Alcoholic hyalin-containing hepatocytes — a characteristic morphologic appearance

ABSTRACT— We studied the morphologic appearance of alcoholic hyalin (AH)-containing hepatocytes in liver biopsies from 14 patients with alcoholic liver disease. Most hepatocytes had a characteristic appearance. The cells were swollen and hydropic with an intact cell membrane. The mitochondria had variable-sized cristae which were both shortened and elongated. The smooth endoplasmic reticulum was markedly decreased. The rough endoplasmic reticulum was bizarre, with detachment of the ribosomes that surrounded the AH. The hepatocytes that contained AH bodies had lost almost all the glucose-6-phosphate activity but had variable amounts of succinic dehydrogenase and diphosphopyridine nucleotide diaphorase activities. The neutrophils admixed with mononuclear cells attached themselves to the hepatocytes and then invaginated into the hepatocytic cytoplasm with focal lysis of the cell membrane mediated via the release of neutrophilic lysosomes. The distortion of protein-synthesizing organelles and decrease in glucose-6-phosphatase activity suggest that the AH-containing hepatocyte is metabolically decompensated. The final cell death may be related to the neutrophilic attack, rather than the metabolic derangement.     

CONGENITAL HEPATIC FIBROSIS ASSOCIATED WITH MALLORY BODIES AND COPPER RETENTION

New observations are described in a case of congenital hepatic fibrosis. Histochemical stains of liver tissue for copper (rhodanine) and copper associated protein (orcein) were positive and hepatic copper concentration, measured by atomic absorption spectroscopy, was markedly elevated being 550 μg/g dry weight (NR <30 μg/g dry weight). Mallory bodies were observed in several areas in liver sections. These observations have not been previously recorded in congenital hepatic fibrosis. Increased hepatic copper concentration in this case may have contributed to the production of liver damage. Hepatic copper concentration should be specifically measured in other patients with congenital hepatic fibrosis.     

RNA interference of VCP/p97 increases Mallory body formation

In the present report, valosin-containing protein (VCP) was present in Mallory bodies (MBs). To determine if VCP plays a role in MB formation, primary cultured hepatocytes from drug-primed mice that spontaneously form MBs in vitro were studied. The results were compared with control normal hepatocytes. Gene-specific FITC-labeled gripNA (gVCP) was added to the medium of the primary cultures to inhibit the expression of VCP. gVCP increased MB formation by 230% in drug-primed mouse hepatocytes compared with primed liver cells where no VCP oligos were added. Blocking VCP expression induced both multiple small ubiquitin (Ub) and cytokeratin (CK) aggregates to form within the cytoplasm in normal mouse hepatocytes. Inhibition of VCP expression in both drug-primed and control hepatocytes caused a decrease in proteasome chymotrypsin-like (ChT-L) activity. Overexpression of VCP was achieved by transfecting the hepatocytes with a plasmid containing green fluorescent protein (GFP)-fused VCP (pVCP-GFP). Overexpressed VCP was located in both the cytoplasm and nucleus of pVCP-GFP overexpressing drug-primed hepatocytes. VCP was also concentrated within MBs. MB formation was not decreased by the overexpression of VCP in the cells. These results indicate that VCP plays an important role in inducing MB formation, probably through its molecular chaperone function in the ubiquitin-proteasome system (UPS).     

A case of bone metastasis of hepatocellular carcinoma: Mallory hyaline bodies can lead to the correct cytological diagnosis

Hepatocellular carcinoma (HCC) accounts for most primary tumors of the liver. Although bone metastasis does not occur in a high percentage of patients, bone metastasis is often found first, which leads to the diagnosis of HCC. In this report, we describe a case of bone metastasis from HCC in which bone lesions were detected incidentally, and in which a cytological diagnosis was difficult to make. The patient was a 78-year-old man with a history of renal dysfunction after orthopedic surgery. He underwent a thorough examination after a bone tumor was incidentally found on abdominal CT. Plasmacytoma was suspected. Fine needle aspiration cytology revealed irregular clusters of medium-to-large atypical epithelioid polygonal cells with relatively abundant eosinophilic, somewhat granular cytoplasm, and indistinct cell borders, which led to a diagnosis of malignancy. Histologically and immunohistochemically, the tumor was diagnosed as bone metastasis of HCC. Re-examination of the cytological specimen revealed characteristic Mallory hyaline bodies (MHBs). Immunohistochemistry using a cell transfer method revealed that they were positive for low molecular weight cytokeratin, Cam5.2, in a densely granular fashion. In this case, the cytological diagnosis of HCC was difficult to make due to the unclear cytoplasmic borders and absence of bile pigment. However, the identification of MHBs can potentially guide me to the correct cytological diagnosis.     

Mallory bodies and liver diseases

Abstract   Mallory bodies are cytoplasmic inclusions in hepatocytes consisting of abnormal keratins, ubiquitin and several proteins (p62, heat shock proteins) involved in the unfolded protein response. They are morphologic hallmarks of alcoholic and nonalcoholic steatohepatitis but may also be associated with metabolic and toxic liver cell injury and hepatocellular neoplasms. Mallory bodies can be experimentally produced in mouse liver by chronic intoxication with griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mallory body formation is associated with derangement of the keratin intermediate filament cytoskeleton of the hepatocyte. The analysis of Mallory body composition and particularly their experimental induction in animal models and in tissue culture cells disclosed a major role of oxidative stress in the underlying liver cell injury.     

Severe cytological atypia (large cell change) in focal nodular hyperplasia with numerous mallory bodies. A benign (adaptive) change?

Focal nodular hyperplasia (FNH) is a benign hepatocellular lesion composed of hyperplastic appearing hepatocytes arranged in nodules separated by fibrous septa that usually form a central stellate scar. Rare lesions that show unusual cytological or architectural features were reported as variants of focal nodular hyperplasia. We present the morphological features of a case of FNH with severe cytological atypia (so-called large cell change) in a 73-year-old man. In addition to diffuse cytological atypia, Mallory hyaline bodies were found in almost all lesional cells. This rare variant of FNH should be differentiated from other neoplastic lesions, in particular from the fibrolamellar variant of hepatocellular carcinoma.     

The mechanism of cytokeratin aggresome formation: the role of mutant ubiquitin (UBB+1)

Aggresome formation in cells involves the failure of the ubiquitin-proteasome pathway to dispose of proteins destined for degradation by the 26S proteasome. UBB(+1) is present in Mallory bodies in alcoholic liver disease and in aggresomes formed in Alzheimer's desease. The present investigation focuses on the role that UBB(+1) plays in cytokeratin aggresome formation in Mallory bodies (MBs) in vitro. Immunoprecipitation with a monoclonal antibody to cytokeratin-8 (CK-8) was used. The immunoprecipitate was incubated for 24 h in the presence of different constituents involved in aggresome formation including ubiquitin, UBB(+1), the proteasome inhibitor PS341, an ATP generating energy source, a deubiquitinating enzyme inhibitor, a purified proteasome fraction, and an E(1-3) conjugating enzyme fraction. MB-like protein aggregates formed in the presence of ubiquitin, plus UBB(+1) or PS341. These aggregates stained positively for CK-8. UBB(+1), and a proteasome subunit Tbp7, as demonstrated on Western blots. A second approach was used to form MBs in vitro in cultured hepatocytes transfected with UBB(+1) protein using Chariot. The cells were double stained using CK-8 and ubiquitin antibodies. The two proteins colocalized in MB-like aggregates. The results support the possibility that aggresome formation is a complex multifactor process, which is favored by inhibition of the proteasome and by the presence of UBB(+1).     

食管贲门黏膜撕裂综合征20例临床分析

目的探讨食管贲门黏膜撕裂综合征(MWS)的临床特点、内镜下表现及治疗。方法对2005年7月至2009年9月收治的20例MWS患者的临床资料进行回顾性分析。结果饮酒后呕吐是WMS的主要发病原因,MWS内镜下均为贲门纵形撕裂,20例患者全部采用保守治疗治愈。结论早期胃镜检查为诊断MWS的主要方法,保守治疗疗效良好。     

Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis

There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and glutathione-S-transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug-primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes.