Hepatology highlights
Authors: Elwyn Elias
Journal: Hepatology (2004)

Two studies have examined the effect that therapeutic maneuvers have on intracranial pressure in patients with acute liver failure. Both cerebral edema and increased cerebral blood flow are major determinants of intracranial pressure, and herniation of the midbrain due to elevated intracranial pressure remains a common cause of death. Cerebral edema is one of the most serious and sinister complications of acute liver failure (ALF). Water movement across the blood–brain barrier is more dependent on diffusion across osmotic gradients than on pressure filtration which is the main determinant in organs where endothelia are fenestrated. Consequently, much experimental work has focused on the contribution of intracerebral osmolytes—including glutamine—to brain swelling. In many countries, intravenous bolus terlipressin is used with obvious benefit for treatment of the hepatorenal syndrome in patients with chronic liver disease. Under those circumstances the aim is to constrict the splanchnic circulation and improve renal perfusion through improvement systemic hemodynamics. In a recent study by Shawcross and colleagues, terlipressin was administered to six patients with ALF in a single small bolus dose that had no detectable effect on the systemic circulation. Nevertheless, ICP increased significantly because of a significant rise in cerebral blood flow. The concern thus raised by Shawcross and colleagues illustrates the fundamentally different pathophysiologies of acute and chronic liver failure and the pitfalls of failing to distinguish between them in therapy. (See HEPATOLOGY 2004;39:471–475.) Clinical research in nonalcoholic steatohepatitis (NASH) has reached an interim phase wherein many of the issues have been clarified and clear pointers have been provided. The two major clinical dilemmas for the clinician confronted by nonalcoholic fatty liver disease (NAFLD) remain “Should we biopsy?” and, when the biopsy is diagnostic of NASH, “How to treat?” The aim of biopsy is mainly to detect steatohepatitis and cirrhosis-threatening fibrosis. Bugianesi and colleagues report on a large Italian study in which 263 patients were enrolled with NAFLD but no overt symptoms of diabetes. Univariate analysis identified older age, female gender, obesity, increased aspartate aminotransferase–alanine aminotransferase ratio, higher serum ferritin level, increased fasting glucose, and decreased insulin sensitivity as predictors of severe fibrosis; the presence of these factors strengthens the case for biopsy. The importance of insulin resistance in the cause of NASH is once more confirmed by the finding that reduced oral glucose insulin sensitivity (OR = 0.53; CI = 0.33–0.87; P = .0113) was an independent predictor of severe fibrosis. The hyperferritinemia should not be interpreted as an indicator of iron overload, which in the past has been proposed as a common cofactor in the pathogenesis of NASH. There was no increased prevalence of genetic hemochromatosis (C282Y or H69D) in the NAFLD cohort above that found in the background population. Histologic evidence of hepatic iron overload was present in only 9%, but hyperferritinemia occurred in 21% and constituted an independent predictor of severe fibrosis (OR = 1.77; 95% CI = 1.21–2.58; P = .0032); therefore, in this context hyperferritinemia appears to be an index of hepatic injury rather than of iron stores. (See HEPATOLOGY 2004;39:179–187.) Consolidation of the view that insulin resistance plays a key role is provided by another report by Promrat and colleagues of improvement in NASH during therapy to enhance sensitivity to insulin, this time with pioglitazone. As highlighted in the December 2003 issue of HEPATOLOGY in a closely parallel study with Rosiglitazone (HEPATOLOGY 2003:38:1008–1017), these agents improve serum transaminases, hepatic steatosis, and histologic features of steatohepatitis, presumably as a direct consequence of improving sensitivity to insulin. Both trials of treatment of NASH with these thiazolidinedione derivatives reported that the main adverse event was weight gain. (See HEPATOLOGY 2004;39:188–196.) An important negative result is reported by Lindor and colleagues, who found no benefit in 166 patients with biopsy-proven NASH randomized to 2 years' treatment with ursodeoxycholic acid (13–15mg/kg/d) or placebo. (See HEPATOLOGY 2004;39:770–778.) The identification of a group of adenosine triphosphate–binding cassette transporters in the bile canalicular membrane and the recognition that inherited mutations of their encoding genes are responsible for a group of inherited progressive familial intrahepatic cholestatic (PFIC) diseases begged the question of whether or not they may have a role in the chronic cholestatic diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). This speculation was fueled by the realization that different point mutations in the same gene account for the phenotypically polarized progressive familial intrahepatic cholestasis of childhood and benign remitting recurrent intrahepatic cholestasis. Pauli-Magnus and colleagues report on their findings from sequencing the promoter, coding, and flanking intronic regions of genes encoding for the bile salt export pump and phospholipid flippase, mutations of which account for PFIC2 and PFIC3, respectively. One hundred and forty-nine healthy Caucasians acted as a control group and were compared with 76 PBC patients and 46 PSC patients. Although many variants were defined, there were no disease-specific differences in haplotype distribution or linkage disequilibrium, making it very unlikely that these transporters have any causal role in the initiation of these diseases. (See HEPATOLOGY 2004;39:779–791.)