740 disease and the pro-Wbrogenic properties of elevated rate of apoptotic cell death (Friedman 2004; Malhi et al. 2006). Keratins exhibit anti-oxidative properties, as they sequester oxidatively damaged proteins, and similarly, the K18 R89C variant primes the liver towards oxidative injury (Tao et al. 2005; Zhou et al. 2005). This keratin property might be helpful in attenuating both liver Wbrosis and acet- aminophen-induced liver injury (Parola and Robino 2001; Jaeschke et al. 2003). Keratins are also established stress- inducible proteins, which are upregulated both in humans and mice under several, mainly cholestatic conditions (Fickert et al. 2002, 2003; Zatloukal et al. 2007; Ku et al. 2007; Strnad et al. 2008). Keratin variants may interfere with keratin upregulation or simply result in decreased ker- atin levels due to protein instability (as seen for K18 R89C variant in the liver; Ku et al. 1995). The naturally occurring K8/K18 variants interfere with basic IF properties such as K8/K18 Wlament assembly and keratin solubility (Ku et al. 2001; Owens et al. 2004; Ku et al. 2007). Due to altered protein conformation, some of them impair potentially cytoprotective keratin phosphoryla- tion at adjacent residues (as seen in K8 G61C and K8 G434S variant; Ku et al. 2005; Ku and Omary 2006). K8/K18 variants may also aVect organelle function, as seen in K8 knockout mice, which exhibit altered mitochon- drial shape, localization, and alterations in several mito- chondrial proteins (Toivola et al. 2005). Despite the various cytoprotective eVects of keratins, their impact seems to be limited to certain conditions. For example, K18 R89C mice are predisposed to Fas but not TNF-induced apoptosis and the same mice develop more pronounced liver Wbrosis after thioacetamide, but not after carbon tetrachloride injection (Ku et al. 2003b; Strnad et al. 2008). It is also unknown which one of the keratin-medi- ated eVects is important in particular disease settings. The recently established transgenic mouse lines overexpressing the naturally occurring K8 G61C and R340H variants will likely oVer valuable insights in this respect (Ku and Omary 2006; Zhou et al., unpublished data). Keratin network alteration in steatohepatitis of the alcoholic (ASH) and the non-alcoholic (NASH) type Steatohepatitis is characterized by hepatocyte “ballooning”, that is, swelling and rounding with clearing of the cyto- plasm, which prevails in the perivenular zone and is often associated with pericellular Wbrosis, predominantly granu- locytic inXammation (“satellitosis”), steatosis (usually of macrovesicular type), and cholestasis (Brunt 2004; Lefko- witch 2005). Ballooned cells are often associated with granular, rope- or clump-like cytoplasmic inclusions, called Mallory-Denk bodies (MDBs) (originally also designated 123 Histochem Cell Biol (2008) 129:735–749 alcoholic hyalin, which is, however, a misnomer since they are not speciWc for alcoholic etiology) together with derangement or even disappearance of the keratin IF cyto- skeleton (Mallory 1911; Denk et al. 2000; Zatloukal et al. 2007; Fig. 1a, b). The disappearance of the keratin immu- nostaining in ballooned hepatocytes is reasonably speciWc for ASH and NASH, since it is not seen in ballooned cells of viral hepatitis or toxic damage and can therefore be used as an objective morphologic parameter in grading of steato- hepatitis (Lackner et al. 2008). However, ballooning (with concomitant cytoskeletal alterations) and MDB formation are not entirely interchangeable since not all ballooned hepatocytes contain MDBs. MDBs are typical morphological features of ASH and NASH, although NASH usually exhibits slightly less prom- inent MDBs than the ones seen in ASH (Brunt 2004; Zat- loukal et al. 2007). MDBs can also be detected after intestinal bypass surgery for morbid obesity, in chronic cholestasis, particularly in late stages of primary biliary cir- rhosis, Wilson disease and other types of copper toxicosis, various metabolic disturbances, and hepatocellular neo- plasms (Müller et al. 2004; Zatloukal et al. 2007; Fig. 2). In contrast, MDBs have not been observed in the context of acute cholestasis, acute viral hepatitis and a variety of acute toxic or drug-induced liver diseases (Jensen and Gluud 1994, Zatloukal et al. 2007; Ku et al. 2007). However, even in potentially MDB-forming liver diseases, MDBs are found only in a subset of patients, partially (but not com- pletely) depending on the sensitivity of the detection method used. For example, when using immunohistochem- istry for keratin or ubiquitin, MDBs were found in about 70% of ASH cases in contrast to 40% seen in hematoxilin- eosin-stained sections (Ray 1987). This suggests that MDBs require either a speciWc patho- genetic constellation or genetic predisposition for its forma- tion, which is present only in a subset of patients. Apart from MDBs, additional features may be observed in some chronic cholestatic conditions. For example, a low percentage of hepatocytes express keratin 7 and to a lesser extent keratin 19 which indicate that these cells acquire fea- tures of precursor cells which normally express keratin 8, 18, 7, and 19 during regeneration (Van Eyken et al. 1988; Zatloukal et al. 2004). In idiopathic copper toxicosis and hepatocellular carcinoma, MDBs may coincide with another type of cytoplasmic inclusions, termed intracellular hyaline bodies (IHBs), which share several components with MDBs, but do not contain keratins (Stumptner et al. 1999; Denk et al. 2006). The ease of MDB detection makes them attractive morphologic markers. However, correlation between the clinical disease manifestation/progression on one side and hepatocyte ballooning with MDB formation on the other is imperfect. For example, patients with severe clinical