Is Adrenal Insufficiency Under-diagnosed in Hospitalized Cirrhosis Patients?

NCT03368066 | Completed Phase 3 Results FDA Drug

• 1 other identifier: 20212
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The hepatoadrenal syndrome has been well described in the literature and is known to be associated with poorer outcomes in both stable and critically ill cirrhotic patients. In chronic liver disease, adrenal (and more specifically cortisol) insufficiency is thought to be a byproduct of altered lipid metabolism that results in decreased HDL production and thus decreased delivery of cholesterol to the adrenal for subsequent corticosteroid production. Studies to date have implicated lecithin-cholesterol acetyltransferase (LCAT) as the key enzyme which is deficient in some cirrhotic patients, leading to an impaired ability to esterify cholesterol and thus a loss of normal cellular functioning and membrane stability. The investigators seek to quantify this LCAT deficiency in a cohort of cirrhotic patients and demonstrate its association with various abnormal physiologies associated with chronic liver disease, including spur cell anemia, low HDL levels, and adrenal insufficiency. Hospitalized cirrhotic patients at UVA that meet study eligibility criteria will be approached by a member of the study team to obtain consent for participation. If a patient agrees to become a study subject, they will have an approximate total of 35ml of blood drawn the following morning. Lab tests to be performed include: peripheral blood smear, lipid panel, free cortisol, cortisol binding globulin, serum cholesterol esters (surrogate for LCAT enzyme activity), and a standard-dose cortisol stimulation test. The latter involves blood drawn with the initial collection, administration of an intravenous 250mcg dose of synthetic ACTH, and then repeat small-volume blood draws at 30 minutes and 60 minutes later. Subjects will be classified as adrenally sufficient or insufficient on the basis of as standard-dose cortisol stimulation test. Variables of interest for comparison between the groups include MELD score, Child-Turcotte-Pugh (CTP) classification, high-density lipoprotein (HDL) levels, presence of spur cell anemia, serum cholesterol ester percentage (surrogate for LCAT enzymatic activity), cortisol binding globulin levels, and free cortisol levels. Student's t-test and Chi Square tests will be utilized to determine significance; a p \<0.05 value will be used as our threshold for significance. If multiple factors are found to be significantly different in a univariate fashion between classification groups, a multivariate logistic regression analysis will be performed for adjusted analysis. The investigators will also seek to define any correlations between variables. Furthermore, the investigators will assess correlation between MELD score and serum cholesterol ester percentage, spur cell anemia, HDL levels, cortisol binding globulin levels, and free cortisol levels; similar correlate analysis will be done using CTP classification instead of MELD score.

Conditions

Adrenal Insufficiency; Cirrhosis; Spur Cell Anemia; Lecithin Acyltransferase Deficiency

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Cholesterol Esterification Deficiency

  A percent quantification of serum cholesterol esterification will be measured via blood draw. Low values represent deficiency in esterification, which is a surrogate measure of lecthicin-cholesterol acetyltransferase (LCAT) enzymatic deficiency.

  24 hours

• Number of Participants With Spur Cell Anemia

  A peripheral blood smear will be obtained and assessed for presence of acanthocytes (spur cells). Spur cell anemia is defined as a serum hemoglobin \< 10g/dL and the presence of \>= 5% spur cells on blood smear.

  24 hours

• Participant Transplant-Free Survival

  Transplant and Death are considered equivalent outcomes

  6 months

Secondary Outcomes (8)

• Number of Participants With Relative Adrenal Insufficiency (RAI)

  24 hours

• Number of Participants With Low Free Cortisol

  24 hours

• Number of Participants Who Received Liver Transplantation at 90 Days

  90 days

• Number of Participants Who Received Liver Transplantation at 6 Months

  6 months

• Number of Participants Who Died Within Index Hospitalization

  Within Hospitalization

Study Arms (1)

Hospitalized cirrhosis patients

EXPERIMENTAL

Administration of cortisol stimulation test to assess for presence or absence of adrenal insufficiency

Drug: Cosyntropin

Interventions

Cosyntropin DRUG

Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency

Hospitalized cirrhosis patients

Eligibility Criteria

• Age: 18 Years - 110 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>=18 years
• Diagnosis of cirrhosis
• Admission to hospital

You may not qualify if:

• Age \< 18 years
• Prior enrollment in study (i.e. readmission)
• Prisoner
• Pregnancy
• Prednisone or Hydrocortisone use in last 24 hours

Sponsors & Collaborators

• University of Virginia: lead

Study Sites (1)

University of Virginia Health System

Charlottesville, Virginia, 22903, United States

Location

Related Publications (14)

• Fede G, Spadaro L, Tomaselli T, Privitera G, Germani G, Tsochatzis E, Thomas M, Bouloux PM, Burroughs AK, Purrello F. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology. 2012 Apr;55(4):1282-91. doi: 10.1002/hep.25573.

  PMID: 22234976 BACKGROUND

• O'Beirne J, Holmes M, Agarwal B, Bouloux P, Shaw S, Patch D, Burroughs A. Adrenal insufficiency in liver disease - what is the evidence? J Hepatol. 2007 Sep;47(3):418-23. doi: 10.1016/j.jhep.2007.06.008. Epub 2007 Jun 28.

  PMID: 17629587 BACKGROUND

• Triantos CK, Marzigie M, Fede G, Michalaki M, Giannakopoulou D, Thomopoulos K, Garcovich M, Kalafateli M, Chronis A, Kyriazopoulou V, Jelastopoulou E, Nikolopoulou V, O'Beirne J, Burroughs AK. Critical illness-related corticosteroid insufficiency in patients with cirrhosis and variceal bleeding. Clin Gastroenterol Hepatol. 2011 Jul;9(7):595-601. doi: 10.1016/j.cgh.2011.03.033. Epub 2011 Apr 8.

  PMID: 21545846 BACKGROUND

• Fede G, Spadaro L, Tomaselli T, Privitera G, Piro S, Rabuazzo AM, Sigalas A, Xirouchakis E, O'Beirne J, Garcovich M, Tsochatzis E, Purrello F, Burroughs AK. Assessment of adrenocortical reserve in stable patients with cirrhosis. J Hepatol. 2011 Feb;54(2):243-50. doi: 10.1016/j.jhep.2010.06.034. Epub 2010 Sep 15.

  PMID: 21056503 BACKGROUND

• Fede G, Spadaro L, Tomaselli T, Privitera G, Scicali R, Vasianopoulou P, Thalassinos E, Martin N, Thomas M, Purrello F, Burroughs AK. Comparison of total cortisol, free cortisol, and surrogate markers of free cortisol in diagnosis of adrenal insufficiency in patients with stable cirrhosis. Clin Gastroenterol Hepatol. 2014 Mar;12(3):504-12.e8; quiz e23-4. doi: 10.1016/j.cgh.2013.08.028. Epub 2013 Aug 24.

  PMID: 23978347 BACKGROUND

• Tan T, Chang L, Woodward A, McWhinney B, Galligan J, Macdonald GA, Cohen J, Venkatesh B. Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J Hepatol. 2010 Nov;53(5):841-8. doi: 10.1016/j.jhep.2010.05.020. Epub 2010 Jul 17.

  PMID: 20739086 BACKGROUND

• Jang JY, Kim TY, Sohn JH, Lee TH, Jeong SW, Park EJ, Lee SH, Kim SG, Kim YS, Kim HS, Kim BS. Relative adrenal insufficiency in chronic liver disease: its prevalence and effects on long-term mortality. Aliment Pharmacol Ther. 2014 Oct;40(7):819-26. doi: 10.1111/apt.12891. Epub 2014 Jul 30.

  PMID: 25078874 BACKGROUND

• Tamer S, Cefle K, Palanduz S, Vatansever S. Rheological properties of blood in patients with chronic liver disease. Clin Hemorheol Microcirc. 2002;26(1):9-14.

  PMID: 11904466 BACKGROUND

• Tamer S, Cefle K, Gokkusu C, Ademoglu E, Ozturk S, Vatansever S, Palanduz S, Guler K. Comparison of rheological parameters in patients with post hepatitic and alcoholic cirrhosis. Clin Hemorheol Microcirc. 2007;36(3):247-52.

  PMID: 17361026 BACKGROUND

• Kakimoto H, Imai Y, Kawata S, Inada M, Ito T, Matsuzawa Y. Altered lipid composition and differential changes in activities of membrane-bound enzymes of erythrocytes in hepatic cirrhosis. Metabolism. 1995 Jul;44(7):825-32. doi: 10.1016/0026-0495(95)90233-3.

  PMID: 7616839 BACKGROUND

• Alexopoulou A, Vasilieva L, Kanellopoulou T, Pouriki S, Soultati A, Dourakis SP. Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis. J Gastroenterol Hepatol. 2014 Apr;29(4):830-4. doi: 10.1111/jgh.12473.

  PMID: 24325340 BACKGROUND

• Cooper RA, Diloy Puray M, Lando P, Greenverg MS. An analysis of lipoproteins, bile acids, and red cell membranes associated with target cells and spur cells in patients with liver disease. J Clin Invest. 1972 Dec;51(12):3182-92. doi: 10.1172/JCI107145.

  PMID: 4640953 BACKGROUND

• Miller JP. Dyslipoproteinaemia of liver disease. Baillieres Clin Endocrinol Metab. 1990 Dec;4(4):807-32. doi: 10.1016/s0950-351x(05)80080-1.

  PMID: 2082907 BACKGROUND

• Kaiser T, Kinny-Koster B, Bartels M, Berg T, Scholz M, Engelmann C, Seehofer D, Becker S, Ceglarek U, Thiery J. Cholesterol esterification in plasma as a biomarker for liver function and prediction of mortality. BMC Gastroenterol. 2017 Apr 20;17(1):57. doi: 10.1186/s12876-017-0614-9.

  PMID: 28427335 BACKGROUND

MeSH Terms

Conditions

Adrenal Insufficiency; Fibrosis; Abetalipoproteinemia; Lecithin Cholesterol Acyltransferase Deficiency

Interventions

Cosyntropin

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hypobetalipoproteinemias; Hypolipoproteinemias; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hypoalphalipoproteinemias

Intervention Hierarchy (Ancestors)

Adrenocorticotropic Hormone; Melanocortins; Pro-Opiomelanocortin; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormones, Anterior; Pituitary Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Nerve Tissue Proteins; Proteins

Limitations and Caveats

Excluded patients with Child Pugh A (compensated cirrhosis) given low number (4).

Results Point of Contact

• Title: Dr. Brian Wentworth
• Organization: University of Virginia

bw8xz@hscmail.mcc.virginia.edu

9739436781

Study Officials

• Zachary Henry, MD

  University of Virginia School of Medicine, Department of Medicine, Division of Gastroenterology & Hepatology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 20, 2017
• First Posted: December 11, 2017
• Study Start: January 29, 2018
• Primary Completion: March 12, 2019
• Study Completion: March 12, 2019
• Last Updated: December 9, 2021
• Results First Posted: December 9, 2021

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)