specimens demonstrate hemophagocytosis[12].

In 1991, the International Histiocyte Society established diagnostic guidelines in an effort to facilitate early diagnosis and management[13]. According to the updated guideline, the diagnosis of HLH is definitive[14,15]. On the other hand, in contrast to the complex origins of HLH, drug-induced cholestasis has its definite inducing agent. Cholestasis can occur with nearly all classes of drugs although antibiotics seem to be responsible more often than other groups. The most often reported culprits are erythromycin and amoxycillin-clavulanate[16]. The most severe form of cholestatic injury is VBDS. This condition is characterized by progressive ductopenia with portal tract fibrosis that leads to secondary liver cirrhosis with a complete absence of small bile ducts. Drug induced ductopenia has been described to continue long after the offending drug is withdrawn[17]. The syndrome is extremely rare, representing 0.5% of small bile duct disease[18].

Results of the international consensus protocol sponsored by the Histiocyte Society for treatment of patients newly diagnosed with HLH (HLH-94) were published in 2005. The goals of the trial were to achieve clinical remission of the life-threatening inflammation and to provide potentially curative therapy through allogenic hematopoeitic cell transplantation. HLH can be rapidly fatal in the absence of specific intervention bleeding; infection and progressive cerebral damage are the usual causes of death. Therefore, it is recommended that treatment should be started when there is a high degree of clinical suspicion, even when results of diagnostic studies are still pending[19]. Today, effective initial therapy of HLH consists of combinations of proapoptotic chemotherapy and immunosuppressive drugs targeting the hyperactivated T cells and histiocytes[20]. The recommended treatment consists of a combination of etoposide and dexamethasone (for central nervous system penetration), with or without intrathecal methotrexate, followed by maintenance therapy with the addition of closporine A. Projected survival rates, 5 years from diagnosis, range from 50% to 70%[21].

By comparison, therapy of toxin or drug-induced bile duct injury has remained largely ineffective and is mainly limited to the treatment of symptoms and the consequences of prolonged cholestasis. Corticosteroids have been invariably ineffective. The role of ursodeoxycholic acid remains controversial[22]. Although ursodeoxycholic acid has also been shown to be effective in other cases of VBDS related to drugs, it remains ineffective in cases of bile duct damage related to amoxicillin-clavulanate, as in the current case[23,24]. Liver transplantation is obviously the only alternative in patients who develop secondary biliary cirrhosis and liver failure.

In conclusion, immune-mediated destruction triggered by drugs is the underlying mechanism common to both HLH and VBDS, and antibiotics have been linked to both of these conditions. The initial episode seems to be the result of a direct hypersensitivity disorder. This is the first description of a diagnosis of VBDS combined with HLH. This case illustrates the importance of considering all possible underlying causes in a patient, including an infectious etiology, a drug-induced factor and an underlying immunologically mediated reaction. The co-existence of VBDS and HLH suggests that common pathogenic mechanisms are involved, with excessive activation of T lymphocytes or cytokine storm[24,25].

Footnotes

Peer reviewers: Venerino Poletti, MD, Professor, Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; Michael Swan, MBBS, FRACP, Department of Gastroenterology, Monash Medical Centre, Clayton Road, Clayton, 3168 Victoria, Australia; Wai-Keung Chow, Visiting Staff, Division of Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, China

S- Editor Song XX L- Editor Hughes D E- Editor Zheng XM

References
1.  Filipovich AH. Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol. 2006;6:410-415.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 97]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
2.  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.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7:814-822.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 378]  [Cited by in F6Publishing: 400]  [Article Influence: 25.0]  [Reference Citation Analysis (0)]
4.  Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am. 2008;28:293-313, viii.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 74]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
5.  Tristano AG. Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases. Med Sci Monit. 2008;14:RA27-RA36.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Lambotte O, Khellaf M, Harmouche H, Bader-Meunier B, Manceron V, Goujard C, Amoura Z, Godeau B, Piette JC, Delfraissy JF. Characteristics and long-term outcome of 15 episodes of systemic lupus erythematosus-associated hemophagocytic syndrome. Medicine (Baltimore). 2006;85:169-182.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 99]  [Cited by in F6Publishing: 91]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
7.  Ben m'rad M, Leclerc-Mercier S, Blanche P, Franck N, Rozenberg F, Fulla Y, Guesmi M, Rollot F, Dehoux M, Guillevin L. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore). 2009;88:131-140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 136]  [Cited by in F6Publishing: 118]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
8.  Komatsuda A, Okamoto Y, Hatakeyama T, Wakui H, Sawada K. Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus. Clin Rheumatol. 2008;27:395-397.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 18]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
9.  Gutiérrez-Ravé Pecero VM, Luque Márquez R, Ayerza Lerchundi MA, Fernández Jurado A. Phenytoin-induced hemocytophagic histiocytosis indistinguishable from malignant histiocytosis. South Med J. 1991;84:649-650.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Goo HW, Weon YC. A spectrum of neuroradiological findings in children with haemophagocytic lymphohistiocytosis. Pediatr Radiol. 2007;37:1110-1117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 60]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
11.  Takahashi S, Oki J, Miyamoto A, Koyano S, Ito K, Azuma H, Okuno A. Encephalopathy associated with haemophagocytic lymphohistiocytosis following rotavirus infection. Eur J Pediatr. 1999;158:133-137.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 35]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
12.  Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992;9:63-74.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18:29-33.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3075]  [Cited by in F6Publishing: 3385]  [Article Influence: 199.1]  [Reference Citation Analysis (1)]
15.  Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21:245-253.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
16.  Juricic D, Hrstic I, Radic D, Skegro M, Coric M, Vucelic B, Francetic I. Vanishing bile duct syndrome associated with azithromycin in a 62-year-old man. Basic Clin Pharmacol Toxicol. 2010;106:62-65.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 14]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
17.  Degott C, Feldmann G, Larrey D, Durand-Schneider AM, Grange D, Machayekhi JP, Moreau A, Potet F, Benhamou JP. Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia. Hepatology. 1992;15:244-251.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 143]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
18.  Ludwig J. Idiopathic adulthood ductopenia: an update. Mayo Clin Proc. 1998;73:285-291.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 79]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
19.  Morrell DS, Pepping MA, Scott JP, Esterly NB, Drolet BA. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. 2002;138:1208-1212.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367-2373.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 572]  [Cited by in F6Publishing: 588]  [Article Influence: 26.7]  [Reference Citation Analysis (0)]
21.  Horne A, Janka G, Maarten Egeler R, Gadner H, Imashuku S, Ladisch S, Locatelli F, Montgomery SM, Webb D, Winiarski J. Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol. 2005;129:622-630.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 169]  [Cited by in F6Publishing: 181]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
22.  Duerksen DR, Van Aerde JE, Gramlich L, Meddings JB, Chan G, Thomson AB, Clandinin MT. Intravenous ursodeoxycholic acid reduces cholestasis in parenterally fed newborn piglets. Gastroenterology. 1996;111:1111-1117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 34]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
23.  O'Brien CB, Shields DS, Saul SH, Reddy KR. Drug-induced vanishing bile duct syndrome: response to ursodiol. Am J Gastroenterol. 1996;91:1456-1457.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Moradpour D, Altorfer J, Flury R, Greminger P, Meyenberger C, Jost R, Schmid M. Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology. 1994;20:1437-1441.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 90]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
25.  Lambotte O, Costedoat-Chalumeau N, Amoura Z, Piette JC, Cacoub P. Drug-induced hemophagocytosis. Am J Med. 2002;112:592-593.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 46]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]