Biomarkers for immune-mediated liver diseases
Learn more about how our biomarkers can be used to distinguish between healthy and diseased, monitor disease activity, understand pharmacodynamics and identify population responding to treatment.
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 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.
How many people have immune-mediated liver disease?
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 6.7to 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.
How is immune-mediated liver disease treated?
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.
How is immune-mediated liver disease diagnosed?
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.
There is an urgent need for novel biomarkers of liver disease that can adequately determine the risk of disease progression and the likelihood of response to treatment. Fibrosis is a key histologic feature of immune-mediated liver disease; however, the severity of liver fibrosis is primarily determined by liver biopsy. The use of serological biomarkers offers a novel alternative for determining and monitoring the severity of liver fibrosis and the dynamics of ongoing fibrotic processes. Nordic Bioscience's serum biomarkers offer an accurate liver fibrosis biomarker panel that provides information on disease progression.
Since the development of cirrhosis is a common endpoint of all chronic liver diseases, the inclusion of fibrosis biomarkers in the field of immune-mediated liver disease could address several unmet needs. Such biomarkers could be used as early determinants for the treatment of diseases such as primary biliary cholangitis. In addition, Protein Fingerprint biomarkers of liver function have shown prognostic value in chronic liver diseases and could be used to determine the risk of disease progression and the likelihood of response to treatment.
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Twenty types of collagen have been identified in the liver, and their localization reflects their function. Fibrillar collagens (such as type I, III, and V collagens) are located around the portal tract and the walls of the central veins and provide structural support. Basement membrane collagens, such as type IV collagen, are found in a network in the walls of the sinusoids.
The different types of immune-mediated liver diseases each have different histological fibrosis patterns, which is due to differences in the underlying pathology and targets. Consequently, there are also different serological profiles for the different diseases. For example, while all immune-mediated liver diseases have high turnover, basement membrane matrix turnover is more pronounced in primary biliary cholangitis than in primary sclerosing cholangitis.
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A series of protein fingerprint biomarkers of liver function were measured in patients with various immune-mediated liver diseases (AIH, PBC, and PSC) and compared with patients with Ulcerative Colitis (UC), a common concomitant disease of immune-mediated liver disease.
These data, presented by Nielsen et al. at AASLD (2017), demonstrate the different collagen profiles of the various immune-mediated liver diseases.
Protein Fingerprint biomarkers such as PRO-C3 have been shown to correlate with key factors such as bile acids in immune-mediated liver disease primary sclerosing cholangitis (Hirschfield et al. at EASL 2019).
Bile acids and PRO-C3
Protein Fingerprint biomarkers of liver function measured in serum at baseline are predictive of transplant-free survival in patients with primary sclerosing cholangitis (Nielsen et al Aliment Pharmacol Ther. 2018).
Protein Fingerprint biomarkers allow pharmacodynamic profiling of novel treatments by directly measuring protein fragments in a serum sample, as demonstrated by Hirschfield et al. (2019), who demonstrated a rapid and sustained effect of treatment with aldafermin in primary sclerosing cholangitis patients.
Harrison et al. showed at AASLD 2019 that aldafermin decreased the ratio of fibrogenesis to fibrolysis of collagen type III, suggesting a beneficial effect on primary sclerosing cholangitis-associated fibrosis.
Aldafermin treatment reduces fibrogenesis to fibrolysis ratio in primary sclerosing cholangitis patients presented by Harrison et al at AASLD 2019.
Patients with high fibrogenesis are more likely to respond to therapy, as shown by Hirschfield et al (2019), who found that primary sclerosing cholangitis patients treated with aldafermin whose baseline PRO-C3 levels were ≥20 ng/mL had the greatest decrease in PRO-C3 levels.
The applications presented here are for research use only.
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