The mallory body: Theories on development and pathological significance (part 2 of a literature survey)

Abstract

Drawing on data from a previously published literature survey on the clinical and experimental epidemiology of the Mallory body, we discuss current theories on its development in a pro et contra manner. Conclusions have been largely left open to the interpretations of the reader because many are still speculative. The main results of this study characterize Mallory bodies as stereotypical histological byproducts to diverse hepatic injuries (mostly alcohol associated) of questionable pathogenic importance. The temporal characteristics of Mallory bodies cast doubt on their role in hepatic neoplasia both as a disease marker and a causative agent, and prognosis studies suggest that they may be considered preterminal markers in some nonalcoholic liver diseases but remain prognostically unimportant in most studies on alcoholic patients. By similar line of inquiry, no consistent relationships may be found with disease severity or duration in alcoholic liver diseases. The roles of vitamin A deficiency and protein-calorie malnutrition are circumstantial. Drugs known to have calcium-antagonist properties and the physiological characteristics of the stress-response protein ubiquitin support the concept of defective protein systems in Mallory body pathogenesis. Disproportionate hepatic copper accumulation seems both epidemiologically and topographically associated with Mallory bodies, but these connections are largely unsupported by exposure studies. Many arguments still downplay the importance of uncoordinated changes in hepatic oxygen delivery and consumption, but ischemia-reperfusion studies suggest a role of oxygen-derived free radicals in the liver injuries under scrutiny. Finally, the role of Mallory bodies in the control system of hepatocyte function is addressed, and indirect evidence lends credence to a cybernetic approach in future study designs. It is reasonable to assume that different elements of a multifactorial setting operate with varying intensity over time as this may account for some of the controversies that exist. In conclusion, the biological significance of Mallory bodies is still mystery. It is not known whether Mallory bodies represent an epiphenomenon or play a role themselves in the initiation and continuation of liver damage.

The mallory body: Morphological, clinical and experimental studies (part 1 of a literature survey)

“…Although hypoxia (84), a direct effect of ethanol or its metabolite acetaldehyde (851, microsomal enzyme induction (86) or the immunological reaction to MB (87) have been proposed as possible causes of liver cell damage, little is known about the essential process through which liver cell necrosis is caused. A variety of immunological and tinctorial changes have been found in liver biopsy specimens with AH; they are the subject of another paper, to which the reader is referred (88).…”

Expression of a mutant ER-retained polytope membrane protein in cultured rat hepatocytes results in Mallory body formation

“…By light and electron microscopic immunolabeling, the inclusion bodies in T126M-AQP2-expressing clone 9 hepatocytes were strongly positive for cytokeratin. Denk and his colleagues and other investigators have unequivocally demonstrated that cytokeratins, in particular cytokeratin 8 and 18, are major components of Mallory bodies, whereas other proteins such as heat shock protein 70 and 25 represent minor components (for reviews see Denk et al 1979bDenk et al , 2000Jensen and Gluud 1994). Furthermore, Mallory bodies exhibit characteristic ultrastructural features since they are composed of a meshwork of randomly oriented filaments and do not contain cellular organelles such as ER, mitochondria, and Golgi apparatus.…”

“…Last but not least Mallory bodies themselves seem not to be a single entity since they share compositional similarities with Lewy bodies observed in Parkinson's disease, neurofibrillar tangles in Alzheimer's disease, and neuronal inclusions in motor neuron disease (Fidzianska et al 1983;Issidorides et al 1990;Lowe et al 1988;Mayer et al 1989;Preisegger et al 1992). Mallory bodies in man and mice are of a complex filamentous nature composed of cytokeratins, ubiquitinated cytokeratin 8, and a number of non-cytokeratin proteins (Denk et al 1979a(Denk et al , 1982Franke et al 1979;Stumptner et al 2001;Zatloukal et al 1990; for reviews see Denk et al 1979bDenk et al , 2000Jensen and Gluud 1994).…”

Alcohol Induced Hepatic Degeneration in a Hepatitis C Virus Core Protein Transgenic Mouse Model

“…Many cirrhotic patients will have had a liver biopsy that shows the morphological features of alcoholic hepatitis, defined by an international group of hepatologists as characterized by hepatocyte necrosis and a neutrophil infiltration, usually with Mallory bodies (MBs) and fatty change [28–30]. For many years, MBs, hyaline inclusion body, were observed characteristically in alcoholic liver disease, but it was soon realized that MBs are not specific for this and may occur in other non-alcoholic and chronic liver diseases of animal models [29,30]. Recent reports have demonstrated that CK8 and CK18 were identified as major components of MBs in humans and experimental animals [22].…”