Alpha‐fetoprotein: A biomarker for the recruitment of progenitor cells in the liver in patients with acute liver injury or failure

Kakisaka, Keisuke; Kataoka, Kojiro; Onodera, Mio; Suzuki, Akiko; Endo, Kei; Tatemichi, Yoshinori; Kuroda, Hidekatsu; Ishida, Kazuyuki; Takikawa, Yasuhiro

doi:10.1111/hepr.12448

Cited by 36 publications

(36 citation statements)

References 29 publications

(77 reference statements)

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“…(26) The association between elevated ALT and AFP in the absence of HCC suggests that AFP production increase in the presence of enhanced hepatocyte destruction and regeneration of liver progenitor cells with a less differentiated phenotype. (27) However this association seems to be etiology and race specific given that both race and etiology are important determinants of elevated AFP even after controlling for serum ALT. Underlying mechanisms connecting severity of hepatic inflammation, Non White race, viral etiology of liver disease and elevated AFP levels should be further investigated in future studies.…”

Section: Discussionmentioning

confidence: 91%

“…A larger phase three prospective multicenter cohort biomarker study is now underway to validate the current findings. (27,28) This ongoing biomarker study will be able to address whether baseline serum AFP can predict subsequent development of HCC on imaging. Due to sample size limitations, subgroup analysis results might not be as reliable, particularly in non HCV subgroups.…”

Section: Discussionmentioning

confidence: 99%

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Improved Performance of Serum Alpha-Fetoprotein for Hepatocellular Carcinoma Diagnosis in HCV Cirrhosis with Normal Alanine Transaminase

Yang

Dai

Singal

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background The utility of alpha fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is controversial. We aimed to identify factors associated with elevated AFP and define the patients for whom AFP is effective for surveillance. Methods Data from the National Cancer Institute Early Detection Research Network Phase 2 HCC biomarker study (233 early stage HCC and 412 cirrhotic patients) were analyzed. We analyzed 110 early stage HCC and 362 cirrhotic HCV patients for external validation. Sensitivity, specificity and area under the ROC curve (AUC) for HCC were calculated. Results HCV etiology, Non-White race, and serum alanine transaminase (ALT) predicted elevated AFP in cirrhotics. Non-White race and ALT predicted elevated AFP in HCC patients. Higher AUC of AFP for HCC was noted in patients with HBV (0.85) and alcohol (0.84) while it was lower in patients with HCV (0.80) and Non-viral/Alcohol etiology (0.76). The AUC was higher in HCV patients with serum ALT ≤ 40 U/L than patients with serum ALT>40 U/L (0.91 vs 0.75, P<0.01). At 90% specificity, the sensitivity of AFP increased from 44% to 74% in Whites with HCV and from 50% to 85% in Non-Whites with HCV. There was a trend towards higher AUC in HCV patients with serum ALT≤40 U/L than those with serum ALT>40 U/L (0.79 vs 0.69, P=0.10) in the validation cohort. Conclusions The satisfactory performance of AFP in HCV patients with normal ALT should be further validated. Impact The AFP may serve as a valuable surveillance test in HCV patients with normal ALT.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Improved Performance of Serum Alpha-Fetoprotein for Hepatocellular Carcinoma Diagnosis in HCV Cirrhosis with Normal Alanine Transaminase

Yang

Dai

Singal

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…AFP, a hepatoblast marker, is used clinically as a biomarker for HCC, although an association with fibrosis has previously been observed in chronic HBV[29], and reduced AFP levels were associated with fibrosis regression following interferon therapy in patients with chronic HCV[30]. Given the alternative, hepatic progenitor cell (HPC)-mediated pathway of liver repair is increasingly activated during CLD progression, and immature HPC are the source of AFP[31]; AFP could represent a novel serum biomarker of HPC activation.…”

Section: Discussionmentioning

confidence: 99%

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

et al. 2016

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Background and AimsNon-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis.MethodsWe performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis.ResultsSeventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long’s test).ConclusionsWe have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis.

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“…AFP is produced by bipotent HPCs and yolk sac endoderm, and serum AFP concentrations are increased during embryonic development. On the other hand, serum AFP levels are elevated in the recovery phase of acute hepatic failure10 and active liver cirrhosis11 in adult patients, possibly indicating mobilization and proliferation of HPCs. However, the origin of such AFP‐producing cells induced in injured adult liver tissue is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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Alpha‐fetoprotein: A biomarker for the recruitment of progenitor cells in the liver in patients with acute liver injury or failure

Cited by 36 publications

References 29 publications

Improved Performance of Serum Alpha-Fetoprotein for Hepatocellular Carcinoma Diagnosis in HCV Cirrhosis with Normal Alanine Transaminase

Improved Performance of Serum Alpha-Fetoprotein for Hepatocellular Carcinoma Diagnosis in HCV Cirrhosis with Normal Alanine Transaminase

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

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