Non‐alcoholic steatohepatitis: Impaired antipyrine metabolism and hypertriglyceridaemia may be clues to its pathogenesis

Abstract

Non-alcoholic steatohepatitis resembles alcoholic liver disease in hepatic morphology but appears to have a different natural history. We sought to assess the nature of non-alcoholic steatohepatitis by a prospective study of its clinical progression and the relationship of biochemical abnormalities to changes in serum lipids among 15 patients with this disorder. In addition, antipyrine clearance (Cl-AP), which reflects hepatic microsomal oxidative capacity, was measured serially. Although initial liver histology included micronodular cirrhosis in five cases and bridging fibrosis in another three, only one patient developed a hepatic complication during 1-10 years (median: 3.7) of follow up. This confirms the relatively benign nature of non-alcoholic steatohepatitis. Moreover, Cl-AP, which was below the normal range in 13 patients, did not change significantly during 10-40 months of follow up. However, compared with other chronic liver diseases, the reduced Cl-AP was disproportionately low relative to the uniformly normal serum albumin concentration and other indices of hepatic metabolic function. This is consistent with selective impairment of endoplasmic reticular drug oxidizing enzymes. Hyperlipidaemia was present in 11 patients. In three of these, diet-induced correction of serum triglyceride elevation was associated with reduction of hepatocellular damage as indicated by serum enzyme levels. A hypothesis that unites these and earlier findings is that release of cytokines may occur in non-alcoholic steatohepatitis and produce accumulation of free fatty acids in the liver, leading to focal necro-inflammatory lesions and the destruction or down-regulation of cytochrome P450.

Pregnane X Receptor and Constitutive Androstane Receptor at the Crossroads of Drug Metabolism and Energy Metabolism

“…Down-regulation of constitutive P450 expression in rat liver was proportional to the extent of hepatic lipid accumulation. Moreover, the capacity of drug metabolism was reported to be impaired in human patients with obesity, hepatic steatosis, and NASH (Fiatarone et al, 1991;Blouin and Warren, 1999;Cheymol, 2000). Liver lipid accumulation, especially in the early stage of steatosis, can significantly down-regulate several important P450s (Zhang et al, 2007), which is consistent with the decreased P450 expression in liver microsomes derived from patients with steatosis and NASH (Donato et al, 2006(Donato et al, , 2007Fisher et al, 2009).…”

Impaired Microsomal Oxidation of the Atypical Antipsychotic Agent Clozapine in Hepatic Steatosis

“…It is noteworthy that CYP1A2 and CYP3A4 have been shown to be important enzymes in norCLZ formation in human liver (Tugnait et al, 1999;Olesen and Linnet, 2001). These findings are also in accord with the decrease in antipyrine clearance that has been reported in NASH patients (Fiatarone et al, 1991). Indeed, antipyrine clearance in humans has been shown to be dependent on several P450s, in particular CYP1A2 and CYP3A4 (Engel et al, 1996).…”

“…Suppression of important xenobiotic and steroid hydroxylating P450s from the 2C and 3A subfamilies was proportional to the extent of hepatic lipid deposition in rats (Su et al, 1999) and force-fed geese (Leclercq et al, 1998). Drug clearance may also be impaired in humans with obesity, early steatosis, and NASH (Fiatarone et al, 1991;Blouin and Warren, 1999;Cheymol, 2000). However, changes in the extrahepatic distribution of lipophilic drugs in obese subjects may alter their pharmacokinetic and pharmacodynamic profiles and necessitate dose adjustments (Casati and Putzu, 2005).…”

HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity

“…The other 22 subjects in the database were not enrolled in this study for the following reasons: deceased (6, including 4 who had died from liver failure), lost to follow-up (12), unwilling to participate (2), had secondary causes of NASH (2), one had undergone biliopancreatic diversion for obesity and the other had been using methotrexate for psoriasis (1); the characteristics of most of these cases (n ϭ 66) have been summarized elsewhere. [16][17][18] The pathologic diagnosis of NASH was based on the criteria of Brunt et al 19 as follows: (1) a liver biopsy showing steatosis, lobular inflammation, and hepatocellular degeneration, irrespective of the presence of fibrosis or Mallory bodies; (2) exclusion of patients with secondary causes of NASH; and (3) exclusion of other liver disorders (alcoholic liver disease, viral hepatitis [B, C, D], primary biliary cirrhosis, sclerosing cholangitis, Wilson's disease, ␣ 1 -antitrypsin deficiency, drug-induced liver disease, biliary obstruction, and hemochromatosis). Details regarding the alcohol consumption of each enrolled subject were assessed by careful questioning by at least 2 doctors in the liver clinic; corroborative evidence was always sought from family members and the referring family physician or internist.…”