Biomarkers of Liver Regeneration Allow Early Prediction of Hepatic Recovery After Acute Necrosis

Horn, Katrin; Wax, Paul M.; Schneider, Sandra; Martin, Thomas G.; Nine, Jeffrey S.; Moraca, Michael; Virji, Mohamed A.; Aronica, Patricia A.; Rao, Kalipatnapu N.

doi:10.1093/ajcp/112.3.351

Cited by 65 publications

(31 citation statements)

References 9 publications

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“…13 A number of studies have demonstrated that patients who exhibit timely stimulation of the timely compensatory liver regeneration following APAP overdose have a good prognosis. 8,9,30 Such timely regeneration has been linked to survival following exposure to hepatotoxic drugs and chemicals such as APAP, CCl 4 , and chloroform. 10,12,14,30 Here, we also demonstrate the importance of spontaneous regeneration in survival following APAP-induced ALF and identify the role of Wnt/␤-catenin signaling in this process as well.…”

Section: Discussionmentioning

confidence: 99%

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Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Apte

Singh

Zeng

et al. 2009

The American Journal of Pathology

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137

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Acute liver failure (ALF) remains a disease with poor patient outcome. Improved prognosis is associated with spontaneous liver regeneration, which supports the relevance of exploring 'regenerative' therapies. Therefore, the role of the Wnt/␤-catenin pathway in liver regeneration following ALF was investigated. ALF was induced in mice by acetaminophen overdose, which is also a leading cause of liver failure in patients. ␤-catenin distribution was also studied in liver sections from acetaminophen-induced ALF patients. A nonlethal dose of acetaminophen, which induces liver regeneration, led to stabilization and activation of ␤-catenin for 1 to 12 hours. These data were also verified by increased expression of the ␤-catenin surrogate target glutamine synthetase. ␤-Catenin activation occurred secondary to the inactivation of glycogen synthase kinase-3␤ and an increase in levels of casein kinase 2␣, and led to increased cyclin-D1, another known ␤-catenin target. These observations were next substantiated in ␤-catenin conditional-null mice (␤-catenin-null), which show dampened regeneration after acetaminophen injury following induction of CYP2e1/1a2 expression. In light of decreased acetaminophen injury in ␤-catenin-null mice despite CYP induction, equitoxic studies in control mice were performed. Significant differences in regeneration persisted following comparable injury in ␤-catenin-null and control animals. Retrospective analysis of liver samples from acetaminophen-overdose patients demonstrated a positive correlation between nuclear ␤-catenin, proliferation, and spontaneous liver regeneration. Thus, our studies demonstrate early activation of ␤-catenin signaling during acetaminophen-induced injury, which contributes to hepatic regeneration.

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Section: Discussionmentioning

confidence: 99%

“…[5][6][7] Recently, studies have demonstrated that patients who have a timely increase in spontaneous liver regeneration following APAP overdose have improved prognosis. 8,9 The role of liver regeneration in protection against APAP-induced ALF has also been demonstrated in experimental models.…”

mentioning

confidence: 99%

Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Apte

Singh

Zeng

et al. 2009

The American Journal of Pathology

Self Cite

150

137

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“…2,3 Efficient and timely liver regeneration can prevent hepatotoxic drug-induced acute liver failure in experimental animal models as well as in humans. [4][5][6][7][8] Monitoring the markers of liver regeneration in drug overdose victims has been proposed as a prognostic predictor. 5 Under a variety of circumstances in which liver regeneration is stimulated experimentally either by chemical injury (e.g., low dose of thioacetamide, APAP) [6][7][8][9][10] or by surgical resection (two-thirds partial hepatectomy), [11][12][13][14] the liver is known to exhibit resistance toward the higher doses of the hepatotoxicants.…”

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confidence: 99%

Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

et al. 2006

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Acute liver failure induced by hepatotoxic drugs results from rapid progression of injury. Substantial research has shown that timely liver regeneration can prevent progression of injury leading to a favorable prognosis. However, the mechanism by which compensatory regeneration prevents progression of injury is not known. We have recently reported that calpain released from necrotic hepatocytes mediates progression of liver injury even after the hepatotoxic drug is cleared from the body. By examining expression of calpastatin (CAST), an endogenous inhibitor of calpain in three liver cell division models known to be resistant to hepatotoxicity, we tested the hypothesis that increased CAST in the dividing hepatocytes affords resistance against progression of injury. Liver regeneration that follows CCl 4 -induced liver injury, 70% partial hepatectomy, and postnatal liver development were used. In all three models, CAST was upregulated in the dividing/newly divided hepatocytes and declined to normal levels with the cessation of cell proliferation. To test whether CAST overexpression confers resistance against hepatotoxicity, CAST was overexpressed in the livers of normal SW mice using adenovirus before challenging them with acetaminophen (APAP) overdose. These mice exhibited markedly attenuated progression of liver injury and 57% survival. Whereas APAP-bioactivating enzymes and covalent binding of the APAP-derived reactive metabolites remained unaffected, degradation of calpain specific target substrates such as fodrin was significantly reduced in these mice. In conclusion, CAST overexpression could be used as a therapeutic strategy to prevent progression of liver injury where liver regeneration is severely hampered. (HEPATOLOGY 2006;44:379-388.)

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“…Serial measurements of several biomarkers of liver damage, function, or regeneration have been evaluated as prognostic indicators, but, so far, little attention has been given to the timing of phosphate measurements. [15][16][17] In this study, we prospectively evaluated the prognostic value and clinical implications of serial measurements of serum phosphate in 125 patients with severe acetaminophen poisoning.…”

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Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity

2002

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Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning. Prospectively, serial measurements of serum phosphate were performed in 125 patients with severe acetaminophen poisoning. The optimum threshold value of serum phosphate to discriminate nonsurvivors was identified. Prognostic value and speed of identification were compared with those of the King's College Hospital (KCH) criteria. Phosphate concentrations were significantly higher in nonsurvivors than in survivors at 48 to 72 hours after overdose (mean 2.65 ؎ 1.18 mmol/L vs. 0.68 ؎ 0.22 mmol/L, P < .001) as well as 72 to 96 hours after overdose (2.12 ؎ 0.22 mmol/L vs. 0.59 ؎ 0.23 mmol/L, P < .001). A threshold phosphate concentration of 1.2 mmol/L at 48 to 96 hours after overdose had sensitivity 89%, specificity 100%, accuracy 98%, positive predictive value 100%, and negative predictive value 98%. The phosphate criteria had higher sensitivity, accuracy, and positive and negative predictive values than the KCH criteria, and it identified patients significantly earlier after transferal [median 1 hour (range 1-38 hours) vs. 12 hours (2-192 hours), P < .05, respectively]. In nonsurvivors, the degree of hyperphosphatemia correlated with renal dysfunction (R ‫؍‬ .55; P ‫؍‬ .02). In conclusion, hyperphosphatemia after acetaminophen overdose is seen exclusively in nonsurvivors, which makes it a highly specific as well as sensitive predictor of nonsurvival. We propose that hyperphosphatemia is caused by renal dysfunction in the absence of hepatic regeneration, as the latter appears to be associated with lowering of serum phosphate. (HEPATOLOGY 2002;36:659-665.)

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Biomarkers of Liver Regeneration Allow Early Prediction of Hepatic Recovery After Acute Necrosis

Cited by 65 publications

References 9 publications

Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity

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