In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease

Abstract

In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3-generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly in-

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

“…7,72 Wieckowska et al, measured CK18 fragments in plasma that had been obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy, and correlated the findings with hepatic immunohistochemistry data. 70 Plasma CK18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median 765.7 U/L versus 202.4 U/L or 215.5 U/L, respectively; P < 0.001), and independently predicted NASH (OR 1.95; 95% CI 1.18-3.22 for every 50 U/L increase). This observation was reproduced in several subsequent studies and a recent meta-analysis estimated that plasma CK18 levels have a sensitivity of 78%, specificity of 87%, and an area under the receiver operating curve (AUROC) of 0.82 (95% CI: 0.78-0.88) for steatohepatitis in patients with NAFLD.…”

“…There has been intense interest in non-invasive methods to identify advanced fibrosis in patients with NAFLD 7 ;these include the NAFLD Fibrosis Score 70 , Enhanced Liver Fibrosis (ELF) panel 70 and transient elastography. The NAFLD Fibrosis Score is based on six readily available variables (age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio) and it is calculated using the published formula (http://nafldscore.com).…”

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

“…We and others have recently observed that patients with liver steatosis exhibit strongly elevated caspase activation, which closely correlates with the severity of their fatty liver disease. 30,48 Moreover, adenoviral expression of TRAIL in mouse liver was shown to induce liver apoptosis and steatosis. 49 This is in accordance with experimental models of hepatitis, in which hepatic cell death was strongly reduced in TRAILdeficient mice or mice treated with a blocking TRAIL receptor.…”

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

“…When liver biopsies are performed, tissue should be preserved for Oil Red O staining, which is a sensitive test for microvesicular steatosis. Blood tests will hopefully soon be available for CK-18, a promising marker of apoptosis [40].…”

“…It easily goes undetected if the patient is asymptomatic. Newer, more sensitive tests for apoptosis such as caspase-3-generated cytokeratin-18 (CK-18) may help in its recognition [40].…”