Non-Invasive Biomarkers and Breath Tests for Diagnosis and Monitoring of Chronic Liver Diseases

Abstract

Background: Chronic liver disease (CLD) presents a significant global health burden, demanding effective tools for diagnosis and monitoring. Traditionally, liver biopsy has been the gold standard for evaluating liver fibrosis and other chronic liver conditions. However, biopsy's invasiveness, associated risks, and sampling variability indicate the need for reliable, noninvasive alternatives. This review examines the utility of noninvasive tests (NITs) in assessing liver disease severity, progression, and therapeutic response in patients with CLD. Result: Key modalities discussed include serum biomarker panels (e.g., FIB-4, APRI, ELF), imaging techniques like transient elastography, and magnetic resonance elastography, each offering unique benefits in fibrosis staging. Emerging biomarkers such as extracellular vesicles and circulating microRNAs show promise in early detection and personalized monitoring. Comparative studies indicate that while no single NIT matches biopsy precision, combinations of these modalities improve diagnostic accuracy and patient outcomes by reducing unnecessary biopsies. Moreover, NITs are instrumental in monitoring dynamic changes in liver health, allowing for more responsive and patient-centered care. Conclusions: Challenges remain, including standardization across tests, cost considerations, and the need for larger, diverse population studies to validate findings. Despite these limitations, NITs are increasingly integrated into clinical practice, fostering a paradigm shift toward noninvasive, accessible liver disease management. Continued advancements in NITs are essential for improved patient outcomes and will likely shape the future standard of care for CLD.

Keywords: chronic liver disease; non-invasive test; volatile organic compound.

Figure 1

(A-1) In the first step of ¹³C-methacetin breath test, baseline ¹³C to ¹²C in exhaled breath is measured to establish a reference. (A-2) Next, the patient is administered ¹³C-labeled methacetin, which is then metabolized through cytochrome P450 1A, resulting in ¹³C-labeled formaldehyde and, eventually, ¹³C-labeled carbon dioxide. (A-3) Finally, the rate of ¹³C appearance in exhaled breath is measured at various intervals to determine hepatic microsomal metabolic function. (B) With each progressing stage of chronic liver disease, metabolic hepatic function declines. Metabolic dysfunction-associated steatotic liver disease (MASLD) involves fat accumulation without significant inflammation, so only slightly lower cumulative percentage dose of ¹³C recovery (CPDR) levels is expected. Metabolic dysfunction-associated steatohepatitis (MASH) and compensated cirrhosis involve early inflammation and fibrosis, further reducing the CPDR. Decompensated cirrhosis and hepatocellular carcinoma (HCC), often associated with end-stage liver disease, result in severely decreased CPDR.