Role of Bilirubin Molecular Species in Hepatic Encephalopathy and Acute-on-chronic Liver Failure

Hepatic Encephalopathy Clinical Trial

Official title:

The Importance of Bilirubin Molecular Species in Patients With Liver Cirrhosis Who Develop Hepatic Encephalopathy and Patients With Acute-on-chronic Liver Failure

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05566548
• Other study ID #: 2021-EXT-637
• Status: Recruiting
• Start date: August 1, 2022
• Est. completion date: August 1, 2023

Study information

• Verified date: October 2022
• Source: Medica Sur Clinic & Foundation
• Contact: Nahum Mendez-Sanchez, MD, PhD
• Phone: +52 555 433 5016
• Email: nmendez[@]medicasur.org.mx
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

It has been identified that impaired liver function, as occurs in patients with liver cirrhosis, prevents proper conjugation of glucuronic acid with bilirubin; as a result, unconjugated bilirubin accumulates in the blood, and conjugated bilirubin is markedly altered to form diglucuronides or monoglucuronides. However, in the development and progress of acute-on-chronic liver failure (ACLF) there is not enough information about these processes and the possible concentration levels that they can take.

Also Hepatic encephalopathy (HE) is a reversible complication, but with a high mortality rate in patients with acute or chronic liver failure, as well as a consequence of the formation of portosystemic shunts.

Description:

Liver cirrhosis is a pathological diagnosis characterized by diffuse fibrosis, severe alteration of intrahepatic arterial and venous flow, portal hypertension, and, ultimately, liver failure. The prevalence of liver cirrhosis in the Mexican population depends on various factors, including gender, ethnic groups, and geographic regions, in addition to the nature, frequency, and time of acquisition of the main risk factors for cirrhosis, such as the hepatitis B virus, hepatitis C virus (HCV) in addition to non-alcoholic steatohepatitis, non-alcoholic fatty liver or alcoholic liver disease. Liver cirrhosis has been classified as decompensated or compensated. Decompensated liver cirrhosis occurs when there is gradual progression over months causing liver and extrahepatic organ failure. On the other hand, if it appears suddenly, in a short-term deterioration for days or several weeks after the defined triggering disease, it is known as Acute-on-chronic liver failure (ACLF). ACLF is a syndrome characterized by acute and severe liver abnormalities as a result of different types of lesions present in patients with underlying chronic liver disease or cirrhosis, but unlike decompensated cirrhosis, it has a high short-term mortality.

It is important to determine the prognosis of patients with ACLF, in a short period of time, in order to act appropriately and reduce the use of temporary liver support or liver transplantation, an important variable that is included in various scores that assess liver function in different scenarios such as the Child-Pugh score and Model for End-stage Liver Disease (MELD) systems.

Among liver cirrhosis complications, there is the Hepatic encephalopathy (HE) involves a wide range of neurocognitive and psychiatric abnormalities that can range from subclinical neurological deficits and disturbances in attention to coma. Diagnosis of hepatic encephalopathy can be made using the West Haven (WH) criteria, which are clinical criteria that evaluate the degree of neurological deterioration and divide hepatic encephalopathy into 5 grades (from grade 0 to grade 4), with grades 3 and 4 having a worse prognosis. In addition to these criteria, it can be diagnose based on psychometric tests such as the Portosystemic- Encephalopathy- Syndrome test (PSE) and psychophysiological tests, such as the Critical flicker frequency (CFF). Despite the existence of this evidence and the WH criteria, there is no quantitative parameter that can be used to diagnose the hepatic encephalopathy. In addition, although the quantification of ammonia levels is carried out in multiple centers as part of the protocol for diagnosing HE, there are numerous studies showing that ammonia levels cannot be used to diagnose or rule out the presence of HE.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: August 1, 2023
• Est. primary completion date: July 31, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patients with Acute-on-chronic liver failure (ACLF)

• Patients hepatic encephalopathy (HE)

• Any etiology of liver cirrhosis alcoholic liver disease (ALD), HCV, liver disease fatty liver associated with metabolism dysfunction (MAFLD) and diseases autoimmune liver

• With or without the existence of any precipitating event or medical complication:

infection acute bacterial, consumption hepatitis severe alcoholic, variceal bleeding, drug-induced encephalopathy, ascites, coagulopathy, sepsis

• Any ACLF grade

• Any HE grade

Exclusion Criteria:

• Immunodeficiency virus infection human (HIV)

• Cholestatic liver disease,

• Past or current extrahepatic malignant tumor,

• Liver transplant,

• Other serious concomitant diseases heart, lung, kidney, or other organs

• Patients with metastatic hepatocellular carcinoma (HCC)

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• Brain Diseases
• End Stage Liver Disease
• Hepatic Encephalopathy
• Hepatic Insufficiency
• Liver Failure

Intervention

Diagnostic Test:
• Liquid Chromatography-Mass Spectrometry Method to identify bilirubin molecular species
It will determine the concentration of the different molecular species of bilirubin and examine the pattern of increase present in patients with liver cirrhosis who develop hepatic encephalopathy and acute-on-chronic liver failure (ACLF) compared to other groups like patients with liver cirrhosis and healthy people.

Locations

Country	Name	City	State
Mexico	Medica Sur Clinic & Foundation Organization	Mexico City

Sponsors (1)

Lead Sponsor	Collaborator
Medica Sur Clinic & Foundation

Country where clinical trial is conducted

Mexico, 

References & Publications (7)

Bajaj JS, O'Leary JG, Tandon P, Wong F, Garcia-Tsao G, Kamath PS, Maliakkal B, Biggins SW, Thuluvath PJ, Fallon MB, Subramanian RM, Vargas HE, Lai J, Thacker LR, Reddy KR. Hepatic Encephalopathy Is Associated With Mortality in Patients With Cirrhosis Inde — View Citation

Karimzadeh P, Fallahi M, Kazemian M, Taslimi Taleghani N, Nouripour S, Radfar M. Bilirubin Induced Encephalopathy. Iran J Child Neurol. 2020 Winter;14(1):7-19. Review. — View Citation

Lee HA, Jung JY, Lee YS, Jung YK, Kim JH, An H, Yim HJ, Jeen YT, Yeon JE, Byun KS, Um SH, Seo YS. Direct Bilirubin Is More Valuable than Total Bilirubin for Predicting Prognosis in Patients with Liver Cirrhosis. Gut Liver. 2021 Jul 15;15(4):599-605. doi: — View Citation

López-Velázquez JA, Chávez-Tapia NC, Ponciano-Rodríguez G, Sánchez-Valle V, Caldwell SH, Uribe M, Méndez-Sánchez N. Bilirubin alone as a biomarker for short-term mortality in acute-on-chronic liver failure: an important prognostic indicator. Ann Hepatol. — View Citation

Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, Gerbes A, Wendon J, Alessandria C, Laleman W, Zeuzem S, Trebicka J, Bernardi M, Arroyo V; CANONIC Study Investigators of the EASL-CLIF Consortium. Acute — View Citation

Tang L, Zhang M, Li X, Zhang L. Glucuronidated bilirubin: Significantly increased in hepatic encephalopathy. Prog Mol Biol Transl Sci. 2019;162:363-376. doi: 10.1016/bs.pmbts.2018.12.009. Epub 2019 Mar 6. — View Citation

Tapper EB, Rahimi RS. Low-Value Levels: Ammonia Testing Does Not Improve the Outcomes of Overt Hepatic Encephalopathy. Am J Gastroenterol. 2020 May;115(5):685-686. doi: 10.14309/ajg.0000000000000454. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identify levels of Conjugated Bilirubin as Bilirubin monoglucuronide (BMG), bilirubin diglucuronide (BDG) and unconjugated bilirubin (UCB) in patients with acute-on-chronic liver failure	Identification and measured concentration of bilirubin molecular species through liquid chromatography-mass spectrometry (LC-MS)	The serum sample will be taken at the moment of the first patient physician contact (admission, medical visit). The bilirubin measure will be done 24 hours after
Secondary	Comparison of the bilirubin levels of the different groups	The results of the groups will be compared among them to evaluate whether or not there is a change in the concentration.	It will be analyzed when all the results from the LC-MS are done. Approximately 5 months.