Beyond the CMP: Using biomarkers to help identify underlying drivers of liver disease

Chronic liver disease (CLD) is an increasingly common condition in the United States.¹ Driven by the convergence of viral hepatitis, metabolic dysfunction–associated steatotic liver disease (MASLD), and alcohol-related liver injury, CLD is currently the fourth leading cause of death among people in the US age 45-65 years.¹

While the treatment and management of viral hepatitis have improved, the overall burden of liver disease is shifting toward alcoholic liver disease (ALD) and MASLD.¹

Affecting 1 in 3 adults, MASLD is one of the fastest-growing diseases in the US, driven by parallel rising tides of obesity and type 2 diabetes.²

Collectively, these etiologies contribute to rising rates of advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality.³

The possibility that patients may remain asymptomatic until advanced stages underscores the need for a comprehensive, longitudinal approach to liver disease risk assessment, and primary care clinicians are often in a position to identify at-risk individuals early in the disease course.

A structured, evidence-based testing strategy may help change the trajectory of liver disease progression, enabling more timely intervention, access to appropriate therapies, and the potential to improve patient outcomes.

In this article:

Clinical challenge | Why it matters | Ordering recommendations | Interpreting test results | Next steps | Supporting resources

Clinical challenge: Silent progression, underdiagnosis, and fragmented evaluation create missed opportunities

Liver disease may be clinically silent, and normal aminotransferase levels do not exclude clinically significant liver disease. In patients with MASLD, aminotransferase levels may be normal even in the presence of advanced fibrosis. For that reason, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in isolation—typically included in a comprehensive metabolic panel (CMP)—may not be sufficient to assess fibrosis risk.^4,5

With that in mind, it’s likely that many patients are first identified at advanced stages, when therapeutic options are more limited and complications more likely.

Gaps in screening and risk identification: Viral hepatitis

The Centers for Disease Control and Prevention (CDC) recommends universal screening for hepatitis B virus (HBV) and hepatitis C virus (HCV) in all US adults, along with periodic screening for individuals at increased risk.^6,7 Despite these recommendations, screening rates in primary care settings remain suboptimal, and a substantial proportion of individuals with HBV or HCV infection go undiagnosed, contributing to delayed initiation of treatment.^7,8

Gaps in screening and risk identification: MASLD

MASLD is one of the fastest-growing causes of chronic liver disease in the US, closely linked to the rising prevalence of obesity and type 2 diabetes.³ The American Association of Clinical Endocrinology (AACE) 2022 guidelines identify several high-risk groups who should be proactively assessed for liver fibrosis.⁹

• Individuals with obesity and/or features of metabolic dysfunction
• Patients with prediabetes or type 2 diabetes
• Those with hepatic steatosis on imaging and/or persistently elevated aminotransferases (>6 months)

Despite this guidance, MASLD remains significantly underdiagnosed, and noninvasive fibrosis risk stratification is inconsistently applied in routine clinical settings.^10,11

Overlapping and compounding risk factors

Patients with liver disease may have multiple coexisting risk factors, including metabolic dysfunction, alcohol exposure, and viral hepatitis.⁵ Evidence suggests that MASLD can accelerate liver injury in patients with viral hepatitis, increasing the risk of advanced fibrosis and cirrhosis.⁷

Alcohol use can further compound the risk of liver disease progression, with moderate consumption associated with increased risk of advanced fibrosis—particularly among individuals with metabolic risk factors.^4,5

Limitations of current practice

Potential gaps in routine care may include

• Inconsistent use of noninvasive fibrosis scoring tools (eg, FIB-4)
• Limited follow-up testing for patients with indeterminate risk
• Underutilization of objective alcohol biomarkers
• Fragmented evaluation that fails to account for multiple etiologies

These challenges highlight the need for a standardized, progressive approach to liver disease assessment in primary care. Diagnostic screening can help provide the depth of information necessary to identify and differentiate underlying conditions earlier in the progression of CLD, when clinicians can have more significant positive impact.

Why it matters: Untreated hepatitis B, hepatitis C, and MASLD may progress to severe negative outcomes

Unrecognized or undertreated liver disease can progress to³

• Advanced fibrosis and cirrhosis
• Portal hypertension and hepatic decompensation
• Hepatocellular carcinoma
• Liver-related mortality

The presence of multiple etiologies (eg, MASLD plus viral hepatitis or alcohol use) significantly increases the likelihood of progression and adverse outcomes.¹²

Impact on treatment decisions

Accurate fibrosis staging can help support clinical decision-making by informing

• Monitoring intervals
• Need for specialist referral
• Eligibility for pharmacologic therapies

For example, glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide (Wegovy) have received FDA approval for adults with metabolic dysfunction–associated steatohepatitis (MASH) and moderate to advanced fibrosis.¹³ Access to these therapies often requires objective evidence of disease severity, making appropriate testing important for clinical care.

Importance of alcohol use assessment

In patients with chronic liver disease, alcohol consumption may

• Accelerate fibrosis progression
• Worsen liver injury
• Negatively impact long-term outcomes¹⁴

Alcohol use may be underreported. Direct biomarkers provide objective, complementary evidence of recent alcohol exposure.^15,16,17

Providing proactive, data-driven liver care

The growing burden of liver disease calls for a shift from reactive to proactive care. Primary care clinicians can help play a central role in this transformation by implementing comprehensive, standardized risk assessment strategies.

By integrating viral hepatitis screening, fibrosis risk stratification, and objective alcohol use assessment into routine practice, clinicians can

• Potentially detect disease earlier
• Begin to address multiple contributing etiologies
• Guide treatment and referral
• Help improve long-term patient outcomes

Ordering recommendations: Comprehensive, progressive testing for hepatitis B, hepatitis C, and MASLD across the patient journey

To help identify underlying drivers of liver disease and monitor liver status, Quest offers the CDC-recommended triple-panel test for HBV6 as well as HCV,⁷ the preferred noninvasive initial test for MASLD⁹ with liver fibrosis risk assessment, and noninvasive blood testing for enhanced liver fibrosis (ELF) score.

For HBV and HCV, the CDC recommends screening for¹⁸

• All adults at least once in their lifetime
• All pregnant people during each pregnancy, preferably in the first trimester
• Infants born to HBV- or HCV-infected people

The American Association of Clinical Endocrinology (AACE) 2022 guidelines recommend that adults with any of the following conditions be assessed for liver fibrosis¹⁹

• Obesity and/or features of metabolic syndrome
• Prediabetes or type 2 diabetes
• Hepatic steatosis on any imaging study and/or persistently elevated plasma aminotransferase levels (over 6 months)

According to recommendations for blood testing and referral developed by AACE and cosponsored by the American Association for the Study of Liver Diseases (AASLD), the FIB-4 index is the preferred noninvasive initial test to assess the risk of MASLD with liver fibrosis.⁹

Recommended tests: Fibrosis-4 index, viral hepatitis screening, enhanced liver fibrosis (ELF) score, and alcohol use assessment

Initial assessment and routine screening for patients with risk factors for chronic liver disease:

Liver Fibrosis, Fibrosis-4 (FIB-4) Index Panel

• Test code: 30555
• CPT^® code(s): 84450, 84460, 85049*

Components include AST (822), ALT (823), and Platelet Count (723).

Liver Fibrosis, Hepatic Function Panel with Fibrosis-4 (FIB-4) Index

• Test code: 30710
• CPT code(s): 80076, 85049*

Components include Hepatic Function Panel (10256) [components: Total Protein (754), Albumin (223), Globulin (calculated), Albumin/Globulin Ratio (calculated), Total Bilirubin (287), Direct Bilirubin (285), Indirect Bilirubin (calculated), Alkaline Phosphatase (234), AST (822), ALT (823)] and Platelet Count (723).

Viral hepatitis screening:

HBV Triple Screen Panel with Reflexes

• Test code: 39170
• CPT code(s): 87340,* 86704,* 86317

Components include Hepatitis B Surface Antigen (HBsAg) with Reflex Confirmation (498), Hepatitis B Core Antibody (HBcAb), Total, with Reflex to IgM (37676),* and Hepatitis B Surface Antibody (HBsAb) Immunity, Quantitative (8475).

* Hepatitis B Core Antibody, Total (test code 501[X]) is a measure of both IgM and IgG antibodies to hepatitis B core antigen (HBcAg), for which there is no direct antigen test. The test does not distinguish between IgG and IgM antibodies. HBcAb may be detected before or at the onset of symptoms; however, such reactivity can persist for years after illness, and may even outlast HBsAb. Occasionally, HBcAb may be the only marker of either current or past hepatitis B infection. HBV vaccination leads to development of HBsAb but not to HBcAb.

Hepatitis C Antibody with Reflex to HCV, RNA, Quantitative, Real-Time PCR

• Test code: 8472
• CPT code: 86803*

Hepatitis C Antibody with Reflex to HCV RNA, PCR with Reflex to Genotype

• Test code: 94345
• CPT code: 86803*

If Hepatitis C Antibody is reactive or borderline, then Hepatitis C Viral RNA, Quantitative, Real-Time PCR (35645) will be performed at an additional charge. If Hepatitis C Viral RNA, Quantitative, Real-Time PCR is ≥2000 IU/mL, then Hepatitis C Virus RNA Genotype (37811) will be performed at an additional charge.

Alcohol use assessment:

Drug Monitoring, Phosphatidylethanol (PEth), Blood

• Test code: 12198
• CPT code(s): 80321 (HCPCS: G0480)

Related test: MASH disease progression assessment

According to AACE and AASLD, patients in high-risk groups with an indeterminate or high FIB-4 index should be considered for further testing,⁹ including the Enhanced Liver Fibrosis (ELF™) Score.

Enhanced Liver Fibrosis (ELF) Score

• Test code: 10350
• CPT code: 81517

* CPT Code is subject to a Medicare Limited Coverage Policy and may require a signed ABN when ordering.

Interpreting test results

FIB-4 index values for NAFLD, hepatitis B, and hepatitis C

An elevated FIB-4 index is consistent with the presence of advanced fibrosis, and a low FIB-4 index is consistent with the absence of advanced fibrosis. However, your interpretation should be guided by patient characteristics and clinical profile. For patients with an indeterminate result, consider additional assessment.²⁰

HBV Triple Screen Panel with Reflexes

Results from this panel show the presence of serologic markers interpreted into 5 indication statuses: acute infection, chronic infection, immunity due to past infection, immunity due to vaccination, and susceptible to infection.

HCV Antibody with Reflex to HCV RNA

A negative result means no evidence of past infection, although recent exposure may not yet be detected. A positive result indicates current or past infection and should automatically reflex to HCV RNA testing to determine whether active infection is present. Results showing positive for antibody and negative for RNA generally suggest resolved infection, successful treatment, or a false-positive antibody result.

PEth testing

The PEth test results include 2 components that may indicate probable abstinence or probable chronic drinking. A negative result is not always indicative of abstinence, as a PEth test may not detect a single drink or casual drinking. A positive result may indicate chronic drinking (multiple drinks/day).²¹

ELF score

The ELF score indicates the risk of disease progression to cirrhosis or liver-related events based on established thresholds, providing ranges indicative of lower, mid, or higher risk of disease. Results should be interpreted in conjunction with the patient’s medical history, clinical presentation, and other findings.²²

Next steps: Appropriate treatments and longitudinal monitoring

Liver disease is dynamic. Periodic reassessment using FIB-4 and other biomarkers helps clinicians

• Track progression or regression
• Adjust management strategies
• Reinforce lifestyle and treatment adherence

Clear referral pathways are essential for patients with advanced fibrosis or complex disease. Primary care providers’ collaboration with hepatology, endocrinology, and behavioral health specialists can help optimize outcomes.

Supporting resources

MASLD/MASH

Viral hepatitis

PEth