DIAGNOSIS: Mallory-Denk bodies (a.k.a. Mallory’s hya- line) – seen most commonly in alcoholic liver disease. DISCUSSION Mallory-Denk bodies (MDBs) are eosinophilic cyto- plasmic inclusions in liver cells that are characteristic of alcoholic liver disease. They are composed primarily of cytokeratin intermediate filaments (IF) complexed with other proteins such as ubiquitin and p62. 1,2 Other widely recognized IF inclusion body diseases include Alzheimer’s (the neurofibrillary tangle) and Parkinson (Lewy bodies) disease. MDBs, however, are the most prevalent IF-related aggregates. 3 IF cytokeratins function to maintain structural polarity and provide an intracellular scaffold that helps resist forces applied to the cell. In certain disease states, liver cytokeratin production can be altered and leads to cytokeratin misfolding. Such misfolding causes aberrant aggregation and accumulation of the proteins within the hepatocyte cytoplasm, such that they are rendered micro- scopically visible as MDBs. 4,5 With routine hematoxylin and eosin (H&E) staining, MDBs take on an eosinophilic, twisted-rope-appearance. Though in the hepatocyte cytoplasm, they tend to hover around the cell’s nucleus. In the case presented here, they werewidely distributed and diffusely present throughout all hepatic zones; a representative image from autopsy demon- strates several liver cells with prominent ropey inclusions in a perinuclear location (Figure 1a). By immunohistochemical staining with an anti-pan cytokeratin antibody, the MDBs are further highlighted (Figure 1b). Intracytoplasmic, intrahepatic inclusions visible on H&E must also prompt the pathologist to consider the fol- lowing: intracytoplasmic hyaline bodies (IHBs), ground glass inclusions, glycogen bodies, A1AT droplets, and me- gamitochondria. The size and morphology of the inclusion, the clinical context of the patient, and, on occasion, use of additional special staining modalities, usually makes the distinction between the various bodies a straightforward process. 6 MDBs-like inclusions with similar morphology but different composite proteins have also rarely been seen in cells other than hepatocytes, such as type 2 pneumocytes and trophoblast cells. At the present time, it is currently un- clear why hepatocytes, as contrasted with other cell types, are endowed with such a relative ability to accumulate inclusion bodies. 6 The association of MDBs with alcoholic hepatitis was initially reported in 1911. 7 Though most commonly at-
tributed to an alcohol-related metabolic insult to the liver, MDBs can also be seen within the hepatocyte cytoplasm in Wilson disease, primary biliary cirrhosis, non-alcoholic steatohepatitis (NASH), alpha-1-antitrypsin (A1AT) defi- ciency, porphyria, and morbid obesity. 8 By contrast, MBDs have not been seen in association with viral hepatitis, acute cholestasis, or with the majority of hepatotoxic injuries. As such, the prevailing thought is that MDBs signal chronic injury and are identifiable rather late in the course of disease after oxidative and other stresses have been incurred over some time. 6 The usefulness for the pathologist of finding MDBs on liver biopsy related to discriminating between the diagnoses of steatosis (a.k.a. “fatty liver disease”) due to either alcohol or due to a cryptogenic cause, as would be the case inNASH, has attracted a good deal attention in the literature. The fre- quency of MDBs in steatosis is believed to be approximately 40% by routine H&E and up to 70% if immunohistochemi- cal stains are utilized. 9 Though the literature fails to reach a consensus on their frequency, specifically in NASH, with reports that range from 10-70% of cases, there does seem to be agreement that theMDBs inNASHare smaller in number, less well-developed in their appearance, and virtually absent in pediatric cases. 10-12 As such, MDBs that are abundant and well-developed implicitly favor an alcohol-related etiology when seen in association with steatosis on histopathologic liver biopsy. The clinical and prognostic significance of MDBs is yet to be clearly understood. Several animal models, including transgenic mice, and continued research efforts effectively continue to provide essential information about their patho- genesis and the cells that contain them. For example, such cells remain viable and capable of cellular division. 13 Cells with MDBs are relatively more leukotactic and induce neu- trophilic attraction to their surrounding tissue. 14 And, finally, MDB accumulation appears reversible such that, in the mouse model, MDBs virtually disappear from injured he- patocytes during the recovery phases of experimentation. 15 Alcohol-related diseases are the third most common preventable cause of death in the United States, accounting for approximately one death every seven minutes. 16 The most important risk factor for the development of alcoholic liver disease is the total amount of alcohol consumed. 5 Ac- cording to the Dietary Guidelines for Americans , drinking in moderation is defined as no more than one drink per day for women and no more than two drinks per day for men where a standard drink contains 12 grams of alcohol. 17 Com- parisons of what constitutes a standard drink are shown in
Table 1: What constitutes a standard drink? 18 Type of drink
Amount in ounces
Alcohol content in grams
Wine
5
12 12 12
Beer
12
Liquor (80 proof)
1.5
J La State Med Soc VOL 166 January/February 2014 47
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