Table 3. Histopathology of Wilson disease and diseases included in its differential diagnosis.

Disease	Steatosis	Inflammation	Mallory Denk Bodies	Nuclei	Necrosis	Cirrhosis	Ultrastructure
Wilson Disease	• Prevalent macrovesicular	• Usually scattered throughout the lobule, sometimes predominant in periportal hepatocytes	Often present	• Glycogenated hepatocyte nuclei (early disease)	Focal spotty hepato-cellular necrosis can be seen in early disease	• Usually micronodular or mixed	• Mitochondria: enlargement, separated outer and inner membranes, cristae dilatations
	• Throughout the hepatic lobule	• Predominantly lymphocytic sometimes portal lymphohistiocytic including foci of interface hepatitis		• Disorganized nucleoplasm		• Occasionally micronodular	• Electron dense lysosomes
	• Is an early manifestation of disease
Non-Alcoholic Fatty Liver Disease	• Typically macrovesicular	• Lobular: Mild scattered neutrophilic or mononuclear inflammation	Often present	Glycogenated hepatocyte nuclei can be present	Spotty necrosis (small clusters of small lymphocytes and histiocytes replacing hepatocytes) can be seen	Usually mixed, with micronodular progression to macronodular	Hepatocyte mega-mitochondria may be seen
	• Zone 3	• Hepatocellular ballooning
	• Mixed micro-vesicular & macrovesicular is associated with more severe NASH	• Perisinusoidal fibrosis
		• Lobular perivenular lipogranulomas
		• Kupffer cell aggregates
		• Fat cysts
		• Iron deposition
Alcohol-Associated Liver Disease	• Most common and earliest manifestation	• Lobular: Clusters of PMN’s (“satellitosis”) surrounding MDB-containing hepatocytes	• Common & “typical” in alcoholic hepatitis	No glycogenated nuclei present	Sclerosing hyaline necrosis noted occasionally	• Typically micronodular separated by broad septa	• Proliferation of smooth endoplasmic reticulum
	• Typically macrovesicular	• Portal: mononuclear or mixed with PMNs and periportal fibrosis	• Not necessarily in ballooned hepatocytes			• Mixed micro and macronodular also seen	• Giant mitochondria have been associated with all types of ALD from fatty liver to cirrhosis. In alcoholic steatosis, they are prognostic of poor outcome
	• Begins in zone 3 & can extend to portal triads	• Portal lipogranulomas are common	• May occur in apoptotic hepatocytes
	• Typically centrilobular, but can progress to entire lobule
	• Steatosis à steatohepatitis w/centrilobular accentuation
Autoimmune hepatitis	Only with concurrent alcoholic or non-alcoholic fatty liver disease	• Plasma cell infiltrates	Uncommon	Uncommon: multi-nucleated giant hepatocytes	Uncommon but centrilobular necrosis can be seen in early or acute disease	• 1/3 of patient present with cirrhosis at time of diagnosis	• Dendritic cells and lymphocytes attach to disrupted liver sinusoidal endothelial cells via pseudopods
		• Portal & periportal activity is greater than lobular activity				• Typically macronodular	• Kupffer cells and macrophages: increased phagocytic activity and damaged mitochondria, with intense fibrosis
		• Rosette formation					• Sinusoidal cell cytoplasm: glassy droplet inclusions
		• Emperipolesis