{ "abstract": "Background: Early detection of hepatocellular carcinoma (HCC) remains challenging in hepatitis-endemic settings such as Pakistan, where surveillance commonly relies on ultrasonography and alpha-fetoprotein (AFP), both of which have limited sensitivity for early-stage disease. This study evaluated the diagnostic performance of serum Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II), complete blood count (CBC) parameters, and CBC-derived hematological indices for discriminating HCC from non-malignant chronic liver disease (CLD). Methods: We conducted a case-control biomarker study involving 160 adults with CLD at Liaquat University Hospital, Sindh, Pakistan, between October 2025 and March 2026, including 74 patients with established HCC and 86 with non-malignant CLD. Serum PIVKA-II was measured using electrochemiluminescence immunoassay. CBC-derived neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammation index, and red cell distribution width-to-platelet ratio were calculated. Between-group differences were assessed using non-parametric methods, and receiver operating characteristic (ROC) analysis evaluated discriminatory performance. Benjamini–Hochberg correction was applied to prespecified families of multiple comparisons. Results: PIVKA-II demonstrated the strongest discriminatory performance, with an area under the ROC curve (AUC) of 0.753 (95% CI, 0.670–0.827). At a cutoff of >82.1 mAU/mL, sensitivity was 86.4% and specificity was 56.0%. Platelet count (AUC, 0.642) and the RDW-to-platelet ratio (AUC, 0.638) also demonstrated significant between-group differences that remained significant after false discovery rate correction, although their discriminatory performance was modest. PIVKA-II discrimination was substantially higher among patients with vascular invasion (AUC, 0.853) and advanced BCLC stage C/D disease (AUC, 0.853) than among those with early/intermediate BCLC A/B disease (AUC, 0.571). A combined model incorporating PIVKA-II, lymphocyte percentage, and platelet count yielded an AUC of 0.784, but did not significantly improve discrimination compared with PIVKA-II alone (p = 0.166). Bootstrap validation showed minimal optimism in the overall AUC; however, the optimal PIVKA-II cutoff demonstrated substantial variability, with a 95% percentile range of 58.7–715.8 mAU/mL. This was corroborated by an independent 10-fold cross-validation analysis, which yielded a comparable mean AUC of 0.751 for PIVKA-II (optimism = +0.002). Conclusion: PIVKA-II demonstrated fair diagnostic discrimination between HCC and non-malignant CLD, with relatively high sensitivity but limited specificity. Its substantially lower performance in early/intermediate-stage disease and the marked instability of the optimal cutoff indicate that PIVKA-II should be considered a complementary biomarker rather than a standalone diagnostic test. Larger multicenter studies with standardized control populations and independent external validation are needed to establish robust population-specific thresholds and determine the incremental clinical value of combining PIVKA-II with hematological parameters.", "abstract_shown": true, "affiliations": [ "Department of Medical Laboratory Technology, Faculty of Natural Sciences, University of Sindh, Jamshoro, Sindh, Pakistan", "Department of Physiology, Faculty of Natural Sciences, University of Sindh, Jamshoro, Sindh, Pakistan" ], "article_type": "Research Article", "arxiv": null, "author_total": 2, "authors": [ { "affs": [ 0 ], "name": "Muhammad Sameer Hashmi", "orcid": "0009-0009-3933-4888" }, { "affs": [ 1 ], "name": "Muhammad Aqif Ilyas" } ], "bibtex": "https://research.draconitic.com/paper/a7jzrr4ak5v3f.bib", "cited_by": 0, "doi": "10.1371/journal.pone.0361802", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13730426/", "id": "a7jzrr4ak5v3f", "issns": [ "1932-6203" ], "landing_url": "https://doi.org/10.1371/journal.pone.0361802", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Animal Cells" ], [ "heading", "Biochemistry" ], [ "heading", "Biology and Life Sciences" ], [ "heading", "Biomarkers" ], [ "heading", "Blood Cells" ], [ "heading", "Cancer Detection and Diagnosis" ], [ "heading", "Cancers and Neoplasms" ], [ "heading", "Carcinoma" ], [ "heading", "Cell Biology" ], [ "heading", "Cellular Types" ], [ "heading", "Cirrhosis" ], [ "heading", "Diagnostic Medicine" ], [ "heading", "Gastroenterology and Hepatology" ], [ "heading", "Gastrointestinal Tumors" ], [ "heading", "Hematology" ], [ "heading", "Hepatocellular Carcinoma" ], [ "heading", "Immune Cells" ], [ "heading", "Immunology" ], [ "heading", "Liver Diseases" ], [ "heading", "Lymphocytes" ], [ "heading", "Medicine and Health Sciences" ], [ "heading", "Oncology" ], [ "heading", "Research Article" ], [ "heading", "White Blood Cells" ], [ "openalex", "2721|Hepatocellular Carcinoma Treatment and Prognosis" ], [ "plos", "/Biology and life sciences/Biochemistry/Biomarkers" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Lymphocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Lymphocytes" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Lymphocytes" ], [ "plos", "/Medicine and health sciences/Diagnostic medicine" ], [ "plos", "/Medicine and health sciences/Diagnostic medicine/Cancer detection and diagnosis" ], [ "plos", "/Medicine and health sciences/Gastroenterology and hepatology/Liver diseases/Cirrhosis" ], [ "plos", "/Medicine and health sciences/Gastroenterology and hepatology/Liver diseases/Hepatocellular carcinoma" ], [ "plos", "/Medicine and health sciences/Hematology" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Lymphocytes" ], [ "plos", "/Medicine and health sciences/Oncology/Cancer detection and diagnosis" ], [ "plos", "/Medicine and health sciences/Oncology/Cancers and neoplasms" ], [ "plos", "/Medicine and health sciences/Oncology/Cancers and neoplasms/Carcinoma/Hepatocellular carcinoma" ], [ "plos", "/Medicine and health sciences/Oncology/Cancers and neoplasms/Gastrointestinal tumors/Hepatocellular carcinoma" ] ], "openalex": "W7225193281", "pdf_url": null, "pmcid": "PMC13730426", "pmid": "42976211", "published": "2026-11-03", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/a7jzrr4ak5v3f.ris", "sources": [ { "first_seen": "2026-11-04T12:20:43Z", "native_id": "10.1371/journal.pone.0361802", "source": "plos", "url": "https://doi.org/10.1371/journal.pone.0361802" }, { "first_seen": "2026-11-07T12:22:59Z", "native_id": "PMC13730426", "source": "pmc", "url": "https://doi.org/10.1371/journal.pone.0361802" } ], "subjects": [ { "field": "biochemistry", "origin": "heading:Biochemistry", "subfield": "general" }, { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:oncology", "subfield": "oncology" } ], "title": "PIVKA-II and hematological parameters in hepatocellular carcinoma and non-malignant chronic liver disease: A case-control biomarker comparison in a hepatitis-endemic population", "title_text": "PIVKA-II and hematological parameters in hepatocellular carcinoma and non-malignant chronic liver disease: A case-control biomarker comparison in a hepatitis-endemic population", "type": "peer-reviewed", "updated_at": "2026-11-07T12:22:59Z", "url": "https://research.draconitic.com/paper/a7jzrr4ak5v3f", "venue": "PLOS One", "versions": [] }