Journal of Hepatology 49 (2008) 466–473 www.elsevier.com/locate/jhep
Case report
Primary biliary cirrhosis following lactobacillus vaccination for recurrent vaginitisq Dimitrios Bogdanos1, , Thomas Pusl2, , Christian Rust2, Diego Vergani1, Ulrich Beuers2,3,* 1
Institute of Liver Studies, King’s College, London School of Medicine at King’s College Hospital, London, United Kingdom 2 Department of Medicine II-Grosshadern, University of Munich, Germany 3 Department of Gastroenterology and Hepatology, AMC, University of Amsterdam, G4-213, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands
Background/Aims: Antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex, PDC-E2, and other mitochondrial 2-oxoacid dehydrogenases (AMA-M2) are the hallmark for diagnosis of primary biliary cirrhosis (PBC). AMA-M2 formation as an early step in the pathogenesis of PBC has recently been assumed to be triggered by bacterial mimics of the E2 subunit and certain reactant xenobiotics. We report a case of symptomatic PBC diagnosed after sequential immunization with a lactobacillus vaccine for recurrent vaginitis over years. Methods: Serum AMA-M2 specificity of the patient was evaluated by indirect immunofluorescence, immunoblotting and ELISA. Serum antibody responses against pyruvate dehydrogenase complex-E2 subunit (PDC-E2212–226), the major PBCspecific mitochondrial autoepitope, and microbial mimics revealed cross-reactivity with beta-galactosidase of Lactobacillus delbrueckii (LACDE BGAL266–280) which shows a high local homology with that of Lactobacillus species administered via the vaccine. The relative affinity of antibody reactivity to LACDE BGAL266–280 was significantly higher than that against human PDC-E2212–226. Conclusions: We conclude that lactobacillus vaccination therapy may be another culprit for the development of PBC in genetically susceptible women. Ó 2008 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Keywords: PBC; Molecular mimicry; Lactobacillus; AMA; UDCA; Budesonide
1. Introduction Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by destruction of small intrahepatic bile ducts and subsequent development of liver fibrosis and cirrhosis predominantly in middle-aged Received 23 September 2007; received in revised form 6 April 2008; accepted 12 May 2008; available online 25 June 2008 Associate Editor: M. Trauner q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +31 20 566 2422; fax: +31 20 691 7033. E-mail address:
[email protected] (U. Beuers). These authors contributed equally to the manuscript.
women [1]. Fatigue and pruritus are the most frequent symptoms which may affect up to 80% of patients [2,3]. PBC is regarded as an organ-specific autoimmune disease based on the presence of lymphoid infiltration in the portal tracts and of high titers of specific antibodies directed against the E2 subunit of pyruvate dehydrogenase complex (PDC-E2) or related mitochondrial 2-oxoacid dehydrogenase complexes (AMA-M2) [4,5]. The induction of AMA-M2 formation may be multifactorial [6]. Modification of mitochondrial or bacterial proteins after exposure to reactant xenobiotics such as the cosmetic component, 2-nonynoic acid [7,8] or hazardous aromatic hydrocarbons such as benzene [9] as well as exposure to bacterial proteins with a high degree of sequence homology with the human mitochondrial 2oxoacid dehydrogenase complexes like those of
0168-8278/$34.00 Ó 2008 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. doi:10.1016/j.jhep.2008.05.022
D. Bogdanos et al. / Journal of Hepatology 49 (2008) 466–473
Novosphingobium aromaticivorans [10] or Lactobacillus delbrueckii [11] might induce loss of tolerance to human mitochondrial proteins in genetically susceptible individuals. Aberrant expression of PDC-E2-like proteins possibly derived from phagocytosed apoptotic biliary epithelial cells [12] at the luminal surface of cholangiocytes [6] may contribute to an immune response leading to florid cholangitis and bile duct destruction in PBC [13]. Here, we report a case of primary biliary cirrhosis diagnosed after immunization with a lactobacillus vaccine for years. The laboratory work-up was aimed to investigate the fine specificity of antibody responses against pyruvate dehydrogenase complex-E2 subunit (PDC-E2212–226), the major PBC-specific mitochondrial autoepitope and its microbial mimics in this female patient vaccinated annually for 8 years with Lactobacillus antigens. 1.1. Case report A 39-year-old previously healthy woman was referred to our outpatient clinic in July 2005 with a 3-month history of fatigue, generalized severe pruritus and pruritusassociated sleep disturbance. She and her family had no history of liver disease or other serious disorders. She worked as a banker and reported no regular intake of drugs or herbs. She was a non-smoker and was neither passively exposed to smoke nor to chemical toxins. She had no children and had not used hormones in the past [14]. Her gynaecologist had administered intramuscular lactobacillus vaccine [GynatrenR, >7 109 Lactobacilli of eight strains, L. rhamnosus (3), L. vaginalis (3), L. fermentum (1), L. salivarius (1)] twice within several weeks in the first year and at one-year intervals for 8 years as an immunization therapy for prevention of recurrent vaginitis [15]; serum liver tests or serum samples of the patient from that time were not available. The patient’s physical examination was unremarkable. Laboratory investigations showed elevated levels of total serum bilirubin (1.3 mg/dL; normal (N) < 1.0 mg/ dL), alkaline phosphatase (363 IU/L; N < 135), c-glutamyltransferase (244 IU/L; N < 38), serum aspartate
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aminotransferase (92 IU/L; N < 33) and serum alanine aminotransferase (158 IU/L; N < 35). Antimitochondrial antibody (AMA, 1:5120) and AMA-M2 were strongly positive, and serum IgG (17.2 g/L; N 7.0–16.0) and IgM (4.4 g/L; N 0.4–2.3) were elevated. Serological tests for hepatitis A, B and C and antinuclear (ANA), antismooth muscle (ASMA), and soluble liver antigen (SLA) antibodies were negative. A liver biopsy revealed portal and periportal lymphocellular infiltration with signs of bile duct injury, ductopenia, moderate interface hepatitis and portoseptal fibrosis, compatible with stage 2–3 PBC. The diagnosis of a PBC–AIH overlap syndrome was considered unlikely (AIH score < 10)[16]. Therapy with ursodeoxycholic acid at 1000 mg/day (15 mg/kg/d) was initiated, and budesonide at 2 3 mg/d was added after 9 months when serum liver tests had only partially improved. The patient reported a rapid improvement of pruritus and fatigue within weeks. After 9–24 months, the patient reported general wellbeing. Mild pruritus (
