The Mallory Body: Morphological, Clinical and Experimental Studies (Part 1 of A Literature Survey)

Abstract

To aid understanding of markers of disease and predictors of outcome in alcohol-exposed systems, we undertook a literature survey of more than 700 articles to view the morphological characteristics and the clinical and experimental epidemiology of the Mallory body. Mallory bodies are filaments of intermediate diameter that contain intermediate filament components (e.g., cytokeratins) observable by conventional light microscopy or immunohistochemical methods, identical in structure regardless of initiating factors or putative pathogenesis. Although three morphological types can be identified under electron microscopy (with fibrillar structure parallel, random or absent), they remain stereotypical manifestations of hepatocyte injury. A summary of the conditions associated with Mallory bodies in the literature and their validity and potential etiological relationships is presented and discussed, including estimates on the combined light microscopic and immunohistochemical prevalences and kinetics. Emphasis is placed on proper confounder control (in particular, alcohol history), which is highly essential but often inadequate. These conditions include (mean prevalence of Mallory bodies in parentheses): Indian childhood cirrhosis (73%), alcoholic hepatitis (65%), alcoholic cirrhosis (51%), Wilson's disease (25%), primary biliary cirrhosis (24%), nonalcoholic cirrhosis (24%), hepatocellular carcinoma (23%), morbid obesity (8%) and intestinal bypass surgery (6%). Studies in alcoholic hepatitis strongly suggest a hit-and-run effect of alcohol, whereas other chronic liver diseases show evidence of gradual increase in prevalence of Mallory bodies with severity of hepatic pathology. Mallory bodies in cirrhosis do not imply alcoholic pathogenesis. Obesity, however, is associated with alcoholism and diabetes, and Mallory bodies are only present in diabetic patients if alcoholism or obesity complicates the condition. In addition, case studies on diseases in which Mallory bodies have been identified, along with pharmacological side effects and experimental induction of Mallory bodies by various antimitotic and oncogenic chemicals, are presented. Mallory bodies occur only sporadically in abetalipoproteinemia, von Gierke's disease and focal nodular hyperplasia and during hepatitis due to calcium antagonists or perhexiline maleate. Other conditions and clinical drug side effects are still putative. Finally, a variety of experimental drugs have been developed that cause Mallory body formation, but markedly different cell dynamics and metabolic pathways may raise questions about the relevance of such animal models for human Mallory body formation. In conclusion, the Mallory body is indicative but not pathognomonic of alcohol involvement. A discussion on theories of development and pathological significance transcending the clinical frameworks will be presented in a future paper.

Liver Histology after Chronic Use of Alcohol and Exercise Training in Rats

“…The presence of more pronounced steatosis in animals receiving alcohol by gavage compared to those who did not use this substance confirms the effects already described of alcohol on liver [6][7][8][9]11]. In these two groups, rare MBs (Mallory bodies) were observed, whose presence occurs in approximately 65% to 75% of cases of alcoholic hepatitis [30,31]. MBs are intracytoplasmic hyaline corpuscles that although unspecific, are primarily associated with ALD.…”

Cancer-associated Cleavage of Cytokeratin 8/18 Heterotypic Complexes Exposes a Neoepitope in Human Adenocarcinomas

“…This suggests that additional removal of 6 amino acids may cause conformational changes that prevent COU-1 from binding. Finally, changes in the K8/K18 heterotypic network have been observed in Mallory bodies, which are characteristic cytoplasmic inclusions in hepatocytes associated with alcoholic hepatitis and other chronic hepatocellular injuries including cholestasis and various metabolic disturbances (55)(56)(57). The Mallory bodies consist predominantly of K8 and variable amounts of K18 assembled in a nonfilamentous manner as well as nonkeratin components, such as the M M 120-1 antigen and ubiquitin.…”

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

“…9 MDBs are characteristic of alcoholic steatohepatitis but are also found in other diseases, including nonalcoholic steatohepatitis, primary biliary cirrhosis, and Wilson disease. 9,12,13 MDBs consist mainly of the IFs keratin 8 and 18 (K8/K18) that have undergone several posttranslational modifications, including hyperphosphorylation and transamidation. 9,13 MDB formation requires an alteration in the normal equimolar K8:K18 ratio (under basal conditions) to disproportional K8ϾK18 levels that ultimately lead to K8 cross-linking and insolubility.…”

“…9 Interestingly, DDC-primed mice (i.e., mice fed DDC long-term, then allowed to recover by feeding a normal diet) posses a remarkable ability to rapidly reform MDBs within 5 to 7 days after exposure to a variety of stress-inducing agents. 9,12 This phenomenon is referred to as "toxic memory." 14 Despite the diagnostic importance of MDBs, the precise mechanisms underlying their formation are not completely understood.…”