Adrenal insufficiency in patients with decompensated cirrhosis

Table 1 Characteristics and outcomes of the included studies in critically ill cirrhotics

Ref.	Study design; study period; country	No. of patients; type of liver disease	Adrenal failure	Other observations	Definition of adrenal failure
Etogo-Asse et al[49]	Prospective, observational; 2007-2009; United Kingdom	163 patients; 89 ALF and 74 AOCLF-56 ALF and 36 AOCLF underwent SST	AOCLF: 21/36 58% ALF: 27/56 48%	Among those with AI 17/32 (47%) with HDL < 0.1 mmol/L vs 2/17 (12%) with HDL > 0.6 mmol/L had increment < 250 nmol/L HDL was lower in non survivors both in AOFLD and ALF	SST to those required vasopressor administration or cardiovascular instability CIRCI: Basal cortisol < 275 nmol/L or delta cortisol < 250 nmol/L
Triantos et al[5]	Prospective, observational; NR; NR	20 patients; cirrhosis and variceal bleeding vs 74 controls (14 healthy and 60 stable cirrhosis)	SST: 6/20 30% LDSST: 6/10 60% Healthy (SST and LDSST): 0/14 0% Stable (LDSST): 24/50 48% Stable (SST): 3/10 30%	AI wasn't associated with outcome Those with AI and variceal bleeding had higher baseline and peak level of cortisol with stable cirrhotic, but similar delta cortisol With SST for albumin > 2.5 mg/dL, AI: 4/16 (25%) with variceal bleeding vs 1/8 (12.5%) in cirrhosis control With LDSST, for albumin > 2.5 mg/dL, AI: 6/10 (80%) with variceal bleeding vs 16/39 (41%) in cirrhosis control	SST AI: Peak cortisol < 500 nmol/L in non-stressed patients and delta cortisol of < 250 nmol/L or a random total cortisol < 276 nmol/L in stressed patients LDSST ΑΙ: Peak cortisol < 500 nmol/L in non-stressed patients and peak cortisol level of < 690 nmol/L or a delta cortisol < 250 nmol/L in stressed patients
Thevenot et al[7]	Prospective; 2008-2009; France	30 patients; septic cirrhotic	3/30 10%	Significant correlation between salivary and serum free cortisol (P < 0.0001) Serum total cortisol were significantly lower in Child-Pugh score C than B or A, in contrary with free cortisol which had a non significant rise	SST-AI: Post-SST SC < 510.4 nmol/L Salivary cortisol was also calculated
Arabi et al[48]	Randomized double blind; 2004-2007; Saudi Arabi	75 patients; septic shock and cirrhosis in ICU	57/75 76%		SST RAI: Delta cortisol < 250 nmol/L
du Cheyron et al[6]	Prospective; 2003-2005; France	50 patients; decompensated cirrhosis in ICU (critical ill with acute on chronic liver disease)	31/50 62%		SST AI: Baseline cortisol value < 414 nmol/L, or delta cortisol < 250 nmol/L with a baseline value between 414 and 938 nmol/L
Thierry et al[52]	Prospective; March to December 2005; France	34 patients; septic shock, 14 with and 20 without cirrhosis	Cirrhotic: 11/14 77% Non cirrhotic: 10/20 50%		SST baseline cortisol < 414 nmol/L and/or delta cortisol < 250 nmol/L
Fernández et al[53]	Prospective and retrospective; group 1 2004-2006, group 2 2001-2004	Group 1: 25 patients; cirrhosis and septic shock Group 2: 50 patients; no assessment of adrenal function	17/25 68%		SST RAI: (1) Baseline cortisol concentration < 414 nmol/L or (2) delta cortisol < 250 nmol/L in patients with baseline cortisol concentration < 966 nmol/L
Tsai et al[54]	2004-2005; Taiwan	101; cirrhosis and severe sepsis required ICU	52/101 51.4% Hemodynamically unstable: 43/54 79.61% Stable: 9/47 19.14%	ICU mortality: 71.4% vs 26.5% Hospital mortality: 80.7% vs 36.7% (AI vs normal) Correlation with the severity of liver disease	SST AI: Baseline value < 414 nmol/L, or delta cortisol < 250 nmol/L with a baseline value between 414 and 938 nmol/L
Marik et al[23]	Retrospective; NR; United States	221 patients; LTICU	At admission: 120/221 54% In 3 d: 16/101 16%	Low HDL could predict the development of AI	LDSST AI: (1) a random (stress) cortisol < 552 nmol/L in patients with hypoxemic respiratory failure, hypotension or requiring vasopressor agents and (2) a random level < 414 nmol/L or a 30-min post-low-dose cosyntropin stimulation test level of < 552 nmol/L in non-highly stressed patients
Marik et al[4]	Retrospective; 2002-2004; United States	340 patients; ALD, CLD, post OLT recently and remote LT	Overall: 245/340 72% ALD: 8/24 33% CLD: 97/146 66% Remote LT: 31/51 61% Recent LT: 109/119 92% Among those treated with vasopressors: 125/166 75%	Low HDL could predict the development of AI	LDSST AI: (1) a random (stress) cortisol < 552 nmol/L in patients with hypoxemic respiratory failure, hypotension or requiring vasopressor agents and (2) a random level < 414 nmol/L or a 30-min post-low-dose cosyntropin stimulation test level of < 552 nmol/L in non highly stressed patients
Nair et al[51]	India	Critical ill cirrhotic in ICU, without sepsis	73.5%	AI is not associated with severity of liver disease, CRP or etiology of cirrhosis	SST RAI: random basal TC ≤ 276 nmol/L or delta cortisol ≤ 250 nmol/L
Saffioti et al[55]	2009-2013	80; cirrhotic pre-LT	18/80 22.5%	Patients with AI had higher MELD (19 vs 15; P = 0.003), pre-LT INR, bilirubin and potassium, and lower sodium and haemoglobin levels	SST AI: At least 2 of the following: baseline cortisol < 148 nmol/L, peak cortisol < 550 nmol/L, delta cortisol < 250 nmol/L
Graupera et al[50]	Spain	37; cirrhotic with severe variceal bleeding	14/37 38%	6 wk survival 64% without and 31% with RAI No differences in overall survival	SST RAI: Baseline serum cortisol < 414 nmol/L or delta cortisol < 250 nmol/L

NR: Not reported; AI: Adrenal insufficiency; HDL: High density lipoprotein; SC: Serum cortisol; ICU: Intensive care unit; ALF: Acute liver failure; AOCLF: Acute on chronic liver failure; SST: Short synacthen test; LDSST: Low dose short synacthen test; NR: Not reported; CIRCI: Critical illness related adrenal insufficiency; RAI: Relative adrenal insufficiency; LTICU: Liver transplant intensive care unit; OLT: Orthotopic liver transplantation; CLD: Chronic liver disease; ALD: Acute liver disease; LT: Liver transplantation; MELD: Model for end-stage liver disease; CRP: C-reactive protein; INR: International normalized ratio.