The current diagnostic methods for end-stage liver disease and cirrhosis often involve invasive procedures and may not offer timely results. Blood-based biomarkers can provide tools to offer immediate treatment to patients with liver failure and identify the potential need for liver transplant by enabling early detection and intervention, leading to improved patient outcomes. Such biomarkers could significantly enhance the management and care of patients with chronic liver conditions, offering hope for a better quality of life and reducing the burden on healthcare systems.

Nordic Bioscience's biomarkers are designed to specifically target the dynamics of collagen deposition, which is the main cause of liver scarring in cirrhosis. These biomarkers offer multiple benefits, including efficient patient stratification for advanced fibrosis (F3-F4), the ability to monitor drug response and pharmacodynamics during clinical trials, and the potential to provide valuable prognostic information for clinical outcomes and mortality in patients with end-stage liver disease.

End-stage liver disease consists of advanced stages of liver fibrosis (F3-F4) due to chronic damage and scaring resulting in cirrhosis and acute liver failure. Severe fibrosis is characterized by the accumulation of extracellular matrix (ECM) components such as collagens. This, together with dysregulated liver regeneration impairs liver function leading to further complications, cirrhosis, and liver cancer/hepatocellular carcinoma. Nordic Bioscience developed biomarkers based on neo-epitope technology targeting the formation and degradation of collagens by detecting collagen fragments directly in the blood.

Twenty types of collagen have been identified in the liver, and their individual localization and structure reflect their function in the tissue. The interstitial matrix around the portal tract and the central veins is composed of fibrillar collagens such as type I, III and V collagen which provide structural support to the ECM.

A fragment originating from the cleavage of type VI collagen alpha3, named endotrophin (measured by the nordicPRO-C6™ biomarker), has an important role for the progression of hepatic fibrosis, adipose tissue dysfunction, and insulin resistance. Monitoring the levels of these collagen fragments represents a promising diagnostic and prognostic tool for identifying patients with advanced fibrosis and end-stage liver disease.

Explore our end-stage liver disease biomarker portfolio and choose a panel that suits your specific needs for your clinical/preclinical research or drug development project!

As the best use of our biomarkers depends on disease severity and specific research questions we are happy to have our team of scientists discuss and understand your aims to select the most appropriate neo-epitope biomarkers that can help answer your research questions.

NordicPRO-C3™ and the ADAPT score exhibit superior performance for the diagnosis of significant and advanced fibrosis when compared to other liver scores.[1] The prognostic accuracy of nordicPRO-C3™ can be further improved by incorporating other independent predictors of liver-related events such as platelets and the ratio AST/ALT into a prediction model named ALPACA.

The nordicPRO-C3™-based ALPACA (0.85) score outperforms FIB-4 (0.78), nordicPRO-C3™ (0.80) and ADAPT (0.81) and, is comparable to ELF (0.83) and TE (0.84) for risk stratification of patients with chronic liver disease due to alcohol overuse (Figure 1).

The ALPACA score shows superior discriminative performance over time for predicting LREs when compared to transient elastography (TE), enhanced liver fibrosis test (ELF), ADAPT, nordicPRO-C3™ and fibrosis-4 index (FIB-4).

Figure 1.
Prediction of LREs using nordicPRO-C3™ based scores ALPACA and ADAPT in relation to other liver scores. ELF, enhanced liver fibrosis test; FIB-4, fibrosis-4 index and nordicPRO-C3™ in a derivation cohort.[1]

Figure 2. NordicPRO-C3™ is associated with liver-related outcomes in patients with compensated cirrhosis[2]

The balance between the production and breakdown of type III collagen becomes disrupted in individuals suffering from end-stage liver disease. This imbalance leads to abnormally elevated levels of nordicPRO-C3™ and is linked to a heightened risk of liver-related complications in end-stage liver disease patients[2]. Notably, nordicPRO-C3™ proves to be a highly effective predictor of liver-related clinical outcomes in various models of chronic liver injury.

In a specific cohort of patients with compensated cirrhosis, a twofold increase in nordicPRO-C3™ levels has been shown to correspond to a 2.7-fold increase in the hazard ratio for the development of liver-related complications.

Patients with acute-on-chronic liver failure (ACLF) exhibit short-term mortality and deranged inflammatory responses. ECM biomarkers have a critical role in regulating inflammatory responses and were found to be altered in patients with acute decompensation and ACLF. Elevated nordicPRO-C3™ and nordicPRO-C6™ levels in patients with ACFL showed a strong association to inflammatory markers, liver function, organ injury and failure, mortality and outcomes.[3]

Plasma levels of nordicPRO-C3™ and nordicPRO-C6™ are increased in patients with ACFL in comparison to acute decompensation (AD), stable cirrhosis (SC) and healthy controls (HC). High vs low levels of nordicPRO-C3™ and nordicPRO-C6™ can be used for stratification of patients according to 28-day-transplant-free survival and 90-day-transplant-free survival, respectively.

Figure 3. 
NordicPRO-C3™ and nordicPRO-C6™ plasma levels and association to clinical outcomes[3]


Figure 4. 
PRO-C4, C4M and nordicPRO-C3™ predictive value[4]

The recurrence of cirrhosis after liver transplantation occurs in approximately 10-30% of the patients. Therefore, it is extremely necessary to use non-invasive tests to detect the development of early fibrosis after liver transplantation without the need for a liver biopsy. ECM markers overperform the commonly used liver scores such as APRI and FIB-4 in identifying graft fibrosis following liver transplantation[4].

Markers of formation of type III (nordicPRO-C3™; interstitial matrix) and formation/degradation of type IV collagen (PRO-C4/C4M; basement membrane) can be measured in serum and help to identify intermediate and fast progressors in fibrosis after liver transplantation.[5]

Plasma levels of nordicPRO-C3™ and nordicPRO-C6™ are increased in patients with ACFL in comparison to acute decompensation (AD), stable cirrhosis (SC) and healthy controls (HC). High vs low levels of nordicPRO-C3™ and nordicPRO-C6™ can be used for stratification of patients according to 28-day-transplant-free survival and 90-day-transplant-free survival, respectively (Figure 3.)

The term "end-stage liver disease" refers to the advanced stages of liver fibrosis (F3-F4) caused by chronic damage and scarring, ultimately resulting in cirrhosis and, in some cases, acute liver failure. During this stage, there is a significant accumulation of extracellular matrix (ECM) components, particularly collagens, which contribute to the development of severe fibrosis. This excessive deposition of collagens hinders the liver's ability to regenerate properly, leading to impaired liver function and the onset of various complications, including cirrhosis and potentially liver cancer (hepatocellular carcinoma).

Clinically, end-stage liver disease poses a significant threat to the patient's overall health and can lead to life-threatening conditions. The liver's vital functions, such as detoxification, metabolism, and synthesis of essential proteins, are severely compromised. As a result, patients may experience symptoms like jaundice, ascites (fluid accumulation in the abdomen), hepatic encephalopathy (brain dysfunction due to liver failure), and gastrointestinal bleeding.

Timely diagnosis and proper management of end-stage liver disease are crucial for improving patient outcomes. Treatment options may include lifestyle modifications, medications to manage symptoms and complications, and in some cases, liver transplantation as a definitive therapy for selected patients. Regular monitoring and follow-up with healthcare providers are essential to assess disease progression and optimize the patient's treatment plan

Biomarkers for other hepatic indications

The applications presented here are for research use only.

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