HNA2: biomarkers of liver failure

5. January 2012

Oxidative stress plays a central role in the onset of liver failure, but it is a difficult parameter to measure. Researchers have now been able to show that an increase in the severity of chronic liver failure is also accompanied by an increase of HNA2 in plasma.

The research team under Univ.-Prof. Dr. Rudolf Stauber, Division of Gastroenterology and Hepatology, Department of Internal Medicine at the Medical University of Graz, consequently plans to develop an antibody against HNA2: This might not only enable a simplified mode of determining oxidised albumin as a biomarker for oxidative stress and liver failure to be put into action, but could also provide the basis of a new treatment method for removing HNA2 from the blood.

EU’s fifth most common cause of death

Chronic liver failure (cirrhosis of the liver) is the fifth leading cause of death in the European Union. When additional damage occurs to an initially stable chronic liver disease and leads to critical deterioration of liver function, the condtion is called acute-on-chronic liver failure (or ACLF). Triggering factors for this disease, which is associated with a high fatality rate, can be, for example, infection, binge drinking, or toxins other than alcohol. Researchers at the Medical University of Graz working under Rudolf Stauber, Ao. Univ.-Prof. Dr. Karl Öttl (Institute of Physiological Chemistry) and Ao. Univ.-Prof. Dr. Caroline Lackner (Institute of Pathology) have long dealt with the question of what role oxidative stress plays in this process and the parameters with which it can best be measured. As part of this work, the relationship between albumin oxidation and liver failure has also been subjected to a closer examination.

HNA2 as biomarker

Albumin is the quantitatively most important blood protein. Its main responsibilities include the transport of water-insoluble substances in the blood and maintaining colloid osmotic pressure (ie. albumin in the blood vessel binds itself to water and in this way prevents it leaking into tissue). In addition, albumin is also an important antioxidant: In addition to its reduced form (human mercaptalbumin, or HMA), it is also found in the blood in smaller quantities in reversibly-oxidised (human nonmercaptalbumin-1, HNA1) and irreversibly-oxidised albumin form (human nonmercaptalbumin-2, HNA2). The greater the oxidative load, the more albumin molecules are oxidised irreversibly. Due to this irreversible oxidation, not only does a decrease in the antioxidant function of albumin occur, but there is also impairment to the albumin’s binding capacity and transport function. “Increases in the blood concentration of toxic metabolites and in the impairment of the functions of albumin are also a characteristic feature of liver failure,” explains Stauber. Although many of these toxins can be removed via a liver dialysis (MARS or Prometheus system), elimination of the functionally-impaired HNA2 has not until now been possible. This circumstance could be contributing to the fact that these liver support systems have not brought any survival advantage for patients.

Encouraging study results

In their study of 29 liver patients (20 of them with stable cirrhosis, 9 patients with ACLF) and 15 healthy control subjects, the researchers showed that HNA2 in particular increased steadily with the degree of severity of liver failure. While in the healthy there was an average of only 4% of the albumin present as HNA2, the percentage of irreversibly oxidised albumin increased among the stable cirrhotic patients to 8 percent and for the ACLF patients it was 15 percent. “Its remarkable that until now no other disease studied had found any similarly high values of HNA2 levels”, states Stauber. On account of HNA2, therefore, for the first time there could be a specific biomarker made available for liver failure, which also has prognostic significance: Among the 29 cirrhotic patients, the 90-day survival could be better predicted with HNA2 than by using the previous standard parameters for short-term prognosis in liver failure, the MELD (model for end-stage liver disease) score, which does not record pathophysiological factors such as oxidative stress.

Further antibody studies

These encouraging results should now to be complemented by and verified in further studies. One part of the program is a dissertation, in which the question pursued is: what role does HNA2 have in other internal diseases, which are also associated with oxidative stress (for instance diabetes and joint disorders)? “If the hitherto findings are confirmed, it is planned that an antibody against HNA2 be developed”, explains Stauber. To date, HNA2 has been measured using high-performance liquid chromatography, a costly and lengthy method. By means of an HNA2-antibody, a simplified and widely applicable method of measurement of oxidised albumin could be established which would be employed for the diagnosis and prognosis of liver failure in standard clinical practice. What’s also imaginable is the use of the biomarker for other diseases and chronic conditions involving increased oxidative stress. In addition, the antibodies could find use in a new liver-support system, which eliminates the HNA2-molecule from the blood via antibody-binding.

The development of the biomarker and its possible use in a future liver dialysis system are also included in a patent which has been submitted to the European Patent Office.

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