Serum Levels of Keratin-18 Fragments [Tissue Polypeptide-Specific Antigen (TPS)] Are Correlated with Hepatocyte Apoptosis in Alcoholic Hepatitis

Gonzalez-Quintela, Arturo; Abdulkader, Ihab; Campos, Joaquín; Fernandez-Hernandez, L.; Lojo, S.

doi:10.1007/s10620-008-0371-2

Cited by 22 publications

(16 citation statements)

References 30 publications

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“…The same group showed that serum levels of total CK18 correlated with the apoptotic score in 53 patients (31 with alcoholic hepatitis and 22 with fatty liver) [19]. While these studies were done on a small group of patients, the circulating level of total CK18 was increased in alcoholics.…”

Section: Discussionmentioning

confidence: 95%

“…The serum levels of total CK18 in heavy drinkers (n = 15) were higher than those of healthy controls (n = 10), and even tended to be higher than those of patients with biopsy-proven malignancy of epithelial origin (n = 22) including adenocarcinoma of a variety of origins, small lung carcinoma, hypernephroma and epidermoid easophageal carcinoma [22]. The same group showed that serum levels of total CK18 correlated with the apoptotic score in 53 patients (31 with alcoholic hepatitis and 22 with fatty liver) [19]. More recently, it has been reported that serum levels of CK-18 fragment in patients with alcoholic hepatitis (n = 50) were higher than those of healthy controls (n = 50) and heavy drinkers (n = 50), and even tended to be higher than those of patients with malignancy (n = 50) [21].…”

Section: Introductionmentioning

confidence: 91%

“…In contrast, few studies have been performed on patients with ALD. The level of CK18 or of the CK18 fragment was frequently increased in small groups of alcoholics and may act as a marker of hepatitis [19], [20], [21]. The serum levels of total CK18 in heavy drinkers (n = 15) were higher than those of healthy controls (n = 10), and even tended to be higher than those of patients with biopsy-proven malignancy of epithelial origin (n = 22) including adenocarcinoma of a variety of origins, small lung carcinoma, hypernephroma and epidermoid easophageal carcinoma [22].…”

Section: Introductionmentioning

confidence: 99%

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Serum Markers of Hepatocyte Death and Apoptosis Are Non Invasive Biomarkers of Severe Fibrosis in Patients with Alcoholic Liver Disease

et al. 2011

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BackgroundQuantification of hepatotocyte death is useful to evaluate the progression of alcoholic liver diseases. Our aims were to quantify and correlate the circulating levels of Cytokeratin 18 (CK18) and its caspases-generated fragment to disease severity in heavy alcoholics.Methodology/Principal FindingsCK18 and CK18-fragment were evaluated in the serum of 143 heavy alcoholics. Serum levels of markers of hepatocyte death (CK18), apoptosis (CK18 fragment) and necrosis (CK18 -CK18 fragment) increased in patients with severe fibrosis compared to patients with mild fibrosis. These markers strongly correlated with Mallory-Denk bodies, hepatocyte ballooning, fibrosis and with hepatic TNFα and TGFβ assessed in the liver of 24 patients. Elevated levels of serum hepatocyte death and apoptotic markers were independent risk factors in predicting severe fibrosis in a model combining alkaline phosphatase, bilirubin, prothrombin index, hyaluronate, hepatocyte death and apoptotic markers. The level of markers of hepatocyte death and apoptosis had an area under the receiving operator curve that predicted severe fibrosis of 0.84 and 0.76, respectively.Conclusion/SignificanceDeath of hepatocytes can be easily evaluated with serum markers and correlated with severe fibrosis in heavy alcohol drinkers. These biomarkers could be useful to rapidly evaluate liver injuries and the efficacy of therapies.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Serum Markers of Hepatocyte Death and Apoptosis Are Non Invasive Biomarkers of Severe Fibrosis in Patients with Alcoholic Liver Disease

et al. 2011

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“…For example, during apoptosis K18 is cleaved into small fragments by caspases. As a suitable indicative of hepatocytic apoptosis in vivo , one of the K18 proteolytic fragments, termed tissue polypeptide-specific antigens (TPS), can be readily detected in the plasmas of patients suffering from alcoholic hepatitis [4], nonalcoholic steatohepatitis[5,6], chronic cholecystitis [7] and chronic hepatitis B (CHB) [8]. In addition to scaffolding function, keratin filaments form complex signaling platforms and interact with kinases, adaptors and apoptotic proteins.…”

Section: Introductionmentioning

confidence: 99%

Keratin 18 phosphorylation as a progression marker of chronic hepatitis B

Shi

Sun

Liu

et al. 2010

Virol J

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BackgroundThe intermediate filament proteins keratins 18 (K18) and 8 (K8) polymerize to form the cytoskeletal network in the mature hepatocytes. It has been shown that the phosphorylation of K18 at two serine residues, 33 and 52, correlates with the progression of hepatitis C, but little is known of chronic hepatitis B (CHB). In this study, we examined K18 phosphorylation in relation to CHB.ResultsSite-specific phosphorylation of K18 was determined in livers of twelve healthy donors, and non-cirrhosis (n = 40) and cirrhosis (n = 21) patients. On average, progressively higher level of Ser52 phosphorylation was observed in non-cirrhotic and cirrhotic livers, while elevated Ser33 phosphorylation was detected in both livers but no significant difference. Progressive increase of Ser33 and Ser52 phosphorylation correlated with the elevation of both histological lesions and enzymatic activities of alanine aminotransferase in non-cirrhotic livers. In the hepatocytes of an inactive HBV carrier, strong signals of Ser33 phosphorylation were co-localized with viral infection, while only basal level of Ser52 phosphorylation was detected in infected cells.ConclusionAssuming all obtained data, our data suggest that K18 phosphorylation is a progression marker for CHB.

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“…CK-18 is not an exclusively validated biomarker for AH but is a direct marker of hepatocyte apoptosis and, as such, probably should not be considered a diagnostic tool. (2) High levels of CK-18 has been most validated in patients with nonalcoholic steatohepatitis (versus simple steatosis) (3) and toxinassociated steatohepatitis. (4) Obese alcoholics with AH could have components of nonalcoholic steatohepatitis and AH working in tandem.…”

Section: To the Editormentioning

confidence: 99%

Plasma biomarkers to diagnose alcoholic hepatitis: Are we there yet?

Philips

Augustine

2017

Hepatology

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We read with interest the study by Bissonnette et al. (1) that was published recently in HEPATOLOGY. The authors attempted to fill the gap in noninvasive diagnosis of alcoholic hepatitis in a prospective study. They demonstrate that circulating fragments of cytokeratin-18 (CK-18), especially the M65 component, had good diagnostic performance for estimating the presence of alcoholic hepatitis (AH) among patients with clinical suspicion in a test and validation cohort. This was particularly true in patients without recent bacterial infection. They also concluded that analyzing CK-18 fragment levels could help avoid transjugular liver biopsy (TJLB) in two thirds of AH patients. CK-18 is not an exclusively validated biomarker for AH but is a direct marker of hepatocyte apoptosis and, as such, probably should not be considered a diagnostic tool. (2) High levels of CK-18 has been most validated in patients with nonalcoholic steatohepatitis (versus simple steatosis) (3) and toxinassociated steatohepatitis. (4) Obese alcoholics with AH could have components of nonalcoholic steatohepatitis and AH working in tandem. The current study does not shed light on this matter, hence the proposal of CK-18 fragments in noninvasive diagnosis of AH should remain a research tool. With an overall incidence of infections approaching approximately 50% in AH, the noninvasive utility of CK-18 becomes superficial. Discriminating primary liver insults (e.g., druginduced liver injury) among heavy drinkers versus AH still requires a liver biopsy for clarity. In the current study, the authors state that the proposed upper limit cutoffs for CK-18 M65 fragments had a low negative predictive value and that the diagnostic performance was much lower in the validation cohort in which the results were not reproducible using the proposed algorithm, and most patients underwent TJLB. Currently, TJLB is no longer a "cry for the moon," and most liver units have the expertise to implement it. On the contrary, performing advanced laboratory testing for CK-18 fragments requires more prowess with regard to research personnel, equipment, and costs and is less available at many centers. Diagnosing AH relies on astute history taking-including attention to drug history, careful biochemical interpretation, and histopathology-to be certain in cases where multiple insults or a mimic of AH is expected. CJ. Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers.

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Serum Levels of Keratin-18 Fragments [Tissue Polypeptide-Specific Antigen (TPS)] Are Correlated with Hepatocyte Apoptosis in Alcoholic Hepatitis

Cited by 22 publications

References 30 publications

Serum Markers of Hepatocyte Death and Apoptosis Are Non Invasive Biomarkers of Severe Fibrosis in Patients with Alcoholic Liver Disease

Serum Markers of Hepatocyte Death and Apoptosis Are Non Invasive Biomarkers of Severe Fibrosis in Patients with Alcoholic Liver Disease

Keratin 18 phosphorylation as a progression marker of chronic hepatitis B

Plasma biomarkers to diagnose alcoholic hepatitis: Are we there yet?

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