Is Adrenal Insufficiency Under-diagnosed in Hospitalized Cirrhosis Patients?

• Sponsor: University of Virginia (Other)
• Overall Status: Completed
• CT.gov ID: NCT03368066
• Collaborator: (none)
• Enrollment: 100
• Location: 1
• Arm: 1
• Actual Duration (Months): 13.4
• Patients Per Site Per Month: 7.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adrenal Insufficiency; Cirrhosis; Spur Cell Anemia; Lecithin Acyltransferase Deficiency	Drug: Cosyntropin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Is Adrenal Insufficiency Under-diagnosed in Hospitalized Cirrhosis Patients?
• Actual Study Start Date: Jan 29, 2018
• Actual Primary Completion Date: Mar 12, 2019
• Actual Study Completion Date: Mar 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hospitalized cirrhosis patients Administration of cortisol stimulation test to assess for presence or absence of adrenal insufficiency	Drug: Cosyntropin; Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Cholesterol Esterification Deficiency [24 hours]

   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.

2. Number of Participants With Spur Cell Anemia [24 hours]

   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.

3. Participant Transplant-Free Survival [6 months]

   Transplant and Death are considered equivalent outcomes

Secondary Outcome Measures

1. Number of Participants With Relative Adrenal Insufficiency (RAI) [24 hours]

   A baseline total cortisol level will be obtained and then patients will receive a standard-dose synthetic ACTH (250mcg of Cosyntropin) stimulation test to assess for the presence of adrenal insufficiency. RAI is defined as a change in the total cortisol level in response to the stimulation test of <9mcg/dL when measured 60 minutes after the Cosyntropin is administered.

2. Number of Participants With Low Free Cortisol [24 hours]

   Patients will have their free cortisol levels measured to assess for deficiency.

3. Number of Participants Who Received Liver Transplantation at 90 Days [90 days]

   Patients who received a liver transplant within 90 days of enrollment

4. Number of Participants Who Received Liver Transplantation at 6 Months [6 months]

   Patients who received a liver transplant within 6 months of enrollment

5. Number of Participants Who Died Within Index Hospitalization [Within Hospitalization]

   Patients who died within the same hospitalization as enrollment

6. Number of Participants Who Died at 30 Days [30 days]

   Patients who died within 30 days of enrollment

7. Number of Participants Who Died at 90 Days [90 days]

   Patients who died within 90 days of enrollment

8. Number of Participants Who Died at 6 Months [6 months]

   Patients who died within 6 months of enrollment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 110 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age >=18 years

• Diagnosis of cirrhosis

• Admission to hospital

Exclusion Criteria:

• Age < 18 years

• Prior enrollment in study (i.e. readmission)

• Prisoner

• Pregnancy

• Prednisone or Hydrocortisone use in last 24 hours

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Virginia Health System	Charlottesville	Virginia	United States	22903

Sponsors and Collaborators

• University of Virginia

Investigators

• Principal Investigator: Zachary Henry, MD, University of Virginia School of Medicine, Department of Medicine, Division of Gastroenterology & Hepatology

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 20, 2017

More Information

Publications

• 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.
• 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.
• 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. Review.
• 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.
• 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.
• 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.
• Kaiser T, Kinny-Köster 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.
• 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.
• Miller JP. Dyslipoproteinaemia of liver disease. Baillieres Clin Endocrinol Metab. 1990 Dec;4(4):807-32. Review.
• 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. Epub 2007 Jun 28. Review.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Zachary Henry, MD, Principal Investigator, University of Virginia
• ClinicalTrials.gov Identifier: NCT03368066
• Other Study ID Numbers: 20212
• First Posted: Dec 11, 2017
• Last Update Posted: Dec 9, 2021
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Liver Cirrhosis; Lecithin Cholesterol Acyltransferase Deficiency; Adrenal Insufficiency; Fibrosis; Cosyntropin

Study Results

Participant Flow

Pre-assignment Detail	5 patients were excluded - 1 patient did not undergo cortisol stimulation testing due to administrative error and 4 patients had compensated cirrhosis (Child Pugh A).

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Period Title: Overall Study
STARTED	58	37
COMPLETED	58	37
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Hospitalized Cirrhosis Patients
Arm/Group Description	Administration of cortisol stimulation test to assess for presence or absence of adrenal insufficiency Cosyntropin: Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency
Overall Participants	95
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	39 41.1%
Male	56 58.9%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	95 100%
Etiology of Cirrhosis (Count of Participants)
Alcohol	33 34.7%
Non-alcoholic steatohepatitis	22 23.2%
Hepatitis C	9 9.5%
Cryptogenic	14 14.7%
Other	17 17.9%
Decompensation (Count of Participants)
Ascites	88 92.6%
Hepatic Encephalopathy	55 57.9%
Esophageal Varices	68 71.6%
Hepatocellular Carcinoma (Count of Participants)
Count of Participants [Participants]	11 11.6%
Aldosterone Antagonist Use (Count of Participants)
Count of Participants [Participants]	55 57.9%
Beta Blocker Use (Count of Participants)
Count of Participants [Participants]	38 40%
Midodrine Use (Count of Participants)
Count of Participants [Participants]	6 6.3%
Infection During Hospitalization (Count of Participants)
Count of Participants [Participants]	24 25.3%
Intensive Care Unit Stay During Hospitalization (Count of Participants)
Count of Participants [Participants]	8 8.4%
Acute Kidney Injury (AKI) (Count of Participants)
Stage 1	24 25.3%
Stage 2	2 2.1%
Stage 3	4 4.2%
Mean Arterial Pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	78
Sodium (mEq/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mEq/L]	136
Potassium (mEq/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mEq/L]	3.9
Model for End-Stage Liver Disease (MELD) score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	17
Child Pugh classification (Count of Participants)
B	51 53.7%
C	44 46.3%
Albumin (g/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dL]	2.8
HDL (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	23
Baseline Cortisol (micrograms/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [micrograms/dL]	7.9
Delta Cortisol (micrograms/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [micrograms/dL]	10.0
Free Cortisol (micrograms/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [micrograms/dL]	0.6
Cortisol Binding Globulin (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	1.7
Cholesterol Esters (percentage of esterified cholesterol) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of esterified cholesterol]	66

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Cholesterol Esterification Deficiency
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

2 patients in normal adrenal response group and 3 patients in RAI group were missing cholesterol ester percentage measurements

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	56	34
Count of Participants [Participants]	10 10.5%	11 NaN

2. Primary Outcome

Title	Number of Participants With Spur Cell Anemia
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

2 patients with RAI were missing peripheral smears to assess for the presence of spur cells

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	35
Count of Participants [Participants]	6 6.3%	8 NaN

3. Primary Outcome

Title	Participant Transplant-Free Survival
Description	Transplant and Death are considered equivalent outcomes
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	41 43.2%	16 NaN

4. Secondary Outcome

Title	Number of Participants With Relative Adrenal Insufficiency (RAI)
Description	A baseline total cortisol level will be obtained and then patients will receive a standard-dose synthetic ACTH (250mcg of Cosyntropin) stimulation test to assess for the presence of adrenal insufficiency. RAI is defined as a change in the total cortisol level in response to the stimulation test of <9mcg/dL when measured 60 minutes after the Cosyntropin is administered.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hospitalized Cirrhosis Patients
Arm/Group Description	Administration of cortisol stimulation test to assess for presence or absence of adrenal insufficiency Cosyntropin: Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency
Measure Participants	95
Count of Participants [Participants]	37 38.9%

5. Secondary Outcome

Title	Number of Participants With Low Free Cortisol
Description	Patients will have their free cortisol levels measured to assess for deficiency.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

1 patient from normal adrenal response group was missing free cortisol data

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	57	37
Count of Participants [Participants]	6 6.3%	1 NaN

6. Secondary Outcome

Title	Number of Participants Who Received Liver Transplantation at 90 Days
Description	Patients who received a liver transplant within 90 days of enrollment
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	6 6.3%	5 NaN

7. Secondary Outcome

Title	Number of Participants Who Received Liver Transplantation at 6 Months
Description	Patients who received a liver transplant within 6 months of enrollment
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	8 8.4%	6 NaN

8. Secondary Outcome

Title	Number of Participants Who Died Within Index Hospitalization
Description	Patients who died within the same hospitalization as enrollment
Time Frame	Within Hospitalization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	1 1.1%	1 NaN

9. Secondary Outcome

Title	Number of Participants Who Died at 30 Days
Description	Patients who died within 30 days of enrollment
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	4 4.2%	4 NaN

10. Secondary Outcome

Title	Number of Participants Who Died at 90 Days
Description	Patients who died within 90 days of enrollment
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	5 5.3%	12 NaN

11. Secondary Outcome

Title	Number of Participants Who Died at 6 Months
Description	Patients who died within 6 months of enrollment
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Adrenal Response	Relative Adrenal Insufficiency
Arm/Group Description	Delta cortisol response to 250mcg Cosyntropin > 9 micrograms/dL	Delta cortisol response to 250mcg Cosyntropin < 9 micrograms/dL
Measure Participants	58	37
Count of Participants [Participants]	9 9.5%	15 NaN

Adverse Events

Time Frame	6 months
Arm/Group Title	Hospitalized Cirrhosis Patients
Arm/Group Description	Administration of cortisol stimulation test to assess for presence or absence of adrenal insufficiency Cosyntropin: Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency
All Cause Mortality
	Hospitalized Cirrhosis Patients
	Affected / at Risk (%)	# Events
Total	25/100 (25%)
Serious Adverse Events
	Hospitalized Cirrhosis Patients
	Affected / at Risk (%)	# Events
Total	25/100 (25%)
General disorders
Non-liver-related death	1/100 (1%)	1
Hepatobiliary disorders
Liver-related death	24/100 (24%)	24
Other (Not Including Serious) Adverse Events
	Hospitalized Cirrhosis Patients
	Affected / at Risk (%)	# Events
Total	1/100 (1%)
Gastrointestinal disorders
Nausea	1/100 (1%)	1

Limitations/Caveats

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

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.