In the liver, cortisol is converted to its inactive metabolite cortisone by the enzyme 11�� – hidroxysteroid dehydrogenase. After diffusion across the cell membrane, cortisol binds to glucocorticoid receptor and translocates into the nucleus those of the cell[37] where its effects are exerted (increased vascular tonus and cardiac output, protein catabolism, lipolysis, hyperglycemia, and decreased cytokine production)[38]. These effects of cortisol are beneficial in critical illness, and several studies have shown that corticosteroid therapy is beneficial in patients with severe sepsis or septic shock[12-14,39,40]. As adrenal glands do not store cortisol, this must urgently be synthesized from its precursor, cholesterol, under any conditions of stress.

In cirrhotic patients there is a low substrate (HDL cholesterol) for the synthesis of cortisol, favoring AI in conditions of stress[26]. PATHOGENESIS Mechanisms leading to AI in liver cirrhosis remain largely unknown, although some hypotheses such as endotoxemia, decreased levels of apolipoprotein A-1, HDL cholesterol and LDL cholesterol, increased levels of proinflammatory mediators, structural damage to the adrenal gland due to infarction or hemorrhage, bacterial translocation of enteric organisms, ��exhaustion�� of the adrenal cortex, and glucocorticoid resistance have been suggested[12,41-49]. Many (if not all) of these pathophysiologic mechanisms are also involved in the genesis of AI in critically ill patients with sepsis[50-56]. As we have mentioned, cholesterol is the main source of steroidogenic substrate in the adrenal gland[26,57].

Several studies reported a significant decrease in the level of serum HDL in cirrhotic patients which was related to the severity of the disease[12,26,47]. Furthermore, increased levels of circulating endotoxin (lipopolysaccharide) and TNF-�� inhibit cortisol synthesis, limiting the delivery of HDL cholesterol to the adrenal gland[58-60]. In addition to this, TNF-��, IL-1 and IL-6 decrease hepatocyte synthesis of apolipoprotein A-1[58], the major component of HDL cholesterol. The lack of substrate for steroidogenesis will eventually lead to the so-called ��adrenal exhaustion syndrome��[42] which contributes to AI in cirrhotic patients. Besides low levels of serum total cholesterol, HDL-cholesterol and LDL-cholesterol, other factors may play a definite role in the pathogenesis Brefeldin_A of AI in patients with liver cirrhosis. Thus, coagulopathy (frequent in liver cirrhosis) may cause adrenal hemorrhage and infarction leading to structural damage of the adrenal gland[5], resulting in AI. Systemic inflammation is common in cirrhotic patients[61]. Bacterial translocation of enteric organisms has been demonstrated in patients with advanced liver cirrhosis[41,62].