Immune-mediated Liver Diseases

Biomarkers in immune-mediated liver diseases (AIH, PBS, PSC)

Immune-mediated liver diseases necessitate new biomarkers that can accurately assess the risk of disease progression and the likelihood of response to treatment. Fibrosis is a key histologic feature of immune-mediated liver diseases, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

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Non-invasive biomarkers have the potential to revolutionize the screening and treatment of immune-mediated liver diseases by providing a novel approach to determining and monitoring the severity of liver fibrosis and the progression of fibrotic processes.

Therefore, the development of such biomarkers has a large potential to improve the current methods of screening and the treatment of immune-mediated liver diseases.

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Nordic ProteinFingerPrint Technology™ biomarkers in end-stage liver disease

There are several types of immune-mediated liver diseases in adults such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).

The development of cirrhosis is a common endpoint of all chronic liver diseases. Nordic Bioscience offers a liver fibrosis biomarker panel that provides information on the risk of disease progression and the likelihood of response to treatment.  In addition, Nordic Bioscience biomarkers have shown prognostic value in chronic liver diseases.

The different types of immune-mediated liver diseases each have different histological fibrosis patterns, for example, PBC features damage to intrahepatic bile ducts while PSC affects the medium to large extrahepatic and intrahepatic bile ducts. Consequently, there are also different serological profiles for different diseases. For example, while PBC, PSC and AIH patients have high turnover compared to ulcerative colitis patients, basement membrane matrix turnover is more pronounced in primary biliary cholangitis than in primary sclerosing cholangitis.

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Biomarkers of liver function in AIH, PBC and PSC

In a study conducted, patients diagnosed with different immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) were examined using a range of Nordic Bioscience’s liver function biomarkers.[1] Specifically, PRO-C3 (nordicPRO-C3™), a marker of tissue formation, and BGM, C3M and C4M, markers of tissue breakdown, were assessed.

Additionally, patients with ulcerative colitis (UC), a frequently coexisting condition with immune-mediated liver disease, were included for comparison. The results of this investigation unveiled distinct collagen profiles across various immune-mediated liver diseases (Figure 1).

The identification and characterization of these collagen profiles hold promise for tailoring targeted treatments and advancing personalized medicine approaches for patients with different immune-mediated liver diseases.

Figure 1. Various immune-mediated liver diseases have different collagen profiles.[1]

Prognostic value of nordicPRO-C3™ and PRO-C5 in PSC

Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Nordic Bioscience’s biomarkers offer a viable alternative by measuring disease activity and providing prognostic models for predicting outcome.[2]

Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients, identified by ECM-based biomarkers. PRO-C3 (nordicPRO-C3™) and PRO-C5 levels in serum at baseline give insights into liver function and are predictive of transplant-free survival in patients with primary sclerosing cholangitis (Figure 2.)

The odds ratio (OR) was calculated to predict transplant-free survival among PSC (Primary Sclerosing Cholangitis) patients by analyzing their serum levels of PRO-C3 (nordicPRO-C3™) and PRO-C5. This calculation compared patients in the highest tertile of serum levels with those in the lowest tertile for various markers, including ELF-test, PRO-C3 (nordicPRO-C3™), PRO-C5, C3M, C4M, and the combination of PRO-C3 (nordicPRO-C3™)™ and PRO-C5.

 

Figure 2. NordicPRO-C3™ and PRO-C5 show strong prognostic value in primary sclerosing cholangitis (OR calculated based on patients in the highest tertile vs the lowest tertiles).[2]

Biomarkers to monitor drug response and pharmacodynamics

NordicPRO-C3™ is our best in-house biomarker to assess fibrosis in patients with different liver diseases. NordicPRO-C3™ has been shown to be useful for the pharmacodynamic profiling of novel treatments for immune-mediated liver diseases.

In primary sclerosing cholangitis patients, nordicPRO-C3™ levels in serum demonstrated a rapid and sustained effect of treatment with aldafermin (Figure 3.)[3]

In another study, it was shown that aldafermin decreased the ratio of fibrogenesis to fibrolysis of collagen type III, measured by nordicPRO-C3™/C3M ratio, suggesting a beneficial effect on primary sclerosing cholangitis-associated fibrosis.[4]

Figure 3. NordicPRO-C3™ demonstrates a strong association between effect of treatment and aldafermin.[4]

NordicPRO-C3™ levels are able to identify which PSC patients with high fibrogenesis are more likely to respond to aldafermin therapy. Research shows that primary sclerosing cholangitis patients whose baseline nordicPRO-C3™ levels were ≥20 ng/mL had the greatest decrease in nordicPRO-C3™ levels following treatment with different doses of aldafermin (Figure 4.) Patients with nordicPRO-C3™ greater than or equal to 20 ng/mL have a significant reduction in their nordicPRO-C3™ level upon treatment with aldafermin[5] (an engineered analog of the gut hormone fibroblast growth factor 19, FGF19).

Figure 4. NordicPRO-C3™ for prediction of treatment response.[5]

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About immune-mediated liver diseases

  • There are several types of immune-mediated liver diseases such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis.

     

    Autoimmune hepatitis is a chronic disease in which the immune system attacks the liver and causes inflammation. If left untreated, autoimmune hepatitis can lead to cirrhosis and liver failure.

     

    Two types of autoimmune hepatitis have been distinguished: type I autoimmune hepatitis is the most common form, while type II is less common and usually affects young girls. The specific type of autoimmune hepatitis depends on the autoantibodies present and their target.

     

    Primary biliary cholangitis is an autoimmune disease characterized by the progressive destruction of the bile ducts in the liver, leading to an accumulation of harmful bile acids called cholestasis.

     

    Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the intra- and extrahepatic bile ducts, eventually leading to biliary strictures.

     

    Primary sclerosing cholangitis is highly heterogeneous and likely immune-mediated, although the underlying etiology is poorly understood.

     

    Primary sclerosing cholangitis eventually leads to the development of cirrhosis, portal hypertension, and hepatic decompensation.

  • The prevalence of autoimmune hepatitis ranges from 4 to 42.9 cases per 100,000, with some races having a greater genetic prevalence than others, such as Alaska Natives.

     

    Primary biliary cholangitis is most prevalent in northern Europe and the United States, with the prevalence of primary biliary cholangitis in the general population ranging from 6.7 to 402 cases per million.

     

    Primary sclerosing cholangitis is more common in people of northern European descent, with a prevalence of 10 cases per 100,000 people.

  • In most patients, autoimmune hepatitis cannot be cured, so the disease is controlled by the use of immunosuppressive drugs.

     

    Autoimmune hepatitis is treated with immunosuppressive drugs such as prednisone and azathioprine.

     

    Primary biliary cholangitis is treated with ursodeoxycholic acid (UDCA) and obeticholic acid. Response to treatment is monitored by biochemical testing, particularly serological alkaline phosphatase (ALP) and total bilirubin.

     

    Currently, there is no specific treatment for primary sclerosing cholangitis. However, studies have shown that UDCA can slow disease progression by increasing bile acid flow and reducing inflammation.

  • Diagnosis of autoimmune hepatitis is based on histologic abnormalities, clinical and biochemical findings, and the presence of autoantibodies.

     

    The diagnosis of primary biliary cholangitis requires the presence of at least two of the following criteria: a) biochemical evidence of cholestasis (i.e., high levels ALP), b) presence of antimitochondrial antibodies, and c) histopathologic evidence of cholangitis and bile duct destruction.

     

    Primary sclerosing cholangitis is diagnosed by a combination of symptoms, biochemical tests, and imaging of the bile ducts called a cholangiogram. In addition, a liver biopsy may be required to confirm the diagnosis and assess the severity of the disease.

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