The hepatoadrenal syndrome: A common yet unrecognized clinical condition*

Abstract

Objective-Adrenal failure is common in critically ill patients, particularly those with sepsis. As liver failure and sepsis are both associated with increased circulating levels of endotoxin and proinflammatory mediators and reduced levels of apoprotein-1/high-density lipoprotein, we postulated that adrenal failure may be common in patients with liver disease. Design-Clinical study.Setting-Liver transplant intensive care unit. Patients-The study cohort included 340 patients with liver disease.Interventions-Based on preliminary observational data, all patients admitted to our 28-bed liver transplant intensive care unit (LTICU) undergo adrenal function testing. An honest broker system was used to extract clinical, hemodynamic, medication, and laboratory data on patients admitted to the LTICU from March 2002 to March 2004. A random (stress) Cortisol level <20 μg/dL in a highly stressed patient (respiratory failure, hypotension) was used to diagnose adrenal insufficiency. In all other patients, a random Cortisol level <15 μg/dL or a 30-min level <20 μg/dL post-low-dose (1 μg) cosyntropin was considered diagnostic of adrenal insufficiency. Patients were grouped as follows: a) chronic liver failure; b) fulminant hepatic failure; c) patients immediately status postorthotopic liver transplantation receiving a steroid-free protocol of immunosuppression; and d) patients status post-remote liver transplant (≥6 months). The decision to treat patients with stress doses of hydrocortisone was at the discretion of the treating intensivist and transplant surgeon.. Measurements and MainResults-Two-hundred and forty-five (72%) patients met our criteria for adrenal insufficiency (the hepatoadrenal syndrome). Eight (33%) patients with fulminant hepatic failure, 97 (66%) patients with chronic liver disease, 31(61%) patients with a remote history of liver transplantation, and 109 (92%) patients who had undergone liver transplantation under steroid-free immunosuppression were diagnosed with adrenal insufficiency. The high-density lipoprotein level at the time of adrenal testing was the only variable predictive of adrenal insufficiency (p < .0001). In vasopressor-dependent patients with adrenal insufficiency, treatment with hydrocortisone was associated with a significant reduction (p = .02) in the dose of norepinephrine at 24 hrs, whereas the dose of norepinephrine was significantly higher (p = .04) in those patients with adrenal failure not treated with hydrocortisone. In vasopressor-dependent patients without adrenal insufficiency, treatment with hydrocortisone did not affect vasopressor dose at 24 hrs. One hundred and forty-one patients (26.4%) died during their hospitalization. The baseline serum Cortisol was 18.8 ± 16.2 μg/ dL in the nonsurvivors compared with 13.0 ± 11.8 μg/dL in the survivors (p < .001). Of those patients with adrenal failure who were treated with glucocorticoids, the mortality rate was 26% compared with 46% (p = .002) in those who were not treated. In those patients receiving vasopressor agents at the t...

High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

“…Two of the ABCA1 mutation study it was shown that low HDL-C in such patients was associated with attenuated adrenal responses to synthetic adrenocorticotropic hormone (ACTH) ( 7 ). In support of this, others reported a high incidence of adrenal failure in critically ill individuals with liver disease, with HDL-C being the only variable predictive of adrenal insuffi ciency ( 8 ).…”

Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial

“…17 Relative adrenal insufficiency has recently been described in 62%-80% of heterogeneous groups of patients with liver disease. 11,12,29,30 Our study shows a prevalence of relative adrenal insufficiency reaching 76% in a homogenous group of patients with cirrhosis presenting with septic shock. Several potential mechanisms have been postulated, including adrenal exhaustion, 31 inhibition of cortisol synthesis by tumour necrosis factor-α 32 and, less likely, adrenal hemorrhage.…”

Perioperative Risk Assessment and Management of Cirrhotic Patients

“…Impaired liver apolipoprotein A-1 (APO-A1) synthesis [59], a lipoprotein in high-density lipoprotein (HDL) [60], reduces HDL's ability to transport the precursor cholesterol, resulting in reduced cortisol synthesis and thus adrenal insufficiency [59]. TNF-α, IL-1β, IL-6, and endotoxin decrease the synthesis and release of apoA-1, and increase both cortisol's tissue resistance and synthesis inhibition in a dose dependent manner in LC [59,61,62]. This may be worsened by certain medications, including etomidate, by inhibition of CYP-11B2 aldolase [63].…”

“…Patients with liver failure and post-LT have a high incidence of adrenal failure, likely due to impaired cortisol biosynthesis (Table 1) [59], as adrenal glands do not store cortisol, rather production and secretion are increased by adrenocorticotropic hormone (ACTH) [59]. Impaired liver apolipoprotein A-1 (APO-A1) synthesis [59], a lipoprotein in high-density lipoprotein (HDL) [60], reduces HDL's ability to transport the precursor cholesterol, resulting in reduced cortisol synthesis and thus adrenal insufficiency [59].…”

“…Decompressive TIPS → ↑ Surgery candidacy [73,[96][97][98][99][100] Maintain Albumin ≥2.5 [78,102] Albumin 1 g/kg/d for 2 d trial [72] Unaffected by PPI administration [95] Endocrine Adrenal Failure [59][60][61][62] Impaired liver synthesis of APO-A1 → ↓ HDL → ↓ cholesterol precursor → impaired cortisol synthesis ↑ TNF-α, IL-1β, IL-6, and endotoxin → ↓ synthesis/release of apoA-1, ↑ tissue cortisol resistance Potential use for supplementary hydrocortisone and fludricortisone treatment during sepsis/septic shock [165] Renal Hepatorenal Syndrome [69] HRS type 1: Doubling of Cr (above 2.5 mg/dL) and ↓ CrCl by 50% (or >20 mL/min) in less than 2 weeks 1 month mortality exceeds 50%.…”