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, it is not surprising that adrenal failure is common in patients with liver disease also. Liver failure is well recognized to cause renal (hepatorenal syndrome) and pulmonary syndrome (hepatopulmonary syndrome). However, the association between liver failure and adrenal insufficiency is less well studied. 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. Recently at least 5 studies have shown that adrenal insufficiency is common in critically ill patients with liver disease even in the absence of clinical sepsis. 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.
Singh and colleagues reported a single case of adrenal insufficiency following liver transplantation. Harry and coworkers demonstrated an abnormal high dose cosyntropin stimulation test in 28 of 45 (62%) patients with acute liver failure. In a cohort of 38 “nonstressed” patients with end-stage liver disease, McDonald et al reported a 64% reduction in peak plasma cortisol following insulin-induced hypoglycemia and a 39% reduction following a high-dose cosyntropin test when compared with healthy controls. In patients with adrenal insufficiency, the mortality rate was lower in those patients treated with glucocorticoids. Hence, untreated patients with adrenal insufficiency (low cortisol levels) and patients with a very high cortisol level may have a high mortality rate. The association between low serum HDL levels and adrenal insufficiency observed in many studies supports the notion that liver disease may lead to impaired cortisol synthesis. The adrenal gland does not store cortisol; increased secretion arises due to increased synthesis under the control of adrenocorticotropin. Cholesterol is the principal precursor for steroid biosynthesis in steroidogenic tissue. Experimental studies suggest that HDL is the preferred lipoprotein source of steroidogenic substrate in the adrenal gland. Recently, mouse SR-B1 (scavenger receptor) and its human homologue (CLA-1) have been identified as the high-affinity HDL receptors mediating selective cholesterol uptake. These receptors are expressed at high levels in the parenchymal cells of the liver and the steroidogenic cells of the adrenal glands, ovary, and testis. CLA-1 m-RNA is highly expressed in human adrenals, and the accumulation of CLA-1 m-RNA is regulated by adrenocorticotropin. Apolipoprotein (apo) A-1, the major protein component of HDL, is synthesized principally by the liver and to a lesser degree in the intestine. Cicognani and coauthors demonstrated a striking decrease in the level of serum HDL in patients with cirrhosis that was related to severity of liver disease. Thus low levels of HDL in patients with liver disease may be pathogenetically related to the high incidence of adrenal insufficiency. Van der Voort and colleagues demonstrated that in critically ill patients, low HDL levels were associated with an attenuated response to cosyntropin. Apart from low HDL levels and the reduced delivery of substrate for cortisol synthesis, other mechanisms may contribute to the pathophysiology of the hepatoadrenal syndrome. Patients with acute and chronic liver disease have increased levels of circulating endotoxin (lipopolysaccharide) and proinflammatory mediators such as tumor necrosis factor (TNF)-alpha. It is postulated that intestinal bacterial overgrowth with increased bacterial translocation together with reduced Kupffer cell activity and porto-systemic shunting results in systemic endotoxemia with increased transcription of proinflammatory mediators. Endotoxin has been shown to bind with high affinity to the HDL receptor (CLA-1) with subsequent internalization of the receptor. Lipopolysaccharide may therefore limit the delivery of HDL cholesterol to the adrenal gland. Furthermore, TNF-alpha as well as interleukin- 1 and interleukin-6 has been demonstrated to decrease hepatocyte synthesis and secretion of apoA-1. In addition to its effects on apoA-1, TNF-alpha has been demonstrated to directly inhibit cortisol synthesis in a dose-dependent manner as well as to cause tissue resistance to cortisol by decreasing the number of glucocorticoid receptors or by up-regulating binding proteins. Tsai et al studied adrenal function using short corticotropin stimulation test (SST) in 101 critically ill patients with cirrhosis and severe sepsis. Adrenal insufficiency occurred in 51.48% of patients. The patients with adrenal insufficiency had a higher hospital mortality rate when compared with those with normal adrenal function (80.76% vs. 36.7%, P < .001). The cumulative rates of survival at 90 days were 15.3% and 63.2% for the adrenal insufficiency and normal adrenal function groups, respectively (P < .0001). The hospital survivors had a higher cortisol response to corticotropin (P < .001) and the cortisol response to corticotropin was inversely correlated with MELD score, and Child-Pugh scores. Mean arterial pressure on the day of SST was lower in patients with adrenal insufficiency (P < .001), and a higher proportion of these patients required vasopressors (P < .001). Mean arterial pressure, serum bilirubin, vasopressor dependency, and bacteremia were independent factors that predicted adrenal insufficiency. In another study 25 cirrhotics with septic shock were studied and RAI was found in 68%. Quicker resolution of shock and apparent survival benefit was seen with low dose hydrocortisone.
In conclusion, relative adrenal insufficiency (RAI) is common in critically ill patients with cirrhosis with or without sepsis. It is related to functional liver reserve and disease severity and is associated with hemodynamic instability, renal dysfunction, and increased mortality. Low dose hydrocortisone may be beneficial in this condition. However, current data doesn’t suffice to recommend steroids in liver disease. Furthermore, assays for free cortisol will be more realistic in this setting as both cortisol binding globulin & S. albumin decrease in this setting and total cortisol level may be misleading. Occult infection must be ruled out in culture negative patients & dose of ACTH for SST should be standardized. Hence, more studies are required in this field, especially from Indian subcontinent.