Alcoholic liver disease (ALD) is an umbrella term for liver damage caused by chronic alcohol abuse. Prolonged excessive alcohol consumption can reduce the livers’ ability to regenerate and can result in liver damage. ALD is normally divided into 3 stages; alcoholic fatty liver disease, alcoholic hepatitis and cirrhosis depending on the level of build-up fat, inflammation and fibrosis.

How many have alcoholic liver disease?
The prevalence of ALD differs across the world as level of alcohol consumption in general is dependent on cultural acceptance. In the United States, it is estimated that 3-5% suffers from some degree of ALD.

How is alcoholic liver disease treated?
Currently, there is no specific treatment for ALD and the most successful intervention is to halt alcohol consumption. Elimination of alcohol consumption reduces the risk of further damage of the liver to where there is a chance of the liver recovering. Severe cases such as decompensated cirrhotics may require liver transplantation.

How is alcoholic liver disease diagnosed?
The diagnosis of ALD relies on blood tests to assess the liver function and questionnaires on alcohol consumption. If blood tests suggest decreased liver function and advanced liver damage, further tests including imaging and liver biopsies might be necessary.

The medical need for biomarkers in alcoholic liver disease (ALD) today is two-fold. Firstly, the diagnosis of ALD remains a challenge as the symptoms mimics those of other liver diseases as non-alcoholic fatty liver disease (NAFLD). Secondarily, prediction of progression to especially cirrhosis has proven difficult. Patients react differently to chronic alcohol abuse and which patients progress and when can currently not be predicted.

Diagnostic and prognostic biomarkers have the potential to greatly benefit patients, by aiding in early diagnosis of disease and directing the most appropriate treatment at the right time. Furthermore, use of predictive or prognostic biomarkers to enrich or stratify patients likely to respond to a therapeutic in drug development trials, may reduce the trial length, and size required to determine therapeutic efficacy.

Alcoholic liver disease (ALD) is characterized by both inflammation and scar formation in tissue (fibrosis).
The liver is rich in different collagens, proteoglycans and matricellular proteins. These proteins and remodeled as part of liver homeostasis and regeneration. During remodeling, proteins are broken down and rebuild as part of normal repair and maintenance of the tissue. In ALD, the balance between degradation and formation of tissue is interrupted resulting in net formation (build-up and scar formation) of the tissue. Protein fingerprint biomarkers can quantify this tissue turnover directly in serum plasma samples.

While there are several diagnostic and disease activity measures in the liver field, some are invasive whereas other predictive capacity is limited. There is therefore still a medical and drug development need for biomarkers that can characterize and quantify structural tissue change and predict disease progression. The tissue-derived Protein Fingerprint biomarkers can be measured in serum and plasma and used to accurately quantify changes in tissue turnover in the different layers of liver tissues in the individual patient.

Biomarkers and tissue characterization:
Pericellular fibrosis by type IV collagen fragments: C4M, PRO-C4.

Bridging fibrosis by type III collagen fragments: PRO-C3, PC3X, C3M.

Reference: Karsdal et al. , Hepatology 2020

Protein Fingerprint formation biomarkers measured in serum and plasma are generally increased in alcoholic liver disease (ALD) patients compared to healthy individuals.

Reference: Presented at EASL 2019 by the GALAXY consortium

Collagen formation of especially the interstitial matrix quantified by type III (PRO-C3) and VI (PRO-C6) collagens formation is elevated in ALD patients compared to healthy subjects (Ctrl).

The basement membrane is further dysregulated in favor of degradation as seen by type IV collagen degradation (C4M) elevated in ALD patients

Protein Fingerprint biomarkers measured in serum are associated with established disease parameters as portal hypertension.

ALD patients suffering from portal hypertension, measured by Hepatic venous pressure gradient (HPVG), has elevated levels of both formation and degradations biomarkers. This include basement membrane (type IV collagen; PRO-C4) and interstitial matrix (type III collagens; PRO-C3, type V collagen; C5M, Elastin; ELM) proteins.

Reference: Leeming et al. 2013 Aliment Pharmacol. Ther.

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