Crit Care Med 33(6): 1254-1259

The hepatoadrenal syndrome: A common yet unrecognized clinical condition

Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, PA (PEM); and Thomas E, Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA (TG, TES)

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 post-orthotopic 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 Main Results

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 time of adrenal testing, the baseline Cortisol was 10.0 ± 4.8 μg/dL in those with adrenal insufficiency compared with 35.6 ± 21.2 μg/dL in those with normal adrenal function. Vasopressor-dependent patients who did not have adrenal failure had a mortality rate of 75%.

Conclusions

Patients with liver failure and patients post-liver transplantation have an exceedingly high incidence of adrenal failure, which may be pathophysiologically related to low levels of high-density lipoprotein. Treatment of patients with adrenal failure may improve outcome. High baseline serum Cortisol levels may be a maker of disease severity and portend a poor prognosis. (Crit Care Med 2005; 33:1254–1259)

Keywords: adrenal insufficiency, cirrhosis, liver transplantation, cortisol, high-density lipoprotein, liver failure

Abstract

Once considered a rare diagnosis in the intensive care unit (ICU), adrenal failure is being reported with increased frequency in critically ill patients with sepsis, HIV infection, and head injury and following cardiac surgery (1–4). Adrenal failure may be associated with structural damage to the adrenal gland, pituitary gland, or hypothalamus: however, many critically ill patients develop reversible failure of the hypothalamic-pituitary-adrenal axis (5). Activation of the hypo-thalamic-pituitary-adrenal axis with the release of Cortisol is an essential component of the general adaptation to illness and stress and contributes to the maintenance of cellular and organ homeostasis. This is clearly demonstrated in adrenalectomized animals, who succumb rapidly to hemorrhagic and septic shock, with steroid replacement being protective against these challenges (6, 7). Furthermore, Annane and colleagues (8) demonstrated that treatment with stress doses of hydrocortisone (and supplemental mineralocorticoid) improved survival in a subgroup of septic shock patients with adrenal failure.

The fact that adrenal failure is common in critically ill patients and that treatment with stress doses of glucocorticoids may be beneficial is difficult to dispute. What remains controversial at this time is the diagnosis of this disorder (9). Circulating Cortisol is bound to corticosteroid-binding globulin with <10% in the free bioavailable form. During acute illness, there is an acute decline in the concentration of corticosteroid-binding globulin as well as decreased binding affinity for Cortisol, resulting in an increase in the free biologically active fraction of the hormone (10, 11). Corticosteroid-binding globulin is also reduced in liver disease (12). In addition, both the number and affinity of the intracellular glucocorticoid receptor may be down-regulated (tissue resistance) during acute illness (13–16). These data suggest that a serum Cortisol (total) level may not be an accurate reflection of glucocorticoid activity at the cellular level. Not withstanding these limitations, and in the absence of a readily available diagnostic test with greater specificity, we and others have demonstrated that the baseline serum Cortisol level may be useful for diagnosing adrenal failure in the critically ill as well as being a prognostic marker (1, 17, 18). There appears to be general consensus that a random Cortisol level (total) <15 μg/dL in an ICU patient is diagnostic of adrenal insufficiency (19). In addition, we contend that a level <20 μg/dL in a highly stressed patient (hypotensive, hypoxic) is abnormal (1, 5, 9).

The incidence of adrenal failure in septic shock has been reported to be as high as 61% (1). As sepsis and end-stage liver disease have a number of pathophysiologic mechanisms in common (endotoxemia, increased levels of proinflammatory mediators, decreased levels of apoprotein-A/high-density lipoprotein), we speculated that adrenal failure may be common in patients with end-stage liver disease (20–22). Indeed, in preliminary data we have observed a high incidence of adrenal failure in patients with end-stage liver disease and patients post-liver transplantation (23). Furthermore, we and others have noted an association between low levels of high-density lipoprotein (HDL) and adrenal failure (23, 24). Based on these observations, we currently routinely assess adrenal function in patients in our liver transplant ICU (LTICU).

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