Toxicant-associated Steatohepatitis

Abstract

Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.

PCB-associated steatohepatitis and the role of nuclear receptors.

“…Most subjects within these cohorts were also overweight or obese, and the ACHS cohort was previously reported to have elevated prevalence of disease components of the metabolic syndrome, therefore, we expected to find increased prevalence of NASH, consistent with these reports, and we hypothesized that mechanism of hepatic injury would be consistent with TASH because of the toxicant exposure. Liver injury in 80% of ACHS and 73.8% of ACHS-II cases was associated with hepatocellular necrosis, a characteristic of TASH 83,84 but not of NASH, or ASH, which are associated with increased hepatocellular apoptosis…”

“…Because steatohepatitis has previously been associated with insulin resistance and systemic inflammation 83,84 , we anticipated that dysregulation in biomarkers of these conditions would be observed along with elevations in indicators of liver damage and death.…”

“…Because the hepatocellular death mechanism appears to vary by etiology of fatty liver disease 83,84 , the pattern of CK18 elevation has been used to differentiate TASH (predominantly necrotic, elevations in CK18 M65 alone) from other fatty liver diseases (predominantly apoptotic, elevated CK18 M30 and M65) 69 . Moreover, unlike transaminases, which the detectable property of enzyme activity is not retained during long-term storage…”

Biomarker discovery of liver diseases using mass spectrometry-based metabolomics.

“…Among PCB congeners, PCB 153 ( Figure 1) is present at the highest levels [69]. Dr.Cave's group has been demonstrated that chronic PCB 153 exposure worsened obesity/NAFLD in mice fed a high fat diet (HFD), but had no pathologic effect in mice fed control diet (CD) [70]. To better understand the biochemical mechanisms underlying these observations, a comprehensive investigation using high throughput analysis such as metabolomics is necessary.…”

“…According to the prevailing two hit hypothesis [127], dietary factors such as excessive fat consumption contribute to the formation of fatty liver, which makes the liver susceptible to a second hit which promotes the progression to more severe liver injury. Several factors have been shown to mediate the progression from simple steatosis (fatty liver) to steatohepatitis (fatty liver with inflammation and cell death) [128] and environmental agents that activate these factors can contribute to the extent of liver injury [129,130]. For example, arsenic was recently shown to contribute to the progression of diet-induced fatty liver disease by increasing inflammatory mediators in mouse liver [131].…”