EP-4740022-A1 - USE OF A BIOMARKER FOR DETERMINING THE RISK OF AN INDIVIDUAL TO HAVE HEPATIC ENCEPHALOPATHY

EP4740022A1EP 4740022 A1EP4740022 A1EP 4740022A1EP-4740022-A1

Abstract

The present invention relates, amongst others, to the use of pyruvate, hydroxybutyrate, or a combination thereof in an in vitro method for determining the risk of an individual to have hepatic encephalopathy.

Inventors

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

Assignees

Numares AG

Dates

Publication Date: 20260513
Application Date: 20240704

Claims (13)

1. Use of pyruvate, hydroxybutyrate, or a combination thereof in an in vitro method for determining the risk of an individual to have hepatic encephalopathy.
2. Use according to claim 1 , characterized in that at least one of pyruvate and hydroxybutyrate forms part of a marker set, wherein the marker set comprises at least three substances chosen from the group consisting of pyruvate, hydroxybutyrate, high- density lipoprotein, apolipoprotein A1 , citrate, fumarate, and dimethyl sulfone.
3. Use according to claim 2, characterized in that the marker set comprises i) pyruvate or hydroxybutyrate, ii) at least one of high-density lipoprotein and apolipoprotein A1 , ill) at least one further substance being different from high-density lipoprotein and apolipoprotein A1.
4. Use according to claim 2 or 3, characterized in that the marker set comprises pyruvate as a first of the at least three substances, hydroxybutyrate as a second of the at least three substances, and high-density lipoprotein or apolipoprotein A1 as a third of the at least three substances.
5. Use according to claim 2, characterized in that the marker set comprises pyruvate as a first of the at least three substances, hydroxybutyrate as a second of the at least three substances, and citrate as a third of the at least three substances.
6. Use according to claim 2, characterized in that the marker set comprises pyruvate as a first of the at least three substances, hydroxybutyrate as a second of the at least three substances, and fumarate as a third of the at least three substances.
7. Use according to claim 2 or 3, characterized in that the marker set comprises pyruvate as a first of the at least three substances, hydroxybutyrate as a second of the at least three substances, fumarate as a third of the at least three substances and high-density lipoprotein or apolipoprotein A1 as a fourth of the at least three substances.
8. Use according to claim 2 or 3, characterized in that the marker set comprises pyruvate as a first of the at least three substances, hydroxybutyrate as a second of the at least three substances, fumarate as a third of the at least three substances and citrate as a fourth of the at least three substances.
9. Use according to claim 2, characterized in that the marker set comprises pyruvate as a first of the at least three substances, hydroxybutyrate as a second of the at least three substances, fumarate as a third of the at least three substances and dimethyl sulfone as a fourth of the at least three substances.
10. Use according to claim 2, characterized in that the marker set comprises hydroxybutyrate as a first of the at least three substances, citrate as a second of the at least three substances, fumarate as a third of the at least three substances and dimethyl sulfone as a fourth of the at least three substances.
1 1 . Pyruvate, hydroxybutyrate, or a combination thereof for use in in-vivo diagnostics of hepatic encephalopathy,
12. Method for analyzing an isolated body fluid sample in vitro, comprising the following steps: a) determining the concentration of at least pyruvate, hydroxybutyrate, or a combination thereof 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 concentration, the score being indicative for determining the risk of the individual to have hepatic encephalopathy.
13. Method according to claim 12, characterized in that calculating the score involves calculating a ratio between at least two concentration values.

Description

Use of a biomarker for determining the risk of an individual to have hepatic encephalopathy Description The present invention relates to the in-vitro use of a biomarker for determining the risk of an individual to have hepatic encephalopathy according to claim 1 , to the further medical use of such a biomarker according to claim 1 1 , and to an analysis method for determining the risk of an individual to have hepatic encephalopathy according to claim 12. Hepatic encephalopathy (HE) is a reversable syndrome of impaired brain function occurring in patients with advanced liver failure of any etiology. Overt HE is seen to develop in 30 % to 45 % of patients with cirrhosis. A consensus by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism defines the onset of disorientation or asterixis as the onset of overt HE. Some patients, however, have subtle findings detectable only using specialized tests - the so-called Minimal HE, which is seen in up to 80% of patients with cirrhosis [1 -3]. Hepatic encephalopathy is characterized by cognitive deficits and impaired neuromuscular function. Patients with minimal hepatic encephalopathy have subtle cognitive deficits, often appear to be asymptomatic, and may only be detected with psychomotor or electrophysiologic testing. Patients with overt hepatic encephalopathy have signs and symptoms that can be detected clinically, without the use of psychomotor testing. The classic initial sign in early HE is sleep disturbance, which is then followed by mood changes, disorientation, distorted motor movement, somnolence, confusion, and finally coma [4], HE severity is graded based on the clinical manifestations as follows [5]: • Minimal: Abnormal results on psychometric or neurophysiological testing without clinical manifestations • Grade I: Changes in behavior, mild confusion, slurred speech, disordered sleep • Grade II: Lethargy, moderate confusion • Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable • Grade IV: Coma, unresponsive to pain The etiology of HE is largely due to ammonia metabolism. The gastrointestinal tract is the primary ammonia source, where it is produced by gut flora, and enters the circulation via the portal vein. A functioning liver would clear all portal vein ammonia via converting it to glutamine. In the cirrhotic liver, this process is inefficient and arterial ammonia accumulates as a result, which interferes with brain function at several sites, leading to the clinical manifestation of HE [6]- Given the debilitating nature of HE, appropriate diagnosis and management is critical. Measurement of ammonia in the diagnostic workup of HE is however difficult. Although arterial ammonia levels correlate with the severity of HE, levels are inconsistently elevated, and its accuracy is influenced by many external factors, such as fist clenching, whether the sample was placed on ice, or use of a torniquet [7], Additionally, no formal diagnostic pathway exists for HE, given the heterogeneity of its presentation. Computed tomography (CT) imaging or magnetic resonance imaging (MRI) is suggested to exclude other organic causes of altered mental status, and commonly performed bedside tests such as a mini-mental state exam (MMSE) or a number connection test are insufficiently sensitive to detect subtle changes in mental function. Psychometric tests have been suggested in order to gauge cognitive pathology; however, these tests are cumbersome and time consuming (some are up to two hours per session). Additionally, there is a poor correlation among tests, and their reliability is decreased simply by a learning effect when the patient receives them repeatedly. Moreover, there are a myriad of reasons why the cirrhotic patient may have a mildly altered mental state, not exclusive to HE [8-1 1]. Treatment for HE is dependent on the severity of illness, and consist of reversal of precipitating cause and general supportive care with nutritional support for milder cases, through to inpatient admission with lactulose and rifaximin antibiotic therapy for more severe cases [12, 13]. Hepatic encephalopathy in cirrhosis is considered a major complication and is thus diagnostic of decompensated liver disease [14], Moreover, HE contributes to one’s Child-Pugh score, a 15-point score which is a global measure of hepatic function and general mortality in cirrhosis, with the scale of HE corresponding to the following point score [15]: No HE: +1 Grade 1 -2 HE: +2 Grade 3-4 HE: +3 Therefore, not only is an accurate and prompt diagnosis of HE essential to commence treatment and improve patient outcomes, but it is also an element of decompensated liver disease and plays a key role in the prognostic outlook as per the Child-Pugh score. Given the non-standardized diagnostic approach to HE which involves inconsistent ammonia evaluation, insensitive bedside mental state examinations, and cumbersome psychometric testing, there is a clear clinical