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Liver involvement in patients with brucellosis: results of the Marmara study

  • D. Ozturk-Engin
  • H. ErdemEmail author
  • S. Gencer
  • S. Kaya
  • A. I. Baran
  • A. Batirel
  • R. Tekin
  • M. K. Celen
  • A. Denk
  • S. Guler
  • M. Ulug
  • H. Turan
  • A. U. Pekok
  • G. Mermut
  • S. Kaya
  • M. Tasbakan
  • N. Tulek
  • Y. Cag
  • A. Inan
  • A. Yalci
  • C. Ataman-Hatipoglu
  • I. Gonen
  • A. Dogan-Celik
  • F. Bozkurt
  • S. Gulsun
  • M. Sunnetcioglu
  • T. Guven
  • F. Duygu
  • E. Parlak
  • H. Sozen
  • S. Tosun
  • T. Demirdal
  • E. Guclu
  • O. Karabay
  • N. Uzun
  • O. Gunal
  • H. Diktas
  • A. Haykir-Solay
  • A. Erbay
  • C. Kader
  • O. Aydin
  • A. Erdem
  • N. Elaldi
  • A. Kadanali
  • Z. Yulugkural
  • L. Gorenek
  • M. Altındis
  • S. Bolukcu
  • C. Agalar
  • N. Ormeci
Article

Abstract

Brucellosis is a zoonotic disease that primarily affects the reticuloendothelial system. But, the extent of liver damage in due course of the disease is unclear. This study included 325 brucellosis patients with significant hepatobiliary involvement identified with microbiological analyses from 30 centers between 2000 and 2013. The patients with ≥5 times of the upper limit of normal for aminotransferases, total bilirubin level ≥2 mg/dl or local liver lesions were enrolled. Clinical hepatitis was detected in 284 patients (87.3 %) and cholestasis was detected in 215 (66.1 %) patients. Fatigue (91 %), fever (86 %), sweating (83 %), arthralgia (79 %), and lack of appetite (79 %) were the major symptoms. Laboratory tests showed anemia in 169 (52 %), thrombocytopenia in 117 (36 %), leukopenia in 81 (25 %), pancytopenia in 42 (13 %), and leukocytosis in 20 (6 %) patients. The most commonly used antibiotic combinations were doxycycline plus an aminoglycoside (n = 73), doxycycline plus rifampicin (n = 71), doxycycline plus rifampicin and an aminoglycoside (n = 27). The duration of ALT normalization differed significantly in three treatment groups (p < 0.001). The use of doxycycline and an aminoglycoside in clinical hepatitis showed better results compared to doxycycline and rifampicin or rifampicin, aminoglycoside, doxycycline regimens (p < 0.05). However, the length of hospital stay did not differ significantly between these three combinations (p > 0.05). During the follow-up, treatment failure occurred in four patients (1 %) and relapse was seen in three patients (0.9 %). Mortality was not observed. Hepatobiliary involvement in brucellosis has a benign course with suitable antibiotics and the use of doxycycline and an aminoglycoside regimen seems a better strategy in select patients.

Keywords

Rifampicin Doxycycline Cholestasis Brucellosis Liver Involvement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ULN

Upper limit of normal

RBT

Rose Bengal test

STA

Standard tube agglutination test

ESR

Erythrocyte sedimentation rate

DOXAG

Doxycycline plus an aminoglycoside

DOXRIF

Doxycycline plus rifampicin

DOXRIFAG

Doxycycline plus rifampicin and an aminoglycoside

Notes

Conflict of interest

We have no competing interests to declare.

Financial support

We did not receive any kind of financial support.

References

  1. 1.
    Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV (2006) The new global map of human brucellosis. Lancet Infect Dis 6(2):91–99PubMedCrossRefGoogle Scholar
  2. 2.
    Albayrak A, Albayrak F (2011) Hepatic granulomas associated with brucellosis: Hepatic granulomas and brucellosis. Hepat Mon 11(1):1–2PubMedPubMedCentralGoogle Scholar
  3. 3.
    Buzgan T, Karahocagil MK, Irmak H, Baran AI, Karsen H, Evirgen O, Akdeniz H (2010) Clinical manifestations and complications in 1028 cases of brucellosis: a retrospective evaluation and review of the literature. Int J Infect Dis 14(6):e469–e478PubMedCrossRefGoogle Scholar
  4. 4.
    Al-Otaibi FE (2010) Acute acalculus cholecystitis and hepatitis caused by Brucella melitensis. J Infect Dev Ctries 4(7):464–467PubMedCrossRefGoogle Scholar
  5. 5.
    Erdem I, Cicekler N, Mert D, Yucesoy-Dede B, Ozyurek S, Goktas P (2005) A case report of acute hepatitis due to brucellosis. Int J Infect Dis 9(6):349–350PubMedCrossRefGoogle Scholar
  6. 6.
    Gotuzzo E, Carillo C (1998) Brucella. In: Gorbach SL, Bartlett JG, Blacklov NR (eds) Infectious diseases. W.B. Saunders Company, Philadelphia, pp 1837–1845Google Scholar
  7. 7.
    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International sepsis definitions conference. Crit Care Med 31(4):1250–1256PubMedCrossRefGoogle Scholar
  8. 8.
    de Benoist B, McLean E, Egli I, Cogswell M (2008) Worldwide prevalence of anaemia 1993-2005. World Health Organization, GenevaGoogle Scholar
  9. 9.
    Miller A, Green M, Robinson D (1983) Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 286(6361):266CrossRefGoogle Scholar
  10. 10.
    European Association for the Study of the Liver (2009) EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51(2):237–267Google Scholar
  11. 11.
    Kratzer W, Fritz V, Mason RA, Haenle MM, Kaechele V (2003) Factors affecting liver size: a sonographic survey of 2080 subjects. J Ultrasound Med 22(11):1155–1161PubMedGoogle Scholar
  12. 12.
    Pozo AL, Godfrey EM, Bowles KM (2009) Splenomegaly: investigation, diagnosis and management. Blood Rev 23(3):105–111PubMedCrossRefGoogle Scholar
  13. 13.
    Erdem H, Ulu-Kilic A, Kilic S, Karahocagil M, Shehata G, Eren-Tulek N, Yetkin F, Celen MK, Ceran N, Gul HC, Mert G, Tekin-Koruk S, Dizbay M, Inal AS, Nayman-Alpat S, Bosilkovski M, Inan D, Saltoglu N, Abdel-Baky L, Adeva-Bartolome MT, Ceylan B, Sacar S, Turhan V, Yilmaz E, Elaldi N, Kocak-Tufan Z, Ugurlu K, Dokuzoguz B, Yilmaz H, Gundes S, Guner R, Ozgunes N, Ulcay A, Unal S, Dayan S, Gorenek L, Karakas A, Tasova Y, Usluer G, Bayindir Y, Kurtaran B, Sipahi OR, Leblebicioglu H (2012) Efficacy and tolerability of antibiotic combinations in neurobrucellosis: results of the istanbul study. Antimicrob Agents Chemother 56(3):1523–1528PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Tekin-Koruk S, Erdem H, Koruk I, Erbay A, Tezer-Tekce Y, Erbay AR, Dayan S, Deveci O, Inan A, Engin DO, Guner R, Dikici N, Doyuk-Kartal E, Kurtaran B, Pehlivanoglu F, Sipahi OR, Yalci A, Yemisen M, Alp-Cavus S, Gencer S, Guzel G, Oncul O, Parlak M, Kazak E, Tulek N, Ulcay A, Savasci U (2012) Management of Brucella endocarditis: results of the Gulhane study. Int J Antimicrob Agents 40(2):145–150CrossRefGoogle Scholar
  15. 15.
    Caballeria E, Masso RM, Arago JV, Sanchis A (1992) Ascites as the first manifestation of Brucella granulomatous hepatitis. J Hepatol 15(3):415–416PubMedCrossRefGoogle Scholar
  16. 16.
    Mc Cullough NB, Eisele CW (1951) Brucella hepatitis leading to cirrhosis of the liver. AMA Arch Intern Med 88(6):793–802CrossRefGoogle Scholar
  17. 17.
    Debat-Zoguereh D, Badiaga S, Uzan E, Le Treut YP, Lebreuil G, Bourgeade A (1995) Necrotizing hepatic granuloma of brucellosis origin. Apropos of a case. Rev Med Interne 16(1):63–66PubMedCrossRefGoogle Scholar
  18. 18.
    Cervantes F, Bruguera M, Carbonell J, Force L, Webb S (1982) Liver disease in brucellosis. A clinical and pathological study of 40 cases. Postgrad Med J 58(680):346–350PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Calik S, Gokengin D (2011) Human brucellosis in Turkey: A review of the literature between 1990 and 2009. Turk J Med Sci 41(3):549–555Google Scholar
  20. 20.
    Bzeizi KI, Benmousa A, Sanai FM (2010) Coincidence of acute brucella hepatitis and dengue fever or serologic cross-reactivity? Saudi J Gastroenterol 16(4):299–301PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Hizel K, Guzel O, Dizbay M, Karakus R, Senol E, Arman D, Aktas F, Ulutan F (2007) Age and duration of disease as factors affecting clinical findings and sacroiliitis in brucellosis. Infection 35(6):434–437PubMedCrossRefGoogle Scholar
  22. 22.
    Bosilkovski M, Krteva L, Dimzova M, Kondova I (2007) Brucellosis in 418 patients from the Balkan Peninsula: exposure-related differences in clinical manifestations, laboratory test results, and therapy outcome. Int J Infect Dis 11(4):342–347PubMedCrossRefGoogle Scholar
  23. 23.
    Bosilkovski M, Krteva L, Dimzova M, Vidinic I, Sopova Z, Spasovska K (2010) Human brucellosis in Macedonia—10 years of clinical experience in endemic region. Croat Med J 51(4):327–336PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Hasanjani Roushan MR, Mohrez M, Smailnejad Gangi SM, Soleimani Amiri MJ, Hajiahmadi M (2004) Epidemiological features and clinical manifestations in 469 adult patients with brucellosis in Babol, Northern Iran. Epidemiol Infect 132(6):1109–1114PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ulug M, Celen MK, Ayaz C (2010) An unusual presentation of brucellosis: acute hepatitis. Braz J Infect Dis 14(6):641–642PubMedCrossRefGoogle Scholar
  26. 26.
    Franco MP, Mulder M, Gilman RH, Smits HL (2007) Human brucellosis. Lancet Infect Dis 7(12):775–786PubMedCrossRefGoogle Scholar
  27. 27.
    Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005) Brucellosis. N Engl J Med 352(22):2325–2336PubMedCrossRefGoogle Scholar
  28. 28.
    Erdem H, Kilic S, Sener B, Acikel C, Alp E, Karahocagil M, Yetkin F, Inan A, Kecik-Bosnak V, Gul HC, Tekin-Koruk S, Ceran N, Demirdal T, Yilmaz G, Ulu-Kilic A, Ceylan B, Dogan-Celik A, Nayman-Alpat S, Tekin R, Yalci A, Turhan V, Karaoglan I, Yilmaz H, Mete B, Batirel A, Ulcay A, Dayan S, Seza Inal A, Ahmed SS, Tufan ZK, Karakas A, Teker B, Namiduru M, Savasci U, Pappas G (2013) Diagnosis of chronic brucellar meningitis and meningoencephalitis: the results of the Istanbul-2 study. Clin Microbiol Infect 19(2):E80–86Google Scholar
  29. 29.
    Erdem H, Inan A, Elaldi N, Tekin R, Gulsun S, Ataman-Hatipoglu C, Beeching N, Deveci O, Yalci A, Bolukcu S, Dagli O (2014) Respiratory system involvement in brucellqosis: rhe results of the Kardelen study. Chest 145(1):87–94Google Scholar
  30. 30.
    Sonika U, Kar P (2012) Tuberculosis and liver disease: management issues. Trop Gastroenterol 33(2):102–106PubMedCrossRefGoogle Scholar
  31. 31.
    Uygur-Bayramicli O, Dabak G, Dabak R (2003) A clinical dilemma: abdominal tuberculosis. World J Gastroenterol 9(5):1098–1101PubMedGoogle Scholar
  32. 32.
    Tan KK, Chen K, Sim R (2009) The spectrum of abdominal tuberculosis in a developed country: a single institution’s experience over 7 years. J Gastrointest Surg 13(1):142–147PubMedCrossRefGoogle Scholar
  33. 33.
    Malik M, Kurban L, Murray GI, Alkari B (2011) Isolated tuberculosis of the liver: a diagnostic challenge. BMJ Case Rep 2011;pii: bcr1220103654Google Scholar
  34. 34.
    Perez Fernandez T, Lopez Serrano P, Tomas E, Gutierrez ML, Lledo JL, Cacho G, Santander C, Fernandez Rodriguez CM (2004) Diagnostic and therapeutic approach to cholestatic liver disease. Rev Esp Enferm Dig 96(1):60–73PubMedCrossRefGoogle Scholar
  35. 35.
    Colmenero JD, Reguera JM, Martos F, Sanchez-De-Mora D, Delgado M, Causse M, Martin-Farfan A, Juarez C (1996) Complications associated with Brucella melitensis infection: a study of 530 cases. Medicine (Baltimore) 75(4):195–211CrossRefGoogle Scholar
  36. 36.
    Ko J, Splitter GA (2003) Molecular host-pathogen interaction in brucellosis: current understanding and future approaches to vaccine development for mice and humans. Clin Microbiol Rev 16(1):65–78PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Dornand J, Gross A, Lafont V, Liautard J, Oliaro J, Liautard JP (2002) The innate immune response against Brucella in humans. Vet Microbiol 90(1–4):383–394PubMedCrossRefGoogle Scholar
  38. 38.
    Rodriguez-Zapata M, Alvarez-Mon M, Salmeron I, Prieto A, Manzano L, Salmeron OJ, Carballido J (1996) Diminished T lymphocyte proliferative response to polyclonal mitogens in acute brucellosis patients. Infection 24(2):115–120PubMedCrossRefGoogle Scholar
  39. 39.
    Rodriguez-Zapata M, Salmeron I, Manzano L, Salmeron OJ, Prieto A, Alvarez-Mon M (1996) Defective interferon-gamma production by T-lymphocytes from patients with acute brucellosis. Eur J Clin Invest 26(2):136–140PubMedCrossRefGoogle Scholar
  40. 40.
    Ugalde RA (1999) Intracellular lifestyle of Brucella spp. Common genes with other animal pathogens, plant pathogens, and endosymbionts. Microbes Infect 1(14):1211–1219PubMedCrossRefGoogle Scholar
  41. 41.
    Hashemi SH, Gachkar L, Keramat F, Mamani M, Hajilooi M, Janbakhsh A, Majzoobi MM, Mahjub H (2012) Comparison of doxycycline-streptomycin, doxycycline-rifampin, and ofloxacin-rifampin in the treatment of brucellosis: a randomized clinical trial. Int J Infect Dis 16(4):e247–e251PubMedCrossRefGoogle Scholar
  42. 42.
    Solera J, Espinosa A, Geijo P, Martinez-Alfaro E, Saez L, Sepulveda MA, Ruiz-Ribo MD (1996) Treatment of human brucellosis with netilmicin and doxycycline. Clin Infect Dis 22(3):441–445PubMedCrossRefGoogle Scholar
  43. 43.
    Garcia S, del Pozo J, Solera J (2012) Systematic review and meta-analysis of randomized clinical trials in the treatment of human brucellosis. PLoS One 7(2):e32090CrossRefGoogle Scholar
  44. 44.
    Corbel MJ (2006) Brucellosis in humans and animals. WHO Press, World Health Organization, GenevaGoogle Scholar
  45. 45.
    Kursun E, Turunc T, Demiroglu Y, Arslan H (2013) Evaluation of four hundred and forty seven brucellosis cases. Intern Med 52(7):745–750PubMedCrossRefGoogle Scholar
  46. 46.
    Solera J, Martinez-Alfaro E, Saez L (1994) Meta-analysis of the efficacy of the combination of + rifampicin and doxycycline in the treatment of human brucellosis. Med Clin (Barc) 102(19):731–738Google Scholar
  47. 47.
    Skalsky K, Yahav D, Bishara J, Pitlik S, Leibovici L, Paul M (2008) Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ 336(7646):701–704PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Baciewicz AM, Sokos DR, Cowan RI (2003) Aminoglycoside-associated nephrotoxicity in the elderly. Ann Pharmacother 37(2):182–186PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • D. Ozturk-Engin
    • 1
  • H. Erdem
    • 2
    Email author
  • S. Gencer
    • 3
  • S. Kaya
    • 4
  • A. I. Baran
    • 5
  • A. Batirel
    • 3
  • R. Tekin
    • 6
  • M. K. Celen
    • 6
  • A. Denk
    • 7
  • S. Guler
    • 8
  • M. Ulug
    • 9
  • H. Turan
    • 10
  • A. U. Pekok
    • 11
  • G. Mermut
    • 12
  • S. Kaya
    • 13
  • M. Tasbakan
    • 14
  • N. Tulek
    • 15
  • Y. Cag
    • 3
  • A. Inan
    • 1
  • A. Yalci
    • 16
  • C. Ataman-Hatipoglu
    • 15
  • I. Gonen
    • 17
  • A. Dogan-Celik
    • 18
  • F. Bozkurt
    • 6
  • S. Gulsun
    • 4
  • M. Sunnetcioglu
    • 5
  • T. Guven
    • 19
  • F. Duygu
    • 20
  • E. Parlak
    • 21
  • H. Sozen
    • 22
  • S. Tosun
    • 12
  • T. Demirdal
    • 23
  • E. Guclu
    • 24
  • O. Karabay
    • 24
  • N. Uzun
    • 25
  • O. Gunal
    • 20
  • H. Diktas
    • 26
  • A. Haykir-Solay
    • 27
  • A. Erbay
    • 28
  • C. Kader
    • 28
  • O. Aydin
    • 29
  • A. Erdem
    • 30
  • N. Elaldi
    • 31
  • A. Kadanali
    • 32
  • Z. Yulugkural
    • 18
  • L. Gorenek
    • 2
  • M. Altındis
    • 33
  • S. Bolukcu
    • 1
  • C. Agalar
    • 34
  • N. Ormeci
    • 35
  1. 1.Department of Infectious Diseases and Clinical MicrobiologyHaydarpasa Numune Training and Research HospitalIstanbulTurkey
  2. 2.Department of Infectious Diseases and Clinical MicrobiologyGATA Haydarpasa Training HospitalIstanbulTurkey
  3. 3.Department of Infectious Diseases and Clinical MicrobiologyLutfi Kirdar Training and Research HospitalIstanbulTurkey
  4. 4.Department of Infectious Diseases and Clinical MicrobiologyDiyarbakir Training and Research HospitalDiyarbakirTurkey
  5. 5.Department of Infectious Diseases and Clinical MicrobiologyYuzuncuyil University School of MedicineVanTurkey
  6. 6.Department of Infectious Diseases and Clinical MicrobiologyDicle University School of MedicineDiyarbakirTurkey
  7. 7.Department of Infectious Diseases and Clinical MicrobiologyFirat University School of MedicineElazigTurkey
  8. 8.Department of Infectious Diseases and Clinical MicrobiologyYenişehir State HospitalKahramanmaraşTurkey
  9. 9.Department of Infectious Diseases and Clinical MicrobiologyPrivate Umit HospitalEskisehirTurkey
  10. 10.Department of Infectious Diseases and Clinical MicrobiologyBaskent University School of MedicineKonyaTurkey
  11. 11.Department of Infectious Diseases and Clinical MicrobiologyPrivate Erzurum Sifa HospitalErzurumTurkey
  12. 12.Department of Infectious diseases and Clinical MicrobiologyIzmir Bozyaka Training and Research HospitalIzmirTurkey
  13. 13.Department of Infectious Diseases and Clinical MicrobiologyKaradeniz Technical University School of MedicineTrabzonTurkey
  14. 14.Department of Infectious Diseases and Clinical MicrobiologyEge University School of MedicineIzmirTurkey
  15. 15.Department of Infectious Diseases and Clinical MicrobiologyAnkara Training and Research HospitalAnkaraTurkey
  16. 16.Department of Infectious Diseases and Clinical MicrobiologyAnkara University School of MedicineAnkaraTurkey
  17. 17.School of Medicine, Department of Infectious Diseases and Clinical MicrobiologySuleyman Demirel UniversityIspartaTurkey
  18. 18.Department of Infectious Diseases and Clinical MicrobiologyTrakya University School of MedicineEdirneTurkey
  19. 19.Ankara Atatürk Training & Research Hospital, Department of Infectious Diseases and Clinical MicrobiologyYildirim Beyazit UniversityAnkaraTurkey
  20. 20.Department of Infectious Diseases and Clinical MicrobiologyGaziosmanpasa University School of MedicineTokatTurkey
  21. 21.Department of Infectious Diseases and Clinical MicrobiologyAtaturk University School of MedicineErzurumTurkey
  22. 22.School of Medicine, Department of Anesthesiology and ReanimationSitki Kocman UniversityMuglaTurkey
  23. 23.Department of Infectious Diseases and Clinical MicrobiologyKatip Celebi University School of MedicineIzmirTurkey
  24. 24.Department of Infectious Diseases and Clinical MicrobiologySakarya University School of MedicineSakaryaTurkey
  25. 25.Department of Infectious Diseases and Clinical MicrobiologySisli Etfal Training and Research HospitalIstanbulTurkey
  26. 26.Tatvan Military HospitalDepartment of Infectious Diseases and Clinical MicrobiologyIstanbulTurkey
  27. 27.Department of Infectious Diseases and Clinical MicrobiologyIgdir State HospitalIgdirTurkey
  28. 28.Department of Infectious Diseases and Clinical MicrobiologyBozok University School of MedicineYozgatTurkey
  29. 29.Goztepe Training and Research Hospital, Department of Infectious Diseases and Clinical MicrobiologyMedeniyet UniversityIstanbulTurkey
  30. 30.Goztepe Training and Research Hospital, Department of PathologyMedeniyet UniversityIstanbulTurkey
  31. 31.Department of Infectious Diseases and Clinical MicrobiologyCumhuriyet University School of MedicineSivasTurkey
  32. 32.Department of Infectious Diseases and Clinical MicrobiologyUmraniye Training and Research HospitalIstanbulTurkey
  33. 33.Department of Clinical MicrobiologySakarya University School of MedicineSakaryaTurkey
  34. 34.Department of Infectious Diseases and Clinical MicrobiologyFatih Sultan Mehmet Training and Research HospitalIstanbulTurkey
  35. 35.Department of GastroenterologyAnkara University School of MedicineAnkaraTurkey

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