Obeticholic acid is a synthetic derivative of the naturally occurring bile acid chenodeoxycholate. Like ursodiol, it is a nontoxic bile acid and is believed to reduce liver injury by decreasing hepatic concentrations of more toxic endogenous bile acids. It also is a ligand for the nuclear farnesoid X receptor, which modulates hepatic inflammation, fibrosis, gluconeogenesis, lipid synthesis, and insulin sensitivity. Obeticholic acid was recently approved for the treatment of PBC at a dose of 5–10 mg/d orally in combination with ursodiol in patients who have had an inadequate response to ursodiol monotherapy. In a randomized, double-blind, placebo-controlled, 12-month trial, almost 50% of patients treated with combination therapy had a clinical response compared with 10% treated with ursodiol alone. Obeticholic acid causes severe pruritus in up to 25% of patients (especially at the 10 mg dose), leading to discontinuation in up to 10% of patients.
Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension is caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstriction of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding.
Several drugs are available that reduce portal pressures. These may be used in the short term for the treatment of active variceal hemorrhage or long term to reduce the risk of hemorrhage.
The pharmacology of octreotide is discussed above under Antidiarrheal Agents. In patients with cirrhosis and portal hypertension, intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h) reduces portal blood flow and variceal pressures; the mechanism by which they do so is poorly understood. They do not appear to induce direct contraction of vascular smooth muscle. Their activity may be mediated through inhibition of release of glucagon and other gut peptides that alter mesenteric blood flow. Although data from clinical trials are conflicting, these agents are probably effective in promoting initial hemostasis from bleeding esophageal varices. They are generally administered for 3–5 days.