Various types of immune-mediated liver diseases have been identified, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). AIH is a chronic disease where the immune system attacks the liver causing inflammation. If untreated AIH can progress to cirrhosis and liver failure. Two types of AIH have been identified; type I AIH is the most common form, whereas type II is less common and generally affects young girls. The specific type of AIH depends on the autoantibodies that are present and their target. PBC is an autoimmune disease characterised by the progressive destruction of the bile ducts in the liver leading to a build-up of noxious bile acids, which is known as cholestasis. PSC is a chronic cholestatic liver disease that is characterised by the intrahepatic and extrahepatic bile duct inflammation and fibrosis, which ultimately leads to bile duct strictures. PSC is highly heterogeneous and likely immune-mediated though the underlying aetiology is poorly understood. PSC ultimately progresses towards the development of cirrhosis, portal hypertension and hepatic decompensation.

How many have immune-mediated liver diseases?
The prevalence of AIH ranges from 4 – 42.9 cases per 100,000, some races show a greater genetic preponderance than others, e.g. Alaskan natives. PBC is most prevalent within northern Europe and the US, the prevalence of PBC in the general population is between 6.7-402 cases per million.  PSC is more common in people of northern European descent, with a prevalence of 10 cases per 100,000 people..

How are immune-mediated liver diseases treated?
For the majority of patients AIH cannot be cured, consequently the disease is controlled through the use of immunosuppressive medication. AIH is treated through the use of immunosuppressive drugs such as prednisone and azathioprine. PBC is treated through the use of ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). Treatment response is monitored through biochemical assessment, namely serum alkaline phosphatase (ALP) and total bilirubin.  Currently, there is no specific treatment available for PSC. However, trials have indicated that UDCA may slow disease progression by increasing bile acid flow and reducing inflammation.

How are immune-mediated liver diseases diagnosed?
AIH diagnosis is based on histological abnormalities, clinical and biochemical findings and the presence of autoantibodies. A diagnosis of PBC requires the presence of at least two of the following criteria: a) biochemical evidence of cholestasis (i.e. high ALP levels), b) presence of anti-mitochondrial antibody (AMA) and c) histopathologic evidence of cholangitis and bile duct destruction. PSC is diagnosed through a combination of symptoms, biochemical tests and imaging of bile ducts, called a cholangiogram. Additionally, a liver biopsy may be needed to confirm the diagnosis and assess the severity of the disease.

There is an urgent need for novel biomarkers that can be used to adequately establish risk of disease progression, as well as likelihood of treatment response. Fibrosis is a key histological feature of immune-mediated liver diseases; however, the severity of liver fibrosis is primarily assessed through the use of a liver biopsy. The use of serological biomarkers offer a novel alternative to determine and monitor the severity of liver fibrosis, as well as the dynamics of the ongoing fibrotic processes.

As the development of cirrhosis is a common endpoint of all chronic liver diseases (CLD), incorporation of fibrosis biomarkers within the immune-mediated liver disease field could address various unmet needs. Such biomarkers could be used as early determinants of treatment in conditions such as PBC. Furthermore, protein fingerprint biomarkers have shown prognostic value in CLD and may be used to determine risk of disease progression and likelihood of treatment response.

20 types of collagen have been identified in the liver, their localisation reflects their function, fibrillar collagens (such as type I, III and V collagen) are located around the portal tract and the walls of the central veins providing structural support. BM collagens, such as type IV collagen, can be found in a network within the walls of the sinusoids.

The various types of immune-mediated liver diseases each have distinct histological fibrosis patterns, owing to the differences in underlying pathology and targets. Consequently, different serological profiles exist for the different conditions. For example, while all immune-mediated liver diseases are high turnover diseases, PBC has more prominent basement membrane matrix turnover than PSC.

An array of protein fingerprint biomarkers were measured in patients with different immune-mediated liver diseases (AIH, PBC and PSC) and were compared to patients with ulcerative colitis (UC), a common comorbidity of immune-mediated liver diseases. These data, presented by Nielsen et al at AASLD (2017) demonstrate the distinct collagen profiles of the various immune-mediated liver diseases.

Protein Fingerprint biomarkers such as PRO-C3 have been shown to be correlated to key drivers, such as bile acids, in the immune-mediated liver disease PSC (Hirschfield et al shown at EASL 2019). 

Protein Fingerprint biomarkers measured in serum at baseline are predictive of transplant-free survival in patients with PSC (Nielsen et al Aliment Pharmacol Ther. 2018).

Protein Fingerprint biomarkers allow pharmacodynamic profiling of novel treatments by measuring protein fragments directly in a serum sample as demonstrated by Hirschfield et al (2019) who showed a rapid and sustained effect of aldafermin treatment in PSC patients. Harrison et al showed at AASLD 2019 that aldafermin reduced the fibrogenesis to fibrolysis ratio of type III collagen indicating a positive effect on PSC associated fibrosis. 

Aldafermin treatment reduces fibrogenesis to fibrolysis ratio in PSC patients
Presented by Harrison et al at AASLD 2019.

Patients with high levels of fibrogenesis are more likely to respond to therapy, as demonstrated by Hirschfield et al (2019) who showed that PSC patients treated with aldafermin with baseline levels PRO-C3 ≥20 ng/mL had the greatest reductions in their PRO-C3 level.

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