Inflammation in Nonalcoholic Steatohepatitis

R Christopher Harmon; Dina G Tiniakos; Curtis K Argo

Disclosures

Expert Rev Gastroenterol Hepatol. 2011;5(2):189-200. 

In This Article

Noninvasive Diagnosis of NASH

Early identification of patients with NASH may allow for intervention that may alter the course of disease. At the time of this writing, liver biopsy remains the standard method for the diagnosis of NASH and differentiation from 'simple steatosis.' However, liver biopsy is subject to sampling error and inter- and intra-observer variability. Unfortunately, biopsy is an invasive diagnostic procedure that has associated direct and indirect costs, morbidity and rare mortality; thus, the development of noninvasive testing is paramount to the management of NASH. To date, there are no reliable serologic tests for the identification of NASH, but this may change in the near future. Identification and validation of such a test would not only aid clinicians in the identification of patients with NASH, but also allow for noninvasive frequent monitoring of disease progression and response to therapy.

Nonspecific Markers of Liver Injury

Markers of hepatocellular injury and function, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and bilirubin, are frequently measured in the evaluation of liver disease. Mild elevations of ALT and AST are common in NASH and these abnormalities are often the primary reason for referral. The degree of ALT and AST elevation is relative to the reference range for these values, but are unlikely to exceed 200.[12,131] An AST/ALT ratio of 1.5 may imply NASH, while an AST:ALT ratio of >2 implies alcoholic liver disease. Population studies utilized to determine the upper limits of normal likely included patients with NAFLD/NASH, and thus there is an international initiative to lower the upper limits of normal. Regardless, ALT and AST are not reliable indicators of NASH as they are nonspecific and are prone to false-negative results, especially in light of the current upper limit of normal values.[12,132] Abnormalities of alkaline phosphatase and bilirubin are less common. Alkaline phosphatase greater than two-times the upper limits of normal are unusual, while elevated bilirubin often indicates advanced disease in the absence of an alternate etiology.

Cytokines & Adipokines

Cytokines and adipokines may also be quantified as markers of NASH. Proinflammatory adipokines, including TNF-α and IL-6, as well as the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), are increased in metabolic syndrome and NASH.[50,133,134] Serum levels of TNF-α correlate with NASH activity; however, levels of IL-6 do not.[50,133] Patients with NASH exhibited a prolonged GIP elevation after fat ingestion that is directly correlated with hepatic steatosis, postprandial resistin and serum FFA.[135] Anti-inflammatory and antilipotoxic adipokines, including adiponectin and leptin, are dysregulated in NASH.[29,135,136] Low serum levels of adiponectin have been strongly correlated with NASH.[50,51] Results for leptin have been inconclusive; thus, its role as a biomarker of NASH is questionable.[50] Changes in cytokine and adipokine concentrations occur in response to meals, thus, if utilized as a biomarker of NASH, timing of blood draw may be critical to accurate results.[135]

Markers of Apoptosis

Hepatocyte apoptosis may be central to the pathogenesis of NAFLD,[136,137] and may be seen in NASH as a result of lipotoxicity.[138] The final common step of apoptosis results in activation of caspases that cleave several cellular substrates, including keratin 18 (K18). The byproducts of this event result in the production of K18 fragments that can be measured in serum.[138,139]

Recently, a large multicenter validation study found that the K18 fragments could accurately detect the presence of NASH with a specificity of more than 90%, or exclude the presence of NASH with a sensitivity close to 80% by adopting different test thresholds.[138] Currently, this test is limited to research studies; however, approval for clinical application is highly anticipated. K18 fragment, either alone or in combination with other tests, may alter the diagnosis and management of NAFLD/NASH.

Composite Scoring Systems

Scoring systems based on combinations of clinical and biochemical data have been developed to predict the presence of NASH. These include the HAIR score (Hypertension, ALT, Insulin Resistance),[140] the NASH Test[141] and, most recently, the Nice model based on the presence of metabolic syndrome, ALT and serum K18 fragments,[142] and a model that incorporates diabetes, ALT, hypetriglyceridemia and sleep apnea.[143] Most of these systems are based on data from bariatric patients, and their utility for predicting necroinflammatory activity in the general NAFLD population has not been evaluated yet.

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