Chronic liver disease (CLD) is responsible for significant morbidity and mortality. Most liver-related outcomes occur in people with advanced CLD, yet liver disease can be asymptomatic until the late stages. This makes early identification of patients at risk for complications imperative.
Although liver biopsy was traditionally used to stage individuals, increasing data support the role of noninvasive liver disease assessment (NILDA) to determine the presence and severity of liver fibrosis, steatosis, and clinically significant portal hypertension.
The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines Committee convened a team of experts with the goal of helping clinicians incorporate NILDA into their treatment of CLD. Their work resulted in a pair of recently published practice guidelines on imaging-based and blood-based NILDA. Of the two options, blood-based NILDA models are more readily available to clinicians; therefore, it is key that they understand the best way to apply them in patients with CLD.
To find out more about best practices surrounding the use of blood-based NILDA in CLD, Medscape contributor Nancy S. Reau, MD, chief of the hepatology section at Rush University Medical Center in Chicago, spoke with the guidelines' lead author, Richard K. Sterling, MD, MSc, professor of medicine, chief of hepatology, and chief clinical officer of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, Richmond, Virginia.
Why NILDA Is Becoming Common Practice
Why is it so important to have a way to determine the degree (or stage) of liver damage without having to do a liver biopsy?
Understanding the fibrosis stage is paramount to managing people with CLD. It not only can provide prognostic information but also identifies those who are at risk for developing complications of portal hypertension, such as ascites, hepatic encephalopathy, and variceal bleeding, and those at risk for developing hepatocellular carcinoma.
Additionally, fibrosis stage is often considered when determining whether treatment is indicated, such as with metabolic dysfunction–associated steatotic liver disease (MASLD).
Liver biopsy is an invasive procedure that can be associated with pain, bleeding, and, rarely, puncture of other organs. It's also subject to sampling error.
Liver biopsy is still used in certain situations, such as in autoimmune hepatitis to confirm the diagnosis and determine whether it's safe to stop immune suppression, in metabolic dysfunction–associated steatohepatitis (MASH) to determine whether treatment is needed, and after transplant to rule out rejection. However, in most other liver disease, NILDA has now replaced liver biopsy in clinical practice.
Differentiating Among NILDA Models
Is there a difference between the various blood-based NILDAs?
Over 35 blood-based biomarker tests have been developed.
Some are simple, nonproprietary models that include only readily available blood tests, data, and patient characteristics, such as age, body mass index, diabetes, liver enzymes, and platelet count. Simple NILDAs do not include direct measurements of fibrosis synthesis or breakdown.
Proprietary, complex NILDA models have been developed to overcome this, because they can also include direct markers of fibrosis formation or degradation. However, they are much more expensive, are not as readily available, and may not add any value over simple, nonproprietary NILDAs.
It is important to mention that for people with MASLD, all blood-based NILDA studies were performed in those with nonalcoholic fatty liver disease (NAFLD), before the recent name change. However, more recent studies show very high correlation between the older definition of NAFLD and the newer definition of MASLD, so the data on NAFLD should also apply to MASLD.
What are direct and indirect NILDAs?
Direct biomarkers include products of fibrosis formation and breakdown, such as tissue inhibitor matrix metalloproteinase 1, amino-terminal propeptide of type III procollagen, hyaluronic acid, and the fibrillary collagen formation marker procollagen type III.
Conversely, indirect NILDA includes liver enzymes (aspartate aminotransferase, alanine aminotransferase) and platelet counts as a marker of hypersplenism associated with portal hypertension seen in cirrhosis.
Settings In Which to Use NILDA
Are there some diseases in which NILDA does not perform well?
Most NILDAs were developed in defined populations to identify people with advanced fibrosis (F3-4), so they do not perform well to identify those with significant fibrosis (at least F2), the population often targeted for some therapies.
Although the sensitivity and specificity of NILDAs are defined, the positive and negative predictive values are dependent on the prevalence of advanced fibrosis in the population.
Therefore, they may work differently in a primary care setting where the prevalence of advanced fibrosis is less than 5% compared with a hepatology referral setting where over 30% of patients may have advanced fibrosis.
In general, NILDA works better to rule out advanced fibrosis in people with values below the lower thresholds than it does to rule it in among those with values above the upper thresholds.
Most studies did not include persons under age 25 years or older than 65 years, so NILDAs that include age may not perform as well in patients at the extremes.
Most NILDAs will also not work in people in acute hepatitis owing to marked inflammation, in those with renal failure often associated with lower liver enzymes, or those with heart failure or severe tricuspid regurgitation associated with hepatic congestion.
Lastly, we did not find that blood-based NILDA to assess steatosis performed that well compared with imaging based-NILDA.
Are there NILDAs that should be used to stage some CLDs but not others?
Although the AASLD systematic review identified sufficient data for chronic untreated hepatitis C virus (HCV), hepatitis B virus (HBV), and NAFLD, there were far fewer studies for other diseases such as primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, and alcohol-related liver disease.
For people with viral hepatitis, it is important to use NILDA prior to initiating treatment, because most improvements in NILDA after treatment are related to decreases in inflammation and not necessarily decreases in fibrosis.
Is there risk to using one NILDA, such as the Fibrosis-4 index (FIB-4), and applying it to all liver disease across the board?
The AASLD NILDA guidelines recommend simple, nonproprietary NILDAs, such as FIB-4, over complex, proprietary tests. This is because most simple NILDAs are essentially free if the routine tests are available and have similar test characteristics to more expensive proprietary tests.
Although FIB-4 performed as well as other tests in chronic untreated HCV, HBV, and NAFLD, there are liver diseases that are less studied.
Are there conditions that make NILDA less reliable that clinicians should be aware of?
If the biomarker panel includes age, it may not work as well in young persons or older persons.
If the biomarker panel includes platelets, then it will not work well in people with thrombocytopenia unrelated to portal hypertension or in those with splenectomy. Similarly, if the panel includes bilirubin, it will not work in people with hemolysis or Gilbert syndrome.
Most NILDAs will also not work in people in acute hepatitis, renal failure, or heart failure.
Therefore, all blood-based NILDAs need to be interpreted with clinical context of each patient to assess whether something other than fibrosis is driving the result.
Additional Considerations
The guideline recommends applying two blood-based biomarkers for both untreated HCV and MASLD. Is this important for all such patients?
Yes, if available.
It is very important to identify those with cirrhosis who may need hepatocellular carcinoma surveillance after cure for HCV. Because treatments for MASLD are just now being approved, we do not yet know if the same will hold true for MASLD.
Any improvements after treatment may reflect improvements in inflammation and not fibrosis. Most clinicians will start with something like FIB-4. Then, in patients with values above the lower threshold (1.45 for viral hepatitis and 1.3 for MASLD), they usually order an imaging-based NILDA, such as elastography. If that is not available in someone with MASLD, the AASLD guidelines recommend the enhanced liver fibrosis test.
When a NILDA improves, can I tell my patient that their liver disease is better?
Because few studies have evaluated NILDAs after therapy compared with biopsy, the AASLD does not recommend they be used routinely after treatment of the underlying liver disease.
Furthermore, with imaging-based elastography, we are learning that owing to variation between operators and techniques, a meaningful difference of at least 30% is needed to suggest fibrosis regression or progression.
One exemption is imaging-based NILDA for clinically significant portal hypertension. If the liver stiffness decreases from > 25 kPa to < 15 kPa with treatment, along with increased platelet count to > 150,000, that patient may no longer be at risk for varices.
The use of NILDA after treatment is one of the major future areas for research.
NILDA for pediatric patients?
The studies are far fewer in the pediatric populations with CLD. The AASLD guidelines do recommend the use of simple, cost-effective, and readily available NILDAs for the detection of advanced fibrosis.
However, a NILDA that includes age, such as FIB-4, does not perform as well in children as it does in adults. Similarly, any biomarker that includes alkaline phosphatase will not perform well in children owing to rapid bone growth.
More data on blood-based NILDAs are needed in pediatric MASLD before they can be incorporated into clinical practice. And, as in adults, NILDAs should not be used to assess response to treatment of the underlying liver disease.
Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.
https://www.medscape.com/viewarticle/enhancing-care-noninvasive-liver-disease-assessment-new-2024a1000ekk
