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Altered mental status, alcohol abuse, and hyperammonemia.

DIAGNOSIS: Mallory-Denk bodies (a.k.a. Mallory's hyaline)-seen most commonly in alcoholic liver disease.

DISCUSSION

Mallory-Denk bodies (MDBs) are eosinophilic cytoplasmic 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 microscopically 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 were widely distributed and diffusely present throughout all hepatic zones; a representative image from autopsy demonstrates 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 following: intracytoplasmic hyaline bodies (IHBs), ground glass inclusions, glycogen bodies, A1AT droplets, and megamitochondria. 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 unclear 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 attributed 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) deficiency, 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 in NASH, has attracted a good deal attention in the literature. The frequency of MDBs in steatosis is believed to be approximately 40% by routine H&E and up to 70% if immunohistochemical 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 the MDBs in NASH are 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 pathogenesis 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 neutrophilic attraction to their surrounding tissue. (14) And, finally, MDB accumulation appears reversible such that, in the mouse model, MDBs virtually disappear from injured hepatocytes 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) According 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) Comparisons of what constitutes a standard drink are shown in Table 1. (18) And, for the risk of alcohol-related liver disease, recent studies have shown that the risk begins at 30 grams of ethanol per day. (19) By report, the decedent in the current case ingested "a pint of gin" each day. With conversion, this translates into roughly 16 ounces of liquor of daily use or 10 times the amount that defines moderate drinking.

Diagnosing alcoholic liver disease can be a challenge for clinicians. Physical and laboratory findings are often nondiagnostic, especially in patients with early alcoholic liver disease. Patients commonly deny alcohol abuse and frequently underreport alcohol consumption. Therefore, clinicians must have a low threshold of suspicion for alcohol abuse and rely on indirect evidence such as information from family, questionnaires, or observation of physical, social, and psychological consequences of abuse. (5) As clinicians may utilize liver biopsy information to help make clinicopathologic correlates about patients, it is important for them to consider whether or not MDBs were demonstrated along with steatosis, whether histologic staining was via the customary H&E or required use of immunohistochemical modalities, and whether there were an abundance of or a paucity of either vague or well-established forms of intracytoplasmic MBDs. By not only adding these descriptive features to the pathologist's report, but also by increasing the clinician's awareness of their meaning, the level of index of suspicion for whether chronic alcohol usage has served to play a role in the liver derangement being demonstrated may effectively be enhanced.

ACKNOWLEDGEMENTS

The authors would like to gratefully acknowledge the support of the Orleans Parish Coroner's Office: Dr. Frank Minyard and Chief Investigator John Gagliano for providing the case material for this report.

REFERENCES

(1.) Franke WW, Denk H, Schmid M et al. Ultrastructural, biochemical and immunologic characterization of Mallory bodies in livers of griseofulvin treated mice. Lab Invest 1979;40:207-220.

(2.) Denk H, Krepler E, Lackinger U, et al. Immunological and biochemical characterization of the keratin related component of Mallory bodies: a pathological pattern of hepatocytic cytokeratins. Liver 1982;2:165-175.

(3.) Strnad P, Zatloukal K, Stumptner C et al. Mallory Denk bodies: lessons learned from keratin containing hepatic inclusion bodies. Bio Biophsy Acta 2008;1782:764-774.

(4.) Crawford JM. Histologic findings in alcoholic liver disease. Clin Liver Dis 2012;16: 699.

(5.) O'Shea RS, Dasarathy S, McCullough AJ, et al. Alcoholic liver disease. Hepatology 2010; 51:307.

(6.) Zatloukal K, French SW, Stumptner C et al. From Mallory to Mallory-Denk bodies: what, how and why? Exper Cell Res 2007:2033-2049.

(7.) Mallory F. Cirrhosis of the liver. Five different types of lesions from which it may arise. Bul Johns Hopkins Hosp 1911;22:69-75.

(8.) Jenson K, Gluud C. The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey). Hepatology 1994; 20:1061-1077.

(9.) Ray MB. Distribution patterns of cytokeratin antigen determinants in alcoholic and nonalcoholic liver diseases. Hum Pathol 1987;18:61-66.

(10.) Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:320.

(11.) Brunt EM. Non alcoholic fatty liver disease in: AD Burt, BC Portmann, LD Farrell (Eds.), McSween's Pathology of the Liver, Churchill Livingstone Elsevier, 2007

(12.) Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106-1110.

(13.) Denk H, Frank WW, Kerkaschki D et al. Mallory bodies in experimental animals and man. Int Rev Exper Pathol 1979; 20:77121.

(14.) Peters M, Liebman HA, Tong MJ et al. Alcoholic hepatitis: granulocyte chemotactic factor form Mallory body stimulated human peripheral blood mononuclear cells. Clin Immunol Immunopathol 1983; 28:418-430.

(15.) Denk H, Franke WW. Rearrangement of the hepatocyte cytoskeleton after toxic damage: involution, dispersal and peripheral accumulation of Mallory body material after drug withdrawl. Dur J Cell Biol 1981;23:241-249

(16.) http://www.cdc.gov/injuryresponse/alcohol-screening (Accessed on October 26, 2013).

(17.) U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 7th Edition, Washington, DC: US Government Printing Office; 2010, p. 30-32.

(18.) http://pubs.niaaa.nih.gov/publications/ RethinkingDrinking (Accessed on October 26, 2013).

(19.) Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997;41:845-850.

Theresa Nuttli, MD; Robin R. McGoey, MD

In the Department of Pathology at Louisiana State University School of Medicine in New Orleans, Dr. Nuttli is a third-year Pathology Resident and Dr. McGoey is an Associate Professor of Pathology and Residency Program Director.

Table 1: What constitutes a standard drink? (18)

Type of drink      Amount in ounces   Alcohol content in grams

Wine                      5                      12
Beer                      12                     12
Liquor (80 proof)        1.5                     12
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Title Annotation:Pathology Image of the Month
Author:Nuttli, Theresa; McGoey, Robin R.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Case study
Date:Jan 1, 2014
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