EP-4740020-A2 - USE OF A MARKER OR A MARKER SET FOR DETERMINING THE RISK OF AN INDIVIDUAL TO HAVE ASCITES

Abstract

The present invention relates, amongst others, to the use of a marker or a marker set in an in vitro method for determining the risk of an individual to have ascites. The marker is chosen from a first group consisting of high-density lipoprotein, apolipoprotein A1, valine, and pyruvate; the marker set comprises at least two substances chosen from a second group consisting of high-density lipoprotein, apolipoprotein A1, valine, pyruvate, lactate, myo-inositol, and anhydrosorbitol.

Inventors

• DE JEL, Sebastian
• STÄMMLER, Frank
• RÖTZER, Sebastian
• ROBERTSON, ANDREW
• EIGLSPERGER, Johannes

Assignees

• Numares AG

Dates

Publication Date

20260513

Application Date

20240704

Claims (15)

1. 1. Use of a marker or of a marker set in an in vitro method for determining the risk of an individual to have ascites, characterized in that the marker is chosen from a first group consisting of high-density lipoprotein, apolipoprotein A1 , valine, and pyruvate and in that the marker set comprises at least two substances chosen from a second group consisting of high-density lipoprotein, apolipoprotein A1 , valine, pyruvate, lactate, myo-inositol, and anhydrosorbitol.
2. 2. Use according to claim 1 , characterized in that the marker set comprises at least one substance chosen from the second group and being different from high-density lipoprotein and apolipoprotein A1 if the marker set comprises any of high-density lipoprotein and apolipoprotein A1 as a first of the at least two substances.
3. 3. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances and anhydrosorbitol as a second of the at least two substances.
4. 4. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances and valine as a second of the at least two substances.
5. 5. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances and pyruvate as a second of the at least two substances.
6. 6. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances and lactate as a second of the at least two substances.
7. 7. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances and myo-inositol as a second of the at least two substances.
8. 8. Use according to claim 1 or 2, characterized in that the marker set comprises pyruvate and valine.
9. 9. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances as well as valine and myo-inositol as further substances.
10. 10. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances as well as valine and pyruvate as further substances.
11. 1 1 . Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances as well as myoinositol and anhydrosorbitol as further substances.
12. 12. Use according to claim 1 or 2, characterized in that the marker set comprises high-density lipoprotein or apolipoprotein A1 as a first of the at least two substances as well as lactate and anhydrosorbitol as further substances.
13. 13. Marker or marker set for use in in-vivo diagnostics of ascites, characterized in that the marker is chosen from a first group consisting of high-density lipoprotein, apolipoprotein A1 , valine, and pyruvate and in that the marker set comprises at least two substances chosen from a second group consisting of high-density lipoprotein, apolipoprotein A1 , valine, pyruvate, lactate, myo-inositol, and anhydrosorbitol.
14. 14. Method for analyzing an isolated body fluid sample in vitro, comprising the following steps: a) determining the concentration of a substance or of at least two substances, wherein the substance is chosen from a first group consisting of high-density lipoprotein, apolipoprotein A1 , valine, and pyruvate and wherein the at least two substances are chosen from a second group consisting of high-density lipoprotein, apolipoprotein A1 , valine, pyruvate, lactate, myo-inositol, and anhydrosorbitol in an isolated body fluid sample from an individual by analyzing the body fluid sample with a suited measuring technique, b) calculating a score from the determined concentrations, the score being indicative for determining the risk of the individual to have ascites.
15. 15. Method according to claim 14, characterized in that calculating the score involves calculating a ratio between at least two concentration values.

Description

Use of a marker or a marker set for determining the risk of an individual to have ascites Description The present invention relates to the in-vitro use of a marker or a marker set for determining the risk of an individual to have ascites according to the preamble of claim 1 , to the further medical use of such a marker or a marker set according to the preamble of claim 13, and to an analysis method for determining the risk of an individual to have ascites according to the preamble of claim 14. Ascites is defined as the accumulation of fluid in the peritoneal cavity and is the most common complication of cirrhosis. Cirrhosis is the most common cause of ascites in the United States, accounting for approximately 85% of ascites cases. 50% of cirrhotic patients within 10 years after the diagnosis of compensated cirrhosis will develop ascites [1]. The other most common causes of ascites include malignancy-related ascites and ascites secondary to heart failure. Less common etiologies include hepatic veno-occlusive disease, constrictive pericarditis, hemodialysis-associated ascites, hypoalbuminemia due to the nephrotic syndrome, and peritoneal diseases. Less than 5% of cases will have a mixed etiology. Successful treatment of ascites depends upon an accurate diagnosis of its cause [2], Development of ascites is the final step in an intricate pathology of anatomic, pathophysiologic, and biochemical abnormalities which primarily stem from the development of portal hypertension secondary to the densely fibrotic liver in cirrhosis [3]. Patients with cirrhosis but without portal hypertension do not develop ascites, and a portal pressure > 12 mmHg appears to be the critical pressure in the development of fluid retention. This causes prominent arterial vasodilation, leading to a significant reduction in systemic vascular resistance and mean arterial pressure, resulting in a hyperdynamic circulation, and particularly splanchnic vasodilation [4, 5]. Literature suggests that the most plausible cause of vasodilation as a result of portal hypertension is a combination of the opening of porto-systemic collaterals and increased synthesis of circulating vasodilators, chiefly nitric oxide (NO) [6]. The consequence of such vasodilation is activation of endogenous vasoconstrictor agents, in an attempt to restore perfusion pressure, proximal tubular sodium and water retention, and renal vasoconstriction. These mechanisms give rise to a general fluid overload which, combined with splanchnic vasodilation and a low decreased colloid osmotic pressure, effectively push fluid into the peritoneal cavity, with ascites resulting [7, 8]. Moreover, renal vasoconstriction can lead to a decreased glomerular filtration rate which is often masked clinically - the so-called hepatorenal syndrome. Creatinine production can be impaired in liver disease and when muscle mass is decreased, with a net effect of serum creatinine concentrations that appear to be within the normal range [9]. The onset of ascites in cirrhosis is considered a major complication of cirrhosis and is thus diagnostic of decompensated liver disease. Ascites is associated with poor prognostic outcomes for this patient group [10]. The presence of ascites also constitutes a crucial component of the 15-point Child-Pugh score, a global measure of hepatic function and mortality in cirrhosis, with the scale of ascites corresponding to the following point score [11]: • Absent: +1 • Slight: +2 (detected on investigation with ultrasound as opposed to patient- reported) • Moderate and above: +3 (obvious to both clinician and patient) Therefore, an accurate diagnosis is paramount not only to determine the etiology, which determines the treatment algorithm, but also as a component of mortality scores. Clinically, patients are likely to report progressive abdominal distension, weight gain, shortness of breath, and early fullness. Other stigmata of cirrhosis is likely to be present, such as spider angioma, palmar erythema, and abdominal wall collaterals. Additionally, other features of decompensated cirrhosis may be present, such as variceal bleeding or hepatic encephalopathy [12], Laboratory investigations typically include liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, bilirubin, albumin, and prothrombin time) alongside renal function, electrolyte counts, and complete blood count [13]. Ultrasound imaging is routinely involved for evaluation of ascites, however, has a lowest detection limit down to 50 mL [14], A definitive diagnosis is made upon paracentesis and subsequent investigation of the abdominal fluid, namely the total protein concentration, LDH levels, serum-to-ascites albumin gradient, bacteriological and cytological (leucocytes, erythrocytes, tumor cells) parameters. The grade of ascites is purely determined by the amount of fluid in the peritoneal cavity, and is scaled as [15]: • Grade 1 : Mild ascit