Review ArticleFrom Mallory to Mallory–Denk bodies: What, how and why?
Introduction
We take the unique opportunity in this review of bringing together several groups actively studying Mallory body (MB) inclusions to provide a historical perspective pertaining to these inclusions. We will cover MB constituents and histological and ultra-structural features, the clinical contexts of their presence, our current understanding of their pathogenesis using in vitro and vivo experimental models, and the clinical and cell biological significance of their appearance. Other hepatocyte inclusions and MB-like rare inclusions of other epithelial tissues are also described. The last comprehensive review on this topic was in 2000 [1] and several other earlier excellent reviews have covered this topic [2], [3], [4]. A unique aspect of the current review, aside from providing a consensus interpretation of MBs is its proposal to modify the name “Mallory bodies” to “Mallory–Denk bodies” (MDB). The proposed name modification is prompted by the many contributions made by Professor Helmut Denk whom we wish to honor. Although MBs have been extensively studied by numerous highly accomplished investigators in the fields of liver disease and liver histopathology during the past 40 years, we felt that the sustained and important contributions made by Denk and colleagues deserve this name modification and recognition. In doing so, we consulted with several colleagues whose names are listed alphabetically in the acknowledgement section.
MBs were first described by Professor Frank B. Mallory as cytoplasmic hyaline inclusions in hepatocytes of patients with alcoholic hepatitis in 1911 [5] (Fig. 1A). A subsequent classic pathology textbook published in 1914 by Mallory (Fig. 1B) [6] included a schematic of the morphologic features of these hyaline inclusions (Fig. 1C) and this schematic remains just as accurate nearly 100 years later. The hepatocyte inclusions associated with alcoholic liver disease were subsequently termed Mallory bodies (MBs) in honor of Professor Mallory and later shown to be associated with several alcohol and non-alcohol-related liver diseases [1], [3], [4]. Major breakthroughs in the field were facilitated in large part by the introduction of mouse models of MBs (Fig. 1D) [7], [8] that have had a tremendous impact on our understanding of MBs as detailed in this review. As many great and sometimes unexpected findings in science, Denk et al. were feeding mice the anti-fungal drug griseofulvin, a compound known to cause porphyria and hepatomas in mice [9], in order to study murine protoporphyria. The surprising finding in the liver, which had not been previously appreciated, was the formation of hyaline that was highly typical of alcoholic hyaline (i.e. MBs) using histochemical and ultrastructural examination [7]. Additional early and more recent studies that Helmut Denk led or participated in include the demonstration of cytoskeletal alterations of MB-containing hepatocytes, especially keratin intermediate filaments (IFs) [10] (Fig. 1E); the description of the morphological and biochemical characteristics of MBs [11], [12]; the improvement of the mouse model by generating so-called primed mice (that provide a model for rapid MB formation) [8], [13]; the potential importance of transamidation [14], p62 [15] and the keratin 8 to 18 ratio [16] in MB formation; and the distinction of MBs from other hepatocyte cytoplasmic inclusions [17].
One important feature that links MBs (henceforth termed MDBs) to other non-MDB tissue-selective cytoplasmic inclusions is the abundant presence of various members of the cell type-specific family of IF proteins. The cytoplasmic IF family of proteins includes keratins in epithelial cells (with more than 20 members of epithelial-specific unique keratins) [18]; desmin in muscle; neurofilaments, glial filbrillay acidic protein and α-internexin in specific subpopulations of neural cells. Mutations in genes coding for these proteins result in numerous tissue-specific human diseases [19]. The non-MDB cytoplasmic inclusions are histological hallmarks of several non-hepatic diseases such as desmin-containing inclusions (termed desmin bodies) in some myopathies [20], glial fibrillary acidic protein-containing inclusions (termed Rosenthal fibers) in Alexander disease [21] and neurofilament and α-internexin-containing inclusions (e.g. Lewy bodies) in neurodegenerative diseases including Alzheimer disease, Parkinson disease, neuronal IF inclusion disease and amyotrophic lateral sclerosis [22], [23]. Some of these inclusions are associated with mutations in the IF protein (e.g. in Alexander disease) while others are disease-associated but not related to an IF mutation per se (e.g. MDBs and the liver diseases they associate with). It is not known whether all IF-containing inclusions share a similar pathogenesis, but among IF-associated inclusions MDBs are very common and extensively studied because of the high prevalence of liver disease.
Section snippets
Constituents of Mallory–Denk bodies
The constituents of MDBs can be divided into several classes of proteins (Table 1) based on studies in animal models and human tissues: (1) keratins and posttranslationally modified keratins, (2) chaperones, (3) proteins involved in the protein degradation machinery, and (4) a small but likely-to-grow category of “other proteins”. The first indication for the presence of cytoskeletal proteins in MDBs came from electron microscopy studies showing that MDBs were composed of fibrillar structures
Clinical contexts, morphological and ultrastructural features of MDBs
MDBs are common and characteristic morphologic features of alcoholic steatohepatitis (ASH) but they also occur in a variety of other liver diseases (Fig. 2) such as non-alcoholic steatohepatitis (NASH) [which represents a progressive form of non-alcoholic fatty liver disease (NAFLD)], intestinal bypass surgery, certain types of drug-induced liver disease (e.g. related to amiodarone), chronic cholestasis (in particular primary biliary cirrhosis), copper storage and intoxication diseases (Wilson
Other epithelial cell MDB-like inclusions
In addition to MDBs, other cytoplasmic inclusions may be present in hepatocytes including intracytoplasmic hyaline bodies (IHBs), pale bodies, ground glass inclusions, glycogen bodies, alpha-1-antitrypsin inclusions and megamitochondria (Fig. 4). A relationship between IHBs and MDBs is emerging based on findings in hepatocellular carcinomas as well as in livers with idiopathic copper toxicosis [17]. In these diseases, IHBs and MDBs were present in the same cell and different stages of
Non-transgenic mouse MDB models
The first small animal MDB model was described by Denk et al. which detailed findings in mice fed a powdered diet containing 2.5% griseofulvin (GF) for 145–194 days [7]. This experiment not only provided the first readily accessible model for MDB formation, but also provided direct experimental evidence that “alcoholic hyaline” can be generated independent of alcohol. It should be noted that Rubin and Lieber reported reproduction of all the findings of human alcoholic liver disease, including
Transgenic animal models of MDBs
The generation and characterization of K8 and K18 knockout or transgenic mouse models have provided essential information about the function of K8 and K18 and their role in MDB formation. For example, K8−/− or K8+/− mice do not form MDBs after DDC treatment and have increased susceptibility to liver injury which suggests that keratins and the ratio of K8 to K18 are important for MDB formation [16] (Table 2). In contrast, K18−/− mice develop MDBs spontaneously upon aging [77]. The K18−/− mice do
Cell culture models
As discussed above, most of the studies on MDBs have been carried out using mouse models. Given the limited understanding of the in vivo molecular mechanisms involved in the regulation of keratins and other MDB-forming affectors (e.g. p62, ubiquitin, TG2) and the technical difficulties encountered in using animals to dissect specific cellular pathways that may be involved, cellular models of MDB formation have been developed. These model systems can be divided into three groups depending on the
Pathogenesis of MDBs
MOur current understanding of MDB formation is summarized in Fig. 7. The relevant proteins and cellular processes that determine whether MDBs form or not include the type of stress, the extent of stress-induced protein misfolding and consequent proteasome overload, a K8 > K18 ratio, transglutaminase activation and transamidation of K8 and possibly other proteins, p62 upregulation and the extent of autophagy. MDB inducing agents cause numerous protein modifications which render them aggregation
Significance of MDBs and clinical correlates
The significance of MDB formation in the diagnosis and prognosis of several liver disorders, particularly ASH and NASH, which largely depends on liver biopsy evaluation, has attracted attention. Morphologic features of alcoholic and non-alcoholic steatohepatitis include hepatocellular injury (fatty change, ballooning hepatocyte degeneration, apoptosis, necrosis, MDBs, giant mitochondria), inflammation and fibrosis (perisinusoidal, pericellular). The inflammation often, but not always, includes
Are MDBs good, bad or bystanders
MDBs result from a complex interplay of genetic and environmental factors with hepatocyte keratins clearly serving as a major target and component [16], [37], [76]. What is less clear is whether MDBs (and other IF-related inclusions) represent an epiphenomenon of injury, a cell protective mechanism or a cellular response that contributes to the initiation or progression of liver damage. MDBs resemble in their pathogenesis and significance other inclusion bodies associated with chronic
Concluding remarks
Our understanding of MDBs has come a long way since their initial description in 1911 by Frank Mallory. The hepatocyte cytoplasmic hyaline inclusions became known as Mallory bodies during the 1950–1960s and now, nearly 50 years later, we are proposing to expand their name to Mallory–Denk bodies in honor of the contributions made by Helmut Denk. The contributions made by Denk and colleagues are easily gleaned from this consensus review authored by five independent groups, and from the response
Acknowledgments
We wish to thank the distinguished group of hepatologist and hepatopathologist colleagues, listed in alphabetic order, for their positive comments on the proposed Mallory–Denk nomenclature: Bruce Bacon, David Brenner, Elizabeth M Brunt, Massimo Colombo, Melissa J Contos, Chris P Day, Valeer J Desmet, Zachary D Goodman, Scott L Friedman, Peter L Jansen, Neil Kaplowitz, Emmet B Keeffe, David E Kleiner, Keith D Lindor, David H Perlmutter, Juan Rodes, Arun J Sanyal, Kyuichi Tanikawa and Roger
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