Page 280 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Liver Toxicity Chapter | 15 247

VetBooks.ir The liver is grossly swollen and friable with panlobular formalin (Plumlee, 2004). Compounds that produce
prominent steatosis associated with mortality include the
injury.
Apoptotic cells undergo cell shrinkage, nuclear con-
antiepileptic drug valproic acid and the antiviral agent fia-
densation and pyknosis (Dahm and Jones, 1996; Treinen- luridine. Other toxins that cause hepatic steatosis include
Moslen, 2001), but mitochondrial function (Pineiro- aflatoxin, white or yellow phosphorus, ethanol, and CCl 4 .
Carrero and Pineiro, 2004) is maintained and the cell Although steatosis has been considered a benign and
membrane remains intact (Zimmerman, 1999). Phagocytes reversible change, studies have determined biochemical
immediately remove the dead cell (Shehu et al., 2016). alterations that lead to steatohepatitis, fibrosis and cirrho-
This type of cell death is not associated with inflamma- sis (Ramaiah et al., 2004). Nonalcoholic fatty liver dis-
tion. Although apoptosis, sometimes termed “programmed ease (NAFLD), a syndrome associated with obesity in
cell death,” is a normal physiological process, it may be humans, often type II diabetics, has a marked inflamma-
induced by xenobiotics causing oxidative stress, decreased tory component (Diehl, 2002). Several endocrine abnor-
expression of apoptotic suppressors, or enhanced expres- malities also result in steatosis, making it challenging to
sion of proapoptosis genes. Apoptotic cells are occasion- determine a cause. Serum transaminase concentrations in
ally seen in the centrilobular area but are rapidly patients with steatosis are variable, but can be moderately
phagocytized by macrophages and other hepatocytes. to markedly increased. Cholestasis occurs with marked
Although necrosis and apoptosis are considered sepa- lipid accumulation.
rate entities, an alternate view is emerging that apoptosis Steatosis is termed microvesicular if fat vacuoles are
and necrosis are frequently the consequence of the same small and do not displace the nucleus. Microvesicular
initiating factors and signaling pathways. Rather than steatosis is often associated with slow lipid accumulation
being separate entities, apoptosis and necrosis represent (Bastianello et al., 1987; Plumlee, 2004). This form of
extremes on a continuum of cell death. Thus necrosis steatosis may indicate deficiency in mitochondrial
resulting from oncosis is termed “oncotic necrosis,” and β-oxidation of fatty acids. This relatively severe form of
that originating from apoptosis is termed “apoptotic steatosis and has been seen in primates and dogs with
necrosis” (Levin et al., 1999; Jaeschke et al., 2004; Malhi aflatoxicosis (Bastianello et al., 1987; Zimmerman, 1999)
et al., 2006). and people with valproic acid toxicosis (Sturgill and
The nature of the lesions can tell us something about Lambert, 1997; Zimmerman, 1999).
the mechanism of injury. Several xenobiotics, such as Macrovesicular steatosis, more common in domestic
CCl 4 , acetaminophen, thioacetamide, allyl alcohol and animals, describes hepatocytes containing one, or occa-
ethanol, produce oncotic necrosis. Centrilobular necrosis sionally a few, large fat vacuole(s) that displace the
is a common pattern seen with CCl 4 , acetaminophen and nucleus to the periphery of the cytoplasm (Plumlee, 2004).
thioacetamide. Hypoxia also causes centrilobular necrosis Macrovesicular steatosis indicates an imbalance between
since zone 3, the centrilobular region, is oxygen stressed. fatty acid uptake and secretion of very low density lipo-
Less commonly, a midzonal pattern is seen in proteins secondary to increased triglyceride mobilization,
endotoxin-mediated hepatitis in the rat model (Ramaiah decreased fatty acid oxidation, decreased synthesis of very
et al., 2004). Necrosis of periportal hepatocytes, although low density lipoproteins, or other metabolic anomalies
rare, can be observed with compounds such as allyl alcohol. (Sturgill and Lambert, 1997; Zimmerman, 1999; Treinen-
Hepatocytes in this region are relatively young and necrosis Moslen, 2001; Plumlee, 2004). Macrovesicular steatosis
can lead to portal fibrosis and bile duct proliferation. occurs with a variety of metabolic disease in domestic
Ethanol produces multifocal, random hepatic necrosis. animals, particularly in obese cats with anorexia and pre-
Necrosis may be a primary event caused by reactive parturient cattle due to mobilization of lipids.
intermediates (e.g., acetaminophen, thioacetamide and Macrovesicular steatosis has been reported in dogs with
CCl 4 ) or a secondary event following infiltration of subacute aflatoxicosis (Bastianello et al., 1987). Zone 1
inflammatory cells, as seen with ethanol. macrovesicular steatosis has been reported with yellow
phosphorus toxicosis (Zimmerman, 1999).
Hepatic Steatosis
Steatohepatitis
Hepatic steatosis/lipidosis or fatty liver is simply the
accumulation of fat vacuoles within hepatocytes. Steatosis Steatohepatitis is usually the next stage of untreated steatosis
is a common response to a variety of hepatotoxins and (Lieber, 1994; Bautista, 2002; French, 2003). Steatohepatitis
represents a potentially reversible injury (Treinen-Moslen, is the hepatocellular accumulation of lipid and inflammation
2001). Grossly, the affected liver is swollen with rounded of hepatic parenchyma. The inflammatory cells involved are
edges, friable, and light brown to yellow. Due to the fat usually neutrophils and mononuclear leukocytes. There is no
accumulation, sections of the affected liver will float in specificity noted with this pathologic stage and the