Digestive Diseases and Sciences

, Volume 62, Issue 4, pp 1067–1079 | Cite as

Relative Adrenal Insufficiency in Patients with Cirrhosis: A Systematic Review and Meta-Analysis

  • Gaeun Kim
  • Ji Hye Huh
  • Kyong Joo Lee
  • Moon Young Kim
  • Kwang Yong Shim
  • Soon Koo BaikEmail author
Original Article



Relative adrenal insufficiency (RAI) is frequently observed in patients with cirrhosis. We sought to identify evidence in the literature regarding the impact of RAI on clinical outcomes in cirrhotic patients.


We conducted a systematic review (SR) and meta-analysis (MA) using the Ovid-MEDLINE, EMBASE, and Cochrane Library databases to identify relevant studies in the literature.


Of the 182 studies identified, 16 were eligible according to our inclusion criteria. The prevalence of RAI was 49.4% (744/1507), and cirrhotic patients with acute critical illnesses such as sepsis were more likely to have RAI compared to those without critical illnesses (P < 0.001). With respect to clinical outcomes, patients with RAI had poorer survival rates and an increased risk of complications such as bleeding and hepatorenal syndrome compared to those without RAI. Corticosteroid therapy had a beneficial effect on critically ill cirrhotic patients in terms of hospital survival rate.


Based on this SR and MA, critically ill patients with cirrhosis have a high risk of RAI, and the presence of RAI is related to a poor prognosis and occurrence of cirrhotic complications.


Adrenal insufficiency Cirrhosis Systematic review Meta-analysis 



Relative adrenal insufficiency


Liver transplantation


Systematic review




Preferred reporting items for systematic reviews and meta-analyses


Standard-dose short synacthen test


Non-randomized controlled trial


Hepatic renal syndrome


Mean arterial pressure


Sequential Organ Failure Assessment


Acute Physiology and Chronic Health Evaluation III


Insulin-induced hypoglycemia test


Corticotropin-releasing hormone test


Adrenocorticotropic hormone



This research was supported by the Bisa Research Grant (2016-0148) of Keimyung University.

Author’s Contribution

G.E.K. and S.K.B. designed the analysis. G.E.K. and S.K.B. formulated the model. G.E.K., H.J.H., K.J.L., M.Y.K., and K.Y.S. analyzed the data. G.E.K., H.J.H., and S.K.B. wrote the manuscript. All authors approved and reviewed the manuscript.

Compliance with ethical standards

Conflict of interest



  1. 1.
    Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477–1488.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Fede G, Spadaro L, Tomaselli T, et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology. 2012;55:1282–1291.CrossRefPubMedGoogle Scholar
  3. 3.
    Trifan A, Chiriac S, Stanciu C. Update on adrenal insufficiency in patients with liver cirrhosis. World J Gastroenterol. 2013;19:445–456.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Tsai MH, Peng YS, Chen YC, et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology. 2006;43:673–681.CrossRefPubMedGoogle Scholar
  5. 5.
    Kim G, Lee SS, Baik SK, et al. The need for histological subclassification of cirrhosis: a systematic review and meta-analysis. Liver Int. 2016;36:847–855.CrossRefPubMedGoogle Scholar
  6. 6.
    Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med. 2015;30:580–589.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kim G, Cho YZ, Baik SK. Assessment for risk of bias in systematic reviews and meta-analyses in the field of hepatology. Gut Liver. 2015;9:701–706.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kim G, Kim J, Lim YL, et al. Renin-angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review. Hepatol Int. 2016;10:819–828.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim G, Shim KY, Baik SK. Diagnostic accuracy of hepatic vein arrival time performed with contrast-enhanced ultrasonography for cirrhosis: a systematic review and meta-analysis. Gut Liver. 2017;11:93–101.CrossRefPubMedGoogle Scholar
  10. 10.
    Jang YO, Jun BG, Baik SK, et al. Inhibition of hepatic stellate cells by bone marrow-derived mesenchymal stem cells in hepatic fibrosis. Clin Mol Hepatol. 2015;21:141–149.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kim G, Eom YW, Baik SK, et al. Therapeutic effects of mesenchymal stem cells for patients with chronic liver diseases: systematic review and meta-analysis. J Korean Med Sci. 2015;30:1405–1415.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kim MY, Suk KT, Baik SK, et al. Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis. Hepatology. 2012;56:1053–1062.CrossRefPubMedGoogle Scholar
  13. 13.
    Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther. 2001;89:221–231.CrossRefPubMedGoogle Scholar
  14. 14.
    Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:727–734.CrossRefPubMedGoogle Scholar
  15. 15.
    Suk KT, Yoon JH, Kim MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology. 2016;64:2185–2197.CrossRefPubMedGoogle Scholar
  16. 16.
    Wong F. Acute kidney injury in liver cirrhosis: new definition and application. Clin Mol Hepatol. 2016;22:415–422.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fernandez J, Escorsell A, Zabalza M, et al. Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival. Hepatology. 2006;44:1288–1295.CrossRefPubMedGoogle Scholar
  18. 18.
    Harry R, Auzinger G, Wendon J. The effects of supraphysiological doses of corticosteroids in hypotensive liver failure. Liver Int. 2003;23:71–77.CrossRefPubMedGoogle Scholar
  19. 19.
    Marik PE, Gayowski T, Starzl TE, et al. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med. 2005;33:1254–1259.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fede G, Spadaro L, Tomaselli T, et al. Assessment of adrenocortical reserve in stable patients with cirrhosis. J Hepatol. 2011;54:243–250.CrossRefPubMedGoogle Scholar
  21. 21.
    Tan T, Chang L, Woodward A, et al. Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J Hepatol. 2010;53:841–848.CrossRefPubMedGoogle Scholar
  22. 22.
    Triantos CK, Marzigie M, Fede G, et al. Critical illness-related corticosteroid insufficiency in patients with cirrhosis and variceal bleeding. Clin Gastroenterol Hepatol. 2011;9:595–601.CrossRefPubMedGoogle Scholar
  23. 23.
    Iwasaki T, Tominaga M, Fukumoto T, et al. Relative adrenal insufficiency manifested with multiple organ dysfunction in a liver transplant patient. Liver Transpl. 2006;12:1896–1899.CrossRefPubMedGoogle Scholar
  24. 24.
    Singh N, Gayowski T, Marino IR, et al. Acute adrenal insufficiency in critically ill liver transplant recipients. Implications for diagnosis. Transplantation. 1995;59:1744–1745.CrossRefPubMedGoogle Scholar
  25. 25.
    Toniutto P, Fabris C, Fumolo E, et al. Prevalence and risk factors for delayed adrenal insufficiency after liver transplantation. Liver Transpl. 2008;14:1014–1019.CrossRefPubMedGoogle Scholar
  26. 26.
    Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–871.CrossRefPubMedGoogle Scholar
  27. 27.
    Arabi YM, Aljumah A, Dabbagh O, et al. Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial. CMAJ. 2010;182:1971–1977.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937–1949.CrossRefPubMedGoogle Scholar
  29. 29.
    El Damarawy M, Hamed G, Heikal A, et al. Meld score as a predictor for hepato adrenal syndrome. J Am Sci. 2012;8:208–211.Google Scholar
  30. 30.
    Acevedo J, Fernandez J, Prado V, et al. Relative adrenal insufficiency in decompensated cirrhosis: relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death. Hepatology. 2013;58:1757–1765.CrossRefPubMedGoogle Scholar
  31. 31.
    Chawlani R, Arora A, Ranjan P, et al. Adrenal insufficiency predicts early mortality in patients with cirrhosis. United European Gastroenterol J. 2015;3:529–538.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fede G, Spadaro L, Tomaselli T, et al. Comparison of total cortisol, free cortisol, and surrogate markers of free cortisol in diagnosis of adrenal insufficiency in patients with stable cirrhosis. Clin Gastroenterol Hepatol. 2014;12:504–512. (e508; quiz e523–504).CrossRefPubMedGoogle Scholar
  33. 33.
    Galbois A, Rudler M, Massard J, et al. Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred. J Hepatol. 2010;52:839–845.CrossRefPubMedGoogle Scholar
  34. 34.
    Graupera I, Pavel O, Hernandez-Gea V, et al. Relative adrenal insufficiency in severe acute variceal and non-variceal bleeding: influence on outcomes. Liver Int. 2015;35:1964–1973.CrossRefPubMedGoogle Scholar
  35. 35.
    Jang JY, Kim TY, Sohn JH, et al. Relative adrenal insufficiency in chronic liver disease: its prevalence and effects on long-term mortality. Aliment Pharmacol Ther. 2014;40:819–826.CrossRefPubMedGoogle Scholar
  36. 36.
    Tsai MH, Huang HC, Peng YS, et al. Critical illness-related corticosteroid insufficiency in cirrhotic patients with acute gastroesophageal variceal bleeding: risk factors and association with outcome*. Crit Care Med. 2014;42:2546–2555.CrossRefPubMedGoogle Scholar
  37. 37.
    Cicognani C, Malavolti M, Morselli-Labate AM, et al. Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis. Arch Intern Med. 1997;157:792–796.CrossRefPubMedGoogle Scholar
  38. 38.
    Cirera I, Bauer TM, Navasa M, et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001;34:32–37.CrossRefPubMedGoogle Scholar
  39. 39.
    Webster JC, Oakley RH, Jewell CM, et al. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci U S A. 2001;98:6865–6870.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:364–389.CrossRefPubMedGoogle Scholar
  41. 41.
    Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. 2008;93:4245–4253.CrossRefPubMedGoogle Scholar
  42. 42.
    Minneci PC, Deans KJ, Banks SM, et al. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141:47–56.CrossRefPubMedGoogle Scholar
  43. 43.
    Annane D, Bellissant E, Sebille V, et al. Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br J Clin Pharmacol. 1998;46:589–597.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645–650.CrossRefPubMedGoogle Scholar
  45. 45.
    Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723–732.CrossRefPubMedGoogle Scholar
  46. 46.
    Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005;171:242–248.CrossRefPubMedGoogle Scholar
  47. 47.
    Oppert M, Schindler R, Husung C, et al. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med. 2005;33:2457–2464.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Gaeun Kim
    • 1
  • Ji Hye Huh
    • 2
  • Kyong Joo Lee
    • 2
  • Moon Young Kim
    • 2
    • 3
  • Kwang Yong Shim
    • 2
  • Soon Koo Baik
    • 2
    • 3
    • 4
    Email author
  1. 1.Research Institute for Nursing Science, College of NursingKeimyung UniversityDaeguRepublic of Korea
  2. 2.Department of Internal MedicineYonsei University Wonju College of MedicineWonjuRepublic of Korea
  3. 3.Cell Therapy and Tissue Engineering CenterYonsei University Wonju College of MedicineWonjuRepublic of Korea
  4. 4.Institute of Evidence Based MedicineYonsei University Wonju College of MedicineWonjuRepublic of Korea

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