Tue Jun 15 2021

Biomarkers for Liver Function: All You Need to Know

The liver is one of the most critical organs of the human body. In an adult, it accounts for approximately 2% of the body weight and performs a wide range of vital biologic functions. The key functions of the liver include bile production, storage of fat-soluble vitamins, detoxification, and metabolism. The liver is intertwined with several organ systems of the body; hence, it is prone to different kinds of diseases and disorders2.
In clinical practice, one of the chief methods of diagnosing liver diseases is the use of liver function tests (LFTs). The LFTs are blood tests that are used for investigating suspected liver diseases, to monitor the activity of the liver, or as routine tests for assessing the overall health of a person2. The LFTs comprise of a set of biochemical markers which are involved in the various functions and metabolic activities of the liver. In case of liver dysfunction due to a disease or an external injury, the levels of the biochemical markers alter. Abnormalities detected on LFTs can help diagnose not only liver diseases, but also disorders in other organ systems of the body3.

What are the Biomarkers for Liver Function?

The main biochemical markers in a panel of LFTs are as follows 3:

  • Serum Bilirubin: Bilirubin is a yellowish compound found in the bloodstream. It is formed following the break-down of red blood cells (heme). The liver plays a crucial role in bilirubin metabolism, therefore, abnormalities in serum bilirubin levels can indicate liver dysfunction. For example: High levels of serum bilirubin can be seen in viral hepatitis, toxic liver injury, and in case of damage to the liver cells.
  • Alanine Amino Transferase (ALT): ALT is an enzyme that is found in high concentrations in the liver. It is also found in the muscles, the kidneys, and the heart, but in lower concentrations than the liver. ALT levels are elevated in case of any liver injury or disease. For example: Markedly elevated ALT levels are observed in viral hepatitis, ischemic liver injury (insufficient blood supply), and toxin-induced liver damage.
  • Aspartate amino transferase (AST): AST is an enzyme that is found in the highest concentrations in the heart. In much lower concentrations, it is found in the liver, the kidneys, and the skeletal muscles. Although AST is found in low concentrations in the liver, it has diagnostic importance in identifying certain liver diseases, such as alcoholic hepatitis, liver cell necrotic type condition, and liver cirrhosis. In all these diseases, AST levels are higher than normal.
  • AST/ALT ratio: This ratio is increased in progressive liver functional impairment. The AST/ALT ratio also has 81.3% sensitivity in detecting liver cirrhosis.
  • Alkaline Phosphatase (ALP): ALP is an enzyme involved in the transportation of lipids in the intestines. It is also important for the calcification of the bones. Elevation in ALP levels can be seen metastatic cancers of the liver and the bones. Other liver diseases such as infiltrative liver disease, liver abscesses, and granulomatous liver disease can also cause elevation of ALP.
  • Gamma Glutamyl Transferase (GGT): GGT is an enzyme found in the cells of the liver and the biliary tract. The levels of GGT are elevated in chronic hepatitis C infection, acute pancreatitis, hyperthyroidism, myocardial infarction, and uncomplicated diabetes mellitus.
  • α- fetoprotein (AFP): AFP is an important serum protein that is highly elevated in patients with hepatocellular carcinoma (liver cancer) and cirrhosis. A high AFP level is directly proportional to the size of the liver tumor.
  • Ceruloplasmin: This protein is synthesized in the liver. It is elevated in obstructive jaundice and chronic active liver disease (CALD). Besides the liver, high levels of ceruloplasmin can be seen in infectious diseases and rheumatoid arthritis.
  • 5’ Nucleotidase (NTP): This is a glycoprotein which is considered a precise marker of early primary or secondary liver tumors. Elevated levels of NTP are also found in parenchymal liver disease, liver metastases, obstructive jaundice, and bone disease.

Alterations in suPAR levels in the bloodstream can indicate presence or absence of chronic inflammation, thereby, assisting in the timely diagnosis of chronic liver diseases

suPAR as a Biomarker for Liver Function

Inflammation is one of the main identified mechanisms in the development and progression of chronic liver diseases, which can lead to liver fibrosis and cirrhosis. In severe cases, chronic liver disease can be life-threatening and cause death of the patient. Early diagnosis and staging of chronic liver disease are significant in appropriate management of the disease. Timely treatment can also reduce the risk of complications and ensure a good prognosis4.

Soluble urokinase-type plasminogen activator (suPAR) is an unspecific biomarker of inflammation. Elevated levels of suPAR in the bloodstream is a strong indicator of chronic inflammation and any underlying pathologies. Alterations in suPAR levels in the bloodstream can indicate presence or absence of chronic inflammation, thereby, assisting in the timely diagnosis of chronic liver diseases5,6.

NAFLD and NASH

Non-alcoholic fatty liver disease (NAFD) is a common chronic liver disease that has a worldwide prevalence of about 25% and 30-40% in the United States. An estimated 12% of the affected adults progress to the more advanced form of the disease known as non-alcoholic steatohepatitis (NASH)7. Individuals with NAFLD and NASH are at a high risk of developing liver cirrhosis and cancer. Hence, early detection of NAFLD/NASH is crucial to prevent occurrence of life-threatening complications like liver cancer7.

Currently, a liver biopsy is the standard method used for evaluating intra-hepatic (inside the liver) inflammation8. However, this method is sub-optimal, as it is invasive with associated bleeding and pain. Furthermore, liver biopsy is not cost-effective and can cost anywhere between $1,500 and $2,7007. It is also found to lengthen hospital stay in 1-5% of the patients. Moreover, it is reported that in 10-30% of the cases a liver biopsy can miss a cirrhotic liver9,10. In such a scenario, a non-invasive, cost-effective biomarker of liver fibrosis and NAFLD/NASH would be highly beneficial8.

suPAR for NAFLD/NASH

In clinical practice, a biomarker with a negative predictive value (NPV) of at least 90% can assist in the early identification of chronic liver disease11. Scientific studies show that suPAR has a strong NPV and in the presence of chronic liver disease suPAR levels are elevated11 . In chronic liver disease, with the progression of liver fibrosis suPAR levels are noted to increase. Also, suPAR levels are found to be higher in patients with liver cirrhosis than those without cirrhosis. Moreover, the level of suPAR in the blood closely relates to the stage of fibrosis8,9,10. Thus, suPAR is an effective diagnostic tool for the identification of liver cirrhosis and for evaluating progression of the disease.

While elevated suPAR levels indicate presence of liver fibrosis, a low suPAR value (< 3ng/ml) indicates that the patient most probably does not have liver disease. Therefore, suPAR can be used for the differential diagnosis of a disease and help rule out liver disease. In patients with liver disease, suPAR can be used as a monitoring tool to evaluate the effectiveness of treatment and assess improvement in the patient’s condition12.

In conclusion, chronic liver disease can have fatal long-term consequences. Hence, early diagnosis and treatment of chronic liver disease is of paramount importance. suPAR is a fast acting, non-invasive, reliable biomarker that can accurately detect presence of chronic liver disease. Timely diagnosis and appropriate treatment of chronic liver disease can help prevent future complications and ensure a good prognosis in patients.

1. Kalra A, Tuma F. Physiology, Liver. [Updated 2018, Dec 18]. In: StatPearls [Internet]. Treasure Island [FL]: StatPearls Publishing; 2019 Jan.
2. Hall P, Cash J. What is the real function of the liver ‘function’ tests? The Ulster Medical Journal. 2012 Jan; 81(1): 30-36.
3. Gowda S, Desai PB, Kulkarni S. A review on laboratory liver function tests. The Pan African Medical Journal. 2009; 3: 17.
4. 6. Karlmark KR, Wasmuth HE, Trautwein C, Tacke F. Chemokine-directed immune cell infiltration in acute and chronic liver disease. Expert Rev Gastroenterol Hepatol 2008; 2: 233–42.
5. Desmedt S, et al. The intriguing role of soluble urokinase receptor in inflammatory diseases. Crit Rev Clin Lab Sci. 2017 Mar;54(2):117-133
6. Rasmussen LJH, et al. Combining National Early Warning Score With Soluble Urokinase Plasminogen Activator Receptor (suPAR) Improves Risk Prediction in Acute Medical Patients: A Registry-Based Cohort Study. Crit Care Med. 2018 Dec;46:1961-8.
7. Tools for Combatting a Silent Epidemic, The search for noninvasive biomarkers intensifies as cases of NAFLD, NASH rise. Whitney J. Palmer, MAY.1.2019, Source: Clinical Laboratory News, https://www.aacc.org/publications/cln/articles/2019/may/tools-for-combatting-a-silent-epidemic
8. Feldman. Sleisenger and Fordtran’s gastrointestinal and liver disease. 9th ed. Philadelphia, PA, United States: Saunders: an imprint of Elsevier, 2010.
9. Abdi W, Millan JC, Mezey E. Sampling variability on percutaneous liver biopsy. Arch Intern Med 1979;139:667–9.
10. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–8.
11. Rasmussen LJ, et al. Soluble urokinase plasminogen activator receptor (suPAR) in acute care: a strong marker of disease presence and severity, readmission and mortality. A retrospective cohort study. Emerg Med J.2016 33(11):769-775.
12. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis, Henning W. Zimmermann, Alexander Koch, Sebastian Seidler, Christian Trautwein and Frank Tacke, Liver International ISSN 1478-3223

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