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

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

RAI:

Relative adrenal insufficiency

LT:

Liver transplantation

SR:

Systematic review

MA:

Meta-analysis

PRISMA:

Preferred reporting items for systematic reviews and meta-analyses

SD-SST:

Standard-dose short synacthen test

Non-RCT:

Non-randomized controlled trial

HRS:

Hepatic renal syndrome

MAP:

Mean arterial pressure

SOFA:

Sequential Organ Failure Assessment

APACHE III:

Acute Physiology and Chronic Health Evaluation III

IIHT:

Insulin-induced hypoglycemia test

CRHT:

Corticotropin-releasing hormone test

ACTH:

Adrenocorticotropic hormone

References

  1. Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477–1488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fede G, Spadaro L, Tomaselli T, et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology. 2012;55:1282–1291.

    Article  CAS  PubMed  Google Scholar 

  3. Trifan A, Chiriac S, Stanciu C. Update on adrenal insufficiency in patients with liver cirrhosis. World J Gastroenterol. 2013;19:445–456.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  6. Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med. 2015;30:580–589.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  13. Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther. 2001;89:221–231.

    Article  CAS  PubMed  Google Scholar 

  14. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:727–734.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. Wong F. Acute kidney injury in liver cirrhosis: new definition and application. Clin Mol Hepatol. 2016;22:415–422.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  18. Harry R, Auzinger G, Wendon J. The effects of supraphysiological doses of corticosteroids in hypotensive liver failure. Liver Int. 2003;23:71–77.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Fede G, Spadaro L, Tomaselli T, et al. Assessment of adrenocortical reserve in stable patients with cirrhosis. J Hepatol. 2011;54:243–250.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  38. Cirera I, Bauer TM, Navasa M, et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001;34:32–37.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Research Institute for Nursing Science, College of Nursing, Keimyung University, Daegu, Republic of Korea

    Gaeun Kim

  2. Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, 26426, Republic of Korea

    Ji Hye Huh, Kyong Joo Lee, Moon Young Kim, Kwang Yong Shim & Soon Koo Baik

  3. Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea

    Moon Young Kim & Soon Koo Baik

  4. Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea

    Soon Koo Baik

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  1. Gaeun Kim
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Correspondence to Soon Koo Baik.

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Kim, G., Huh, J.H., Lee, K.J. et al. Relative Adrenal Insufficiency in Patients with Cirrhosis: A Systematic Review and Meta-Analysis. Dig Dis Sci 62, 1067–1079 (2017). https://doi.org/10.1007/s10620-017-4471-8

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  • DOI: https://doi.org/10.1007/s10620-017-4471-8

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