Simple Blood Ratios Outperform Standard Scores for Spotting Cirrhosis in Suppressed Hepatitis B

Patients with chronic hepatitis B whose viral DNA has been driven below the detection limit by antiviral therapy are often assumed to be in a quiescent phase of infection. Yet a growing body of evidence shows that hepatitis B virus RNA can remain detectable in their serum, signaling that the viral transcriptional machinery inside infected liver cells is still running. A new study published in Frontiers in Medicine suggests that in this HBV DNA-negative, HBV RNA-positive population, two inexpensive blood-derived indices—the Prognostic Nutritional Index (PNI) and the monocyte-to-lymphocyte ratio (MLR)—can identify which patients have already progressed to cirrhosis, and that they do so better than the fibrosis scores clinicians routinely rely on.

The research, conducted by Minying Li, Yan Fang, Yuhong Han, Tuantuan Li, Yan Liu, and Lichang Chen of the Department of Clinical Laboratory at the Second People’s Hospital of Fuyang City in China, enrolled 183 patients with chronic hepatitis B between March 2024 and March 2025. All participants had serum HBV DNA below 10 IU/mL, the detection limit of the quantitative PCR assay used, but HBV RNA at or above 100 copies/mL, the positivity threshold of a capture-probe-based RNA assay. Of these, 87 patients who had developed cirrhosis formed the observation group, while 96 patients without cirrhosis served as controls. All patients were on antiviral therapy, and laboratory measurements were collected after treatment.

The diagnosis of cirrhosis was not based on liver biopsy, which was not routinely performed because of its invasive nature. Instead, the reference standard combined liver stiffness measurement by transient elastography—defined as 12.0 kilopascals or higher—with ultrasonographic features such as a nodular liver surface, blunt liver edge, and splenomegaly, and/or clinical signs of portal hypertension including platelet counts below 100 × 10⁹/L or imaging-confirmed varices. Where biopsy results were available, they were prioritized and showed good concordance with the non-invasive criteria. Patients co-infected with other hepatitis viruses, those with malignancy, autoimmune liver disease, or severe cardiovascular, renal, or hematopoietic disease were excluded to keep the comparison clean.

PNI is a composite score first proposed by Buzby and colleagues in 1980 for perioperative risk assessment. It is calculated as ten times the serum albumin concentration in grams per deciliter plus 0.005 times the total lymphocyte count, and it captures the intertwined status of nutrition and cellular immunity. MLR, by contrast, is simply the monocyte count divided by the lymphocyte count, and it reflects the balance between innate and adaptive immune activity. Both indices can be derived from a standard complete blood count and a routine biochemistry panel, making them far cheaper and more accessible than molecular assays or elastography.

The comparison between groups revealed a coherent biological pattern. Cirrhotic patients had significantly lower white blood cell, lymphocyte, and monocyte counts, along with reduced total protein, albumin, and prealbumin, while aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) were significantly higher. Notably, the mean and median values of most of these individual parameters remained within normal reference ranges in both groups, which is precisely why the composite indices mattered. PNI was significantly lower in the cirrhosis group (52.44 versus 57.10), and MLR was significantly higher (0.21 versus 0.16), with both differences highly significant. Importantly, age, sex, ALT, ALP, and alpha-fetoprotein levels did not differ between groups, establishing baseline comparability.

Diagnostic performance was assessed with receiver operating characteristic analysis. PNI achieved an area under the curve of 0.821 with a sensitivity of 95.8 percent at a cut-off of 53.15, while MLR reached an AUC of 0.743 with a sensitivity of 85.4 percent at a cut-off of 0.195. Strikingly, the established fibrosis scores FIB-4 and APRI managed only AUCs of 0.733 and 0.735, respectively, in the same cohort. The authors attribute this shortfall to the fact that FIB-4 and APRI depend heavily on transaminase and platelet dynamics, which tend to normalize when HBV DNA is suppressed, whereas PNI and MLR capture the nutritional-immune axis and systemic inflammation that continue to shift as cirrhosis develops. Within the cirrhosis group, PNI and MLR were also inversely correlated (r = −0.484, P < 0.001), underscoring that the two markers probe related but distinct facets of the same process.

Multivariable logistic regression, with backward stepwise elimination guided by the Akaike Information Criterion and multicollinearity screened using variance inflation factors, confirmed that both indices were independent predictors. Higher PNI behaved as a protective factor, with an odds ratio of 0.694 per unit increase, while elevated MLR was a risk factor with an odds ratio of 3.176. Because MLR showed a markedly right-skewed distribution that destabilized continuous modeling, the team dichotomized it at the optimal ROC-derived cut-off for screening. From these independent predictors the researchers built a nomogram—a graphical scoring tool that translates individual biomarker values into a personalized probability of cirrhosis. The model achieved a concordance index of 0.829, and calibration curves showed good agreement between predicted and observed probabilities, while decision curve analysis indicated positive net clinical benefit.

The mechanistic story the authors propose is subtle and hinges on the difference between HBV DNA and HBV RNA as virological markers. HBV DNA largely reflects active virion production and correlates with overt cytopathic injury, driving the transaminase spikes and platelet changes that FIB-4 and APRI were designed to detect. Persistent serum HBV RNA, particularly pregenomic RNA, instead signals ongoing transcription from the nuclear cccDNA reservoir—the stable minichromosome that nucleos(t)ide analogues cannot eradicate and the fundamental reason hepatitis B is difficult to cure and prone to relapse after treatment withdrawal. In this DNA-suppressed but RNA-positive state, the inflammatory pattern shifts from cytopathic to a chronic, smoldering, immune-mediated process. Viral RNA acts as a pathogen-associated molecular pattern recognized by Toll-like receptors on monocytes and Kupffer cells, sustaining innate activation and relative lymphopenia, while chronic low-grade inflammation suppresses hepatic albumin synthesis as a negative acute-phase reactant. These shifts preferentially perturb the immuno-nutritional axis that PNI and MLR measure.

The study’s limitations are candidly acknowledged. The retrospective, cross-sectional, single-center design means the findings demonstrate association rather than causation or temporal prediction. The specificity of both biomarkers was modest—56.3 percent for PNI and 57.5 percent for MLR—so false positives are a real risk and the markers should be interpreted alongside imaging and other clinical parameters rather than as standalone tests. The nomogram has not yet been externally validated, and incomplete medical records prevented reliable accounting of antiviral regimens, treatment durations, HBeAg status, and HBV RNA levels, leaving room for residual confounding. The authors call for multicenter prospective studies and suggest exploring whether nutritional interventions guided by these biomarkers could improve outcomes.

Even with those caveats, the practical appeal is considerable. Unlike HBV RNA or quantitative HBsAg testing, which require specialized molecular platforms that may be unavailable in resource-limited settings, PNI and MLR can be calculated from laboratory data that virtually every hospital already generates. The Fuyang team’s work suggests that in the growing population of patients whose HBV DNA has been silenced but whose cccDNA quietly persists, the most informative signals of advancing liver disease may lie not in viral load measurements but in the humble complete blood count and albumin value—indices that cost almost nothing and are already sitting in the medical record.

Subject of Research: Non-invasive diagnosis of cirrhosis using PNI and MLR in HBV DNA-negative, HBV RNA-positive chronic hepatitis B patients

Article Title: Diagnostic value of PNI and MLR in cirrhotic patients with negative HBV DNA and positive HBV RNA:A nomogram–based evaluation model

Article References: Li, M., Fang, Y., Han, Y., Li, T., Liu, Y., & Chen, L. (2026). Diagnostic value of PNI and MLR in cirrhotic patients with negative HBV DNA and positive HBV RNA:A nomogram–based evaluation model. Frontiers in Medicine, 13, Article 1919910. https://doi.org/10.3389/fmed.2026.1919910

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1919910

Keywords: hepatitis B, HBV DNA, HBV RNA, cirrhosis, Prognostic Nutritional Index, monocyte-to-lymphocyte ratio, nomogram, FIB-4, APRI, liver fibrosis, biomarkers, cccDNA