Journal of Hepatology
Volume 47, Issue 3 , Pages 418-423, September 2007

Adrenal insufficiency in liver disease – What is the evidence?☆

  • James O’Beirne

      Affiliations

    • Department of Liver Transplantation and Hepatobiliary Medicine Unit, Royal Free Hospital, Pond Street, Hampstead, London, UK
    • Corresponding Author InformationCorresponding author. Tel.: +44 2077940500x33978.
    • ,
  • Michael Holmes

      Affiliations

    • Department of Liver Transplantation and Hepatobiliary Medicine Unit, Royal Free Hospital, Pond Street, Hampstead, London, UK
    • ,
  • Banwari Agarwal

      Affiliations

    • Intensive Care Unit, Royal Free Hospital, Hampstead, London, UK
    • ,
  • Pierre Bouloux

      Affiliations

    • Department of Endocrinology, Royal Free Hospital, Hampstead, London, UK
    • ,
  • Steve Shaw

      Affiliations

    • Intensive Care Unit, Royal Free Hospital, Hampstead, London, UK
    • ,
  • David Patch

      Affiliations

    • Department of Liver Transplantation and Hepatobiliary Medicine Unit, Royal Free Hospital, Pond Street, Hampstead, London, UK
    • ,
  • Andrew Burroughs

      Affiliations

    • Department of Liver Transplantation and Hepatobiliary Medicine Unit, Royal Free Hospital, Pond Street, Hampstead, London, UK

published online 28 June 2007.

Associate Editor: C. Merkel

Article Outline

Recently, treatment with corticosteroids in the setting of septic shock and adrenal insufficiency has been shown to decrease mortality. In septic patients, a blunted response to adrenal stimulation identifies patients with a poorer prognosis who may benefit from corticosteroid supplementation. This condition has been termed relative adrenal insufficiency (RAI).

Given the similarities between septic shock and liver failure, a number of groups have now studied the incidence of RAI in various forms of liver disease. Although different definitions of RAI exist, the current literature suggests that RAI is common, being seen in 33% of acute liver failure patients and up to 65% of patients with chronic liver disease and sepsis. The finding that RAI can exist in the absence of sepsis and may be as high as 92% of patients undergoing liver transplantation using a steroid free protocol has led one group to propose the term hepatoadrenal syndrome.

The purpose of this review is to summarise the existing evidence for adrenal insufficiency in liver disease, to examine the possibility that adrenal dysfunction in liver disease may have a separate pathogenesis to that observed in sepsis and to provide insight into the potential areas for further research into this condition.

Keywords: Cirrhosis, Liver failure, Adrenal function, Synacthen

 

Back to Article Outline

1. Introduction 

Liver failure, in the context of acute liver injury or due to decompensation of chronic liver disease, is a life threatening condition with many similarities to septic shock. Both conditions are characterized by the presence of hyperdynamic circulatory failure, with a low mean arterial pressure, decreased systemic vascular resistance and an increased cardiac output [1], [2]. Elevated levels of cytokines such as IL-6 and TNF-α can be observed in both conditions and liver failure also leads to decreased monocyte function and immunoparalysis, a finding first noted in septic shock patients [3], [4], [5].

Recent studies have reported that patients with severe sepsis and septic shock commonly have abnormalities in adrenal function [6]. Adrenal insufficiency in this setting is associated with decreased response to catecholamine therapy, haemodynamic instability and a high mortality [7], [8]. Furthermore, corticosteroid supplementation in septic shock has been shown to be beneficial in some patients [9].

Five studies have now been reported showing that adrenal insufficiency is common in critically ill patients with liver disease. These abnormalities have been described in the absence of clinical sepsis raising the possibility that the adrenal insufficiency arising in liver failure may be a different entity to that observed in septic shock [10], [11], [12], [13], [14].

The purpose of this review is to summarise the existing evidence for adrenal insufficiency in liver disease, to examine the possibility that adrenal dysfunction in liver disease may have a separate pathogenesis to that observed in sepsis and to provide insight into the potential areas for further research into this condition.

We searched online electronic databases for references using the keywords: liver, liver failure, sepsis, septic shock, cortisol, corticosteroids, adrenal insufficiency, adrenal failure, and synacthen in both English and non-English languages. Retrieved references were reviewed and the reference lists also examined for relevant references.

Back to Article Outline

2. Physiology of cortisol secretion 

Under basal conditions cortisol is secreted from the adrenal gland under the control of adrenocorticotrophic hormone (ACTH) which is released from the pituitary gland. The stimulus for ACTH release is corticotrophin releasing hormone (CRH) which is secreted from the hypothalamus. During stress, CRH and ACTH levels rise causing release of cortisol into the circulation. ACTH also stimulates cortisol synthesis by up regulation of enzymes and receptors on the adrenal gland involved in cortisol production [15].

Cortisol inhibits the mediators of inflammation such as neutrophil recruitment and cytokine release [16], [17]. In addition to these immunomodulatory effects, corticosteroids may increase vascular tone and cardiac output [18], [19]. Taken together these effects may be seen to be beneficial in critical illness especially where over activation of the inflammatory cascade is harmful such as in septic shock. Indeed, recovery from septic shock is dependent on adequate levels of cortisol. Early studies using adrenalectomised animals with septic shock showed that recovery from sepsis did not occur without supplemental corticosteroid administration, even in the presence of adequate antibiotic therapy [20].

Back to Article Outline

3. The role of adrenal function testing and corticotherapy in sepsis and septic shock 

Investigators have attempted to exploit the potential beneficial effects of corticosteroid therapy for patients with septic shock. Initial reports were favourable, one study showing a dramatic improvement in survival in patients treated with high dose dexamethasone or methylprednisolone in the early stages of the illness [21]. However, further studies using high dose corticosteroid therapy could not reproduce these findings and in one case high dose corticosteroids were associated with increased mortality [22], [23].

Despite these discouraging results, interest in the use of corticosteroids for septic shock continued, and subsequently a number of controlled clinical trials have reported that corticosteroids may indeed be beneficial (Table 1). The major change in these studies was the use of lower doses of corticosteroids, which could be expected to provide more physiological levels of corticosteroid with a lower incidence of adverse events. The first of these major studies investigated the use of 100mg hydrocortisone three times daily for 5 days, in vasopressor-dependent septic patients. Patients receiving corticosteroids had significantly improved reversal of shock, lower vasopressor requirements and a lower mortality (32% vs. 64%) at 28 days [24]. Similar findings were found in the study by Briegel et al. who randomised patients with vasopressor dependent septic shock to low dose (0.18mg/kg/h) hydrocortisone for six days or placebo. No survival benefit was seen in this study but the hydrocortisone treated group showed quicker resolution of shock [25].

Table 1. Published controlled trials of ‘low dose’ or ‘physiological’ corticosteroids in sepsis or septic shock
AuthorTrial designNo. of patientsSteroid doseOutcomes
Bollaert et al. [24]RDBCT41Hydrocortisone 100mg t.d.sImproved haemodynamics, non-significant decrease in mortality
Briegel et al. [25]RDBCT40Hydrocortisone 100mg bolus, infusion 0.18mg/kg/hFaster reversal of shock
Yildiz [37]RDBCT40Prednisolone 5mg mane, 2.5mg nocteImproved shock reversal, trend towards decreased mortality
Annane et al. [27]RDBCT300Hydrocortisone 50mg bolus then 6 hourly. Fludracortisone 50μg/daySurvival benefit in patients with RAI
Keh et al. [38]Crossover40100mg hydrocortisone bolus, 10mg/h infusionDecreased time to shock reversal, improved haemodynamics
Oppert et al. [39]RDBCT4150mg hydrocortisone bolus, infusion 0.18mg/kg/hEarlier shock reversal in treatment group. No survival benefit
Confalonieri et al. [40]RCT46 (severe community acquired pneumonia)200mg bolus hydrocortisone, 10mg/h infusionReduction in PaO2:FiO2 ratio at day 8. Increased survival

RDBCT, randomised double blind controlled clinical trial; RCT, randomised controlled trial.

Even though absolute levels of cortisol may be raised in septic shock the response of some patients to supplemental corticosteroids suggests that in some patients the cortisol response to stress is inadequate [26]. This phenomenon has been termed relative adrenal insufficiency (RAI). Various definitions of RAI now exist but generally there is agreement that patients with critical illness who show a blunted response to adrenocortical stimulation regardless of the baseline cortisol levels may have RAI. Most studies have used baseline cortisol level of <414nmol/L or an increment of <248nmol/L following adrenal stimulation to define RAI in highly stressed patients. Evidence supporting the concept of RAI came from the study by Annane et al. which examined the outcome of 189 septic shock patients who underwent adrenocortical function testing with 250μg of ACTH [8]. The authors found a clear association between outcome and the result of the adrenal function testing. The lowest survival was in the group with the highest baseline cortisol who had a blunted (<248nmol/L) increase in cortisol following stimulation. Conversely, the best survival was in the group with high basal cortisol levels and an appropriate response to stimulation [8]. The same group then performed a multicentre study to examine the hypothesis that adrenal replacement therapy would benefit those patients with RAI. In this randomised trial of 300 patients, the use of hydrocortisone 50mg four times daily and fludracortisone 50μg/day was associated with early withdrawal of vasopressors and improved survival at 28 days [27].

Despite ongoing controversy over dosage, duration and need for adrenal function testing, the administration of stress doses of corticosteroids has become common practice in the treatment of patients with septic shock. Indeed, international guidelines now recommend the use of corticosteroids in patients with vasopressor dependent septic shock [28].

Back to Article Outline

4. Evidence for adrenal insufficiency in liver disease 

There have now been a number of studies of adrenal function in patients with liver disease (Table 2). These studies show that RAI is common and may carry prognostic value.

Table 2. Clinical studies of adrenal insufficiency in patients with liver disease
AuthorNo. of patientsType of liver diseaseDefinition of adrenal insufficiencyPatients fulfilling definition %Outcome in adrenally insufficient patients
Marik et al. [13]340ACLFCortisol<414nmol/L basal<552nmol/L in highly stressed or <552nmol/L following low dose adrenal stimulationACLF 66Adrenal insufficiency associated with increased mortality and haemodynamic instability
ALFALF 33
OLT (remote)Remote OLT 61Increased survival in patients treated with corticosteroids
OLT (immediate)Immediate OLT 92
Harry et al. [11]45ALFShort synacthen test62Adrenal insufficiency associated with haemodynamic instability; mortality and need for emergency transplantation
Peak<500nmol/L
Any part<250nmol/L

Harry et al. [10]20ALF/ACLFShort synacthen test69All patients treated with steroids – no difference in mortality compared to control group
Peak<500nmol/L
Any part<250nmol

Tsai et al. [12]101Cirrhosis with severe sepsisShort synacthen test51.4Decreased survival in adrenal insufficiency patients
Baseline<414nmol/L
Increment<248nmol/L

Fernandez et al. [14]25Cirrhosis with severe sepsisShort synacthen test63Faster resolution of shock
Baseline<414nmol/L Improved survival compared to historical controls
Increment<248nmol/L

ACLF, acute on chronic liver failure; ALF, acute liver failure; OLT, orthotopic liver transplantation; Remote OLT, patients readmitted post liver transplantation requiring intensive care; Immediate OLT, patients immediately post liver transplantation requiring intensive care.

Harry et al. prospectively evaluated 45 patients admitted to a single centre with acute hepatic dysfunction (defined as no evidence of chronic liver disease, increased transaminases and coagulopathy or encephalopathy) [11]. All patients underwent adrenal stimulation with a short synacthen test (SST) using 250μg synthetic ACTH within the first 5 days of admission to the intensive therapy unit (ITU). Paracetomol hepatotoxicity (34/45 patients) was the commonest aetiology, 36 patients were intubated and mechanically ventilated and 22 patients either died or required emergency transplantation. Patients who were considered haemodynamically unstable (mean arterial pressure <60mmHg or need for vasopressors) on the day of adrenal function testing showed significantly lower peak (median 436nmol/L) and incremental levels (median 196nmol/L) of cortisol following SST compared to haemodynamically stable patients (median peak 892nmol/L, median increment 566nmol/L). Subnormal SST results were observed more frequently in patients with more organ failure, need for emergency transplantation and those who did not survive. Microbiological evidence of infection was found in 6 patients in the five days before SST, exclusion of these patients from the analysis did not affect the significance of the results. The authors interpreted their findings as evidence that subnormal adrenal responses in liver dysfunction were related to the severity of the liver and multiple organ failure and independent of the presence of sepsis [11].

The same authors also investigated the effect of corticosteroid therapy (300mg hydrocortisone/day) in 20 vasopressor-dependent patients with acute liver failure (ALF) or acute on chronic liver failure (ACLF) and compared these to a historical control group of patients not treated with steroids. The use of steroids was associated with reduction in vasopressor doses but no survival benefit. Notably, the incidence of infection was higher in the corticosteroid treated group, especially with resistant organisms such as methicillin resistant Staphylococcus aureus (MRSA) [10].

Using a different definition of adrenal insufficiency, Marik et al. reported the outcome of 340 patients with liver disease who underwent adrenal function testing on admission to a dedicated liver ITU [13]. In this study adrenal insufficiency was defined as a random cortisol level of <552nmol/L in hypoxic, hypotensive or vasopressor dependent patients, a random cortisol level of <414nmol/L in less stressed patients or a cortisol level of <552nmol/L following low dose (1μg) ACTH stimulation. Patients with ALF, ACLF and patients either immediately post liver transplantation or who had been transplanted previously but required intensive care were evaluated.

Using the above criteria, the reported incidence of adrenal insufficiency was 72%. The prevalence of adrenal insufficiency varied between the groups, being seen in 66% of ACLF patients, 33% of ALF patients and 61% of patients who had undergone liver transplantation in the past. Interestingly, of the patients recently undergoing liver transplantation with a steroid free regimen, the incidence of adrenal insufficiency was 92%. There were no differences in either the severity of the liver disease or the severity of the critical illness between patients with or without adrenal insufficiency; in fact the only laboratory variable predictive of adrenal insufficiency was the serum HDL cholesterol level. Some patients with adrenal insufficiency were treated with steroids and these patients had a lower mortality rate (26% vs. 46%), compared to patients with adrenal insufficiency who were not treated but this was not assessed prospectively.

Intriguingly, the authors speculate that the surprisingly high incidence of adrenal insufficiency in patients undergoing liver transplantation under a steroid free regimen may have been unrecognized in the past due to the use of corticosteroids in most immunosuppressive regimens [13].

More recently, the issue of adrenal insufficiency has been explored in patients with chronic liver disease complicated by sepsis [12], [14]. In the first study 101 patients with chronic liver disease of varying aetiologies and sepsis underwent adrenal function testing using the SST. The authors found that 51% of their patients fulfilled their criteria for adrenal insufficiency, defined as baseline cortisol <248nmol/L or an increment <248nmol/L after 250μg ACTH stimulation. Patients with adrenal insufficiency had lower mean arterial pressure on the day of SST testing and were more likely to need vasopressor treatment. Moreover, the degree of adrenal dysfunction correlated with disease severity as measured by Childs Pugh, MELD and Apache III scores. The response to adrenal stimulation was also an independent predictor of mortality which was increased in the adrenal insufficiency group. In the second study, the effect of treating patients with cirrhosis and septic shock with low dose hydrocortisone was evaluated [14]. This was a prospective study of the impact of hydrocortisone therapy on the outcome of 25 cirrhotic patients with septic shock. In this study, RAI was defined as a baseline cortisol concentration less than 414nmol/L or an increase in plasma cortisol after SST<248nmol/L in patients with baseline cortisol concentration below 966nmol/L. The patients treated with steroids were compared to a group of patients treated on the same ITU prior to the introduction of adrenal function testing in septic shock. The authors found RAI in 18/25 (68%) and this group of patients was treated with hydrocortisone. In the treated group of patients there was quicker resolution of shock and an apparent survival benefit compared to historical controls that had not undergone adrenal function testing [14].

Back to Article Outline

5. Conclusions 

The above data suggest that patients with liver failure and especially those with sepsis have a high incidence of RAI and that the degree of adrenal dysfunction is correlated with the severity of the liver disease. Although the existing evidence is limited, the finding that RAI can be observed in ALF patients with no apparent evidence of sepsis or in patients immediately post liver transplantation suggests that RAI could be a feature of liver disease per se, leading one group to propose the term ‘hepatoadrenal syndrome’ [13].

If ‘hepatoadrenal syndrome’ exists, what is the mechanism? In sepsis, elevated levels of pro-inflammatory cytokines cause reductions in CRH and ACTH release and therefore low levels of cortisol. Additionally, there is increased conversion of cortisol to inactive cortisone and peripheral resistance to the actions of cortisol [29]. Cortisol levels may also be reduced by adrenal haemorrhage which occurs in septic shock. There is no reason to believe that similar mechanisms do not underlie the finding of RAI in patients with liver failure even in the absence of sepsis as similar elevations of pro-inflammatory cytokines have been reported and evidence of adrenal haemorrhage exists in some patients [30]. However, the finding of a high prevalence of RAI in patients undergoing recent liver transplantation as reported by Marik et al. points to a different mechanism [13]. The authors of this study suggest that low levels of HDL cholesterol may be responsible for the observed defects in adrenal function in liver disease [13]. Although this may be just a marker of disease severity, low levels of HDL cholesterol may have relevance to the pathogenesis of RAI as the adrenal gland does not store cortisol and therefore low cholesterol levels may limit supply of substrate for cortisol synthesis in situations of stress [31]. Further evidence for the role of HDL in the pathogenesis of adrenal insufficiency comes from another study from the same group showing that 16% of patients who originally had normal adrenal function developed adrenal insufficiency over a mean period of three days and this was predicted by low levels of HDL [31]. This is a plausible hypothesis, however, there are limitations in interpreting studies of adrenal function in liver disease mainly arising from the method used to assay cortisol.

In serum, 70% of circulating cortisol exists bound to corticosteroid binding globulin (CBG), 20% is bound to albumin and 10% exists as biologically active free cortisol. Total cortisol is most commonly assayed and therefore in conditions such as liver failure where albumin and CBG levels are reduced, total cortisol levels may be low whereas free cortisol levels may be normal or even increased [32].

The dose of ACTH used for testing adrenal function may also have an important influence on the diagnosis of RAI in liver failure and perhaps accounts for the variability in the prevalence of RAI in the various studies. In septic patients there are differences in peak cortisol levels after 1 and 250μg ACTH tests resulting in increased diagnosis of RAI in the group receiving the lower dose [33]. Notably the 1μg ACTH test was used in the study by Marik et al., perhaps explaining why they were able to find adrenal insufficiency in up to 92% of the patients studied [13]. However some authors argue that the 1μg ACTH test may represent a more sensitive test of underlying adrenal function as the 250μg dose of ACTH represents a dose far in excess of that observed in even the most highly stressed patients [33].

Accurate diagnosis of RAI in liver disease is crucially important because if diagnosed in the setting of critical illness/septic shock most experts would recommend the use of intravenous hydrocortisone in doses ranging from 200 to 300mg/hydrocortisone per day. The use of supplemental hydrocortisone in this setting is supported by controlled data showing improved survival but currently there are no controlled trial data to recommend this approach in liver failure. In the two studies of cirrhotic patients with sepsis, uncontrolled data suggest a mortality benefit from the use of hydrocortisone [13], [14]. However, in the study by Harry et al. the use of hydrocortisone was not associated with survival benefit and the incidence of sepsis, especially with resistant organisms, was increased [10]. One explanation for this finding is that corticosteroid treated patients survived for longer on the ITU leading to increased exposure to resistant organisms. Interestingly, in this study the haemodynamic benefit of steroids was seen in patients independently of whether the results of the SST had demonstrated adrenal insufficiency. These findings are similar to those reported recently in septic shock patients calling into question the role of adrenal function testing in these settings [34]. Current low dose corticosteroid regimens are designed to replace physiological cortisol in patients with RAI, however cortisol levels in blood using such ‘low dose regimens’ are actually much higher than those found in patients who are maximally stressed [33]. Therefore, current regimens of corticosteroid use should be considered to be pharmacological rather than physiological.

Whether RAI in liver disease is an entity specific to liver failure or occurs by the same mechanism as in sepsis is currently unknown and represents an exciting area for clinical research. It is unknown for instance, whether adrenal failure in liver disease is primary or secondary, there are scant data on the prevalence of adrenal dysfunction in cirrhosis and most importantly, the effect of corticosteroid therapy on mortality in patients with liver disease and RAI has never been examined in controlled studies. The finding of a high incidence of RAI in patients undergoing steroid free immunosuppression is provocative and challenges those units that use steroid free regimens to test the hypothesis that RAI affects outcome after liver transplantation especially as a recent case report has highlighted the importance of recognizing and treating adrenal insufficiency in the post liver transplant period [34].

How RAI is defined in the context of liver failure will require studies using different doses of ACTH to determine the optimal performance of this test in liver disease, additionally it would be valuable if such studies included assays for CBG and free cortisol levels. Patients with liver disease are also prone to sepsis, which is frequently culture negative. Therefore, to clarify the role of occult sepsis in future studies of adrenal dysfunction in patients with liver disease, sensitive tests for the presence of infection such as screening for bacterial DNA should be used [35], [36].

At the present time no clear recommendations can be made on the use of adrenal function testing and corticotherapy in liver failure. In those patients that are septic and vasopressor dependent, international guidelines recommend the use of steroids. However, the efficacy of corticosteroids in other patients with liver failure is unclear and must await the results of studies such as those described above.

Back to Article Outline

References 

  1. Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther. 2001;89:221–231
  2. Clemmesen O, Ott P, Larsen FS. Splanchnic metabolism in acute liver failure and sepsis. Curr Opin Crit Care. 2004;10:152–155
  3. Fiuza C, Suffredini AF. Human models of innate immunity: local and systemic inflammatory responses. J Endotoxin Res. 2001;7:385–388
  4. Antoniades CG, Wendon J, Vergani D. Paralysed monocytes in acute on chronic liver disease. J Hepatol. 2005;42:163–165
  5. Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghoner A, Vidacek D, Siewert E, et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol. 2005;42:195–201
  6. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ. 2004;329:480
  7. Hoen S, Mazoit JX, Asehnoune K, Brailly-Tabard S, Benhamou D, Moine P, et al. Hydrocortisone increases the sensitivity to alpha1-adrenoceptor stimulation in humans following hemorrhagic shock. Crit Care Med. 2005;33:2737–2743
  8. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000;283:1038–1045
  9. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141:47–56
  10. Harry R, Auzinger G, Wendon J. The effects of supraphysiological doses of corticosteroids in hypotensive liver failure. Liver Int. 2003;23:71–77
  11. Harry R, Auzinger G, Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology. 2002;36:395–402
  12. Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, Fang JT, et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology. 2006;43:673–681
  13. Marik PE, Gayowski T, Starzl TE. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med. 2005;33:1254–1259
  14. Fernandez J, Escorsell A, Zabalza M, Felipe V, Navasa M, Mas A, et al. Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival. Hepatology. 2006;44:1288–1295
  15. Arlt W, Stewart PM. Adrenal corticosteroid biosynthesis, metabolism, and action. Endocrinol Metab Clin North Am. 2005;34:293–313viii
  16. Snijdewint FG, Kapsenberg ML, Wauben-Penris PJ, Bos JD. Corticosteroids class-dependently inhibit in vitro Th1- and Th2-type cytokine production. Immunopharmacology. 1995;29:93–101
  17. Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA. 1992;89:9991–9995
  18. Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol. 2004;2:1–12
  19. Hellman A, Lundberg D. Hemodynamic effects of high doses of corticosteroids. Acta Chir Scand Suppl. 1985;526:13–18
  20. Hinshaw LB, Beller BK, Chang AC, Murray CK, Flournoy DJ, Passey RB, et al. Corticosteroid/antibiotic treatment of adrenalectomized dogs challenged with lethal E. coli. Circ Shock. 1985;16:265–277
  21. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976;184:333–341
  22. Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653–658
  23. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. The Veterans Administration Systemic Sepsis Cooperative Study Group. N Engl J Med 1987;317:659–65.
  24. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645–650
  25. Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, 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
  26. Baldwin WA, Allo M. Occult hypoadrenalism in critically ill patients. Arch Surg. 1993;128:673–676
  27. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–871
  28. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858–873
  29. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002;122:1784–1796
  30. Sekiyama KD, Yoshiba M, Thomson AW. Circulating proinflammatory cytokines (IL-1 beta, TNF-alpha, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis. Clin Exp Immunol. 1994;98:71–77
  31. Marik PE. Adrenal-exhaustion syndrome in patients with liver disease. Intensive Care Med. 2006;32:275–280
  32. Ho JT, Al-Musalhi H, Chapman MJ, Quach T, Thomas PD, Bagley CJ, et al. Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab. 2006;91:105–114
  33. Widmer IE, Puder JJ, Konig C, Pargger H, Zerkowski HR, Girard J, et al. Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab. 2005;90:4579–4586
  34. Iwasaki T, Tominaga M, Fukumoto T, Kusunoki N, Sugimoto T, Kido M, et al. Relative adrenal insufficiency manifested with multiple organ dysfunction in a liver transplant patient. Liver Transpl. 2006;12:1896–1899
  35. Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis. 2001;33:41–48
  36. Ratanarat R, Cazzavillan S, Ricci Z, Rassu M, Segala C, de Cal M, et al. Usefulness of a molecular strategy for the detection of bacterial DNA in patients with severe sepsis undergoing continuous renal replacement therapy. Blood Purif. 2007;25:106–111
  37. Yildiz O, Doganay M, Aygen B, Guven M, Kelestimur F, Tutuu A. Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Crit Care. 2002;6:251–259
  38. Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, et al. Immunologic and hemodynamic effects of ”low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003;167:512–520
  39. Oppert M, Schindler R, Husung C, Offermann K, Graf KJ, Boenisch O, et al. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med. 2005;33:2457–2464
  40. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005;171:242–248

☆ The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

PII: S0168-8278(07)00353-4

doi:10.1016/j.jhep.2007.06.008

Journal of Hepatology
Volume 47, Issue 3 , Pages 418-423, September 2007

Article Tools