Adrenal Insufficiency, Cirrhosis, Spur Cell Anemia, Lecithin Acyltransferase Deficiency
Conditions
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.
Interventions
DRUGCosyntropin
Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency
Sponsors
University of Virginia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 110 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Participant Transplant-Free Survival | 6 months | Transplant and Death are considered equivalent outcomes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Received Liver Transplantation at 6 Months | 6 months | Patients who received a liver transplant within 6 months of enrollment |
| Number of Participants Who Died Within Index Hospitalization | Within Hospitalization | Patients who died within the same hospitalization as enrollment |
| 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. |
| Number of Participants Who Died at 90 Days | 90 days | Patients who died within 90 days of enrollment |
| Number of Participants Who Died at 6 Months | 6 months | Patients who died within 6 months of enrollment |
| Number of Participants Who Died at 30 Days | 30 days | Patients who died within 30 days of enrollment |
| Number of Participants With Low Free Cortisol | 24 hours | Patients will have their free cortisol levels measured to assess for deficiency. |
| Number of Participants Who Received Liver Transplantation at 90 Days | 90 days | Patients who received a liver transplant within 90 days of enrollment |
Countries
United States
Participant flow
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Hospitalized Cirrhosis Patients 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 | 95 |
| Total | 95 |
Baseline characteristics
| Characteristic | Hospitalized Cirrhosis Patients | — |
|---|---|---|
| Acute Kidney Injury (AKI) Stage 1 | 24 Participants | — |
| Acute Kidney Injury (AKI) Stage 2 | 2 Participants | — |
| Acute Kidney Injury (AKI) Stage 3 | 4 Participants | — |
| Age, Continuous | 58 years | — |
| Albumin | 2.8 g/dL | — |
| Aldosterone Antagonist Use | 55 Participants | — |
| Baseline Cortisol | 7.9 micrograms/dL | — |
| Beta Blocker Use | 38 Participants | — |
| Child Pugh classification B | 51 Participants | — |
| Child Pugh classification C | 44 Participants | — |
| Cholesterol Esters | 66 percentage of esterified cholesterol | — |
| Cortisol Binding Globulin | 1.7 mg/dL | — |
| Decompensation Ascites | 88 Participants | — |
| Decompensation Esophageal Varices | 68 Participants | — |
| Decompensation Hepatic Encephalopathy | 55 Participants | — |
| Delta Cortisol | 10.0 micrograms/dL | — |
| Etiology of Cirrhosis Alcohol | 33 Participants | — |
| Etiology of Cirrhosis Cryptogenic | 14 Participants | — |
| Etiology of Cirrhosis Hepatitis C | 9 Participants | — |
| Etiology of Cirrhosis Non-alcoholic steatohepatitis | 22 Participants | — |
| Etiology of Cirrhosis Other | 17 Participants | — |
| Free Cortisol | 0.6 micrograms/dL | — |
| HDL | 23 mg/dL | — |
| Hepatocellular Carcinoma | 11 Participants | — |
| Infection During Hospitalization | 24 Participants | — |
| Intensive Care Unit Stay During Hospitalization | 8 Participants | — |
| Mean Arterial Pressure | 78 mmHg | — |
| Midodrine Use | 6 Participants | — |
| Model for End-Stage Liver Disease (MELD) score | 17 units on a scale | — |
| Potassium | 3.9 mEq/L | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 95 Participants | — |
| Sex: Female, Male Female | 39 Participants | — |
| Sex: Female, Male Male | 56 Participants | — |
| Sodium | 136 mEq/L | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 25 / 100 |
| other Total, other adverse events | 1 / 100 |
| serious Total, serious adverse events | 25 / 100 |
Outcome results
Primary
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.
Time frame: 24 hours
Population: 2 patients in normal adrenal response group and 3 patients in RAI group were missing cholesterol ester percentage measurements
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants With Cholesterol Esterification Deficiency | 10 Participants |
| Relative Adrenal Insufficiency | Number of Participants With Cholesterol Esterification Deficiency | 11 Participants |
Primary
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.
Time frame: 24 hours
Population: 2 patients with RAI were missing peripheral smears to assess for the presence of spur cells
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants With Spur Cell Anemia | 6 Participants |
| Relative Adrenal Insufficiency | Number of Participants With Spur Cell Anemia | 8 Participants |
Primary
Participant Transplant-Free Survival
Transplant and Death are considered equivalent outcomes
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Participant Transplant-Free Survival | 41 Participants |
| Relative Adrenal Insufficiency | Participant Transplant-Free Survival | 16 Participants |
Secondary
Number of Participants Who Died at 30 Days
Patients who died within 30 days of enrollment
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants Who Died at 30 Days | 4 Participants |
| Relative Adrenal Insufficiency | Number of Participants Who Died at 30 Days | 4 Participants |
Secondary
Number of Participants Who Died at 6 Months
Patients who died within 6 months of enrollment
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants Who Died at 6 Months | 9 Participants |
| Relative Adrenal Insufficiency | Number of Participants Who Died at 6 Months | 15 Participants |
Secondary
Number of Participants Who Died at 90 Days
Patients who died within 90 days of enrollment
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants Who Died at 90 Days | 5 Participants |
| Relative Adrenal Insufficiency | Number of Participants Who Died at 90 Days | 12 Participants |
Secondary
Number of Participants Who Died Within Index Hospitalization
Patients who died within the same hospitalization as enrollment
Time frame: Within Hospitalization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants Who Died Within Index Hospitalization | 1 Participants |
| Relative Adrenal Insufficiency | Number of Participants Who Died Within Index Hospitalization | 1 Participants |
Secondary
Number of Participants Who Received Liver Transplantation at 6 Months
Patients who received a liver transplant within 6 months of enrollment
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants Who Received Liver Transplantation at 6 Months | 8 Participants |
| Relative Adrenal Insufficiency | Number of Participants Who Received Liver Transplantation at 6 Months | 6 Participants |
Secondary
Number of Participants Who Received Liver Transplantation at 90 Days
Patients who received a liver transplant within 90 days of enrollment
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants Who Received Liver Transplantation at 90 Days | 6 Participants |
| Relative Adrenal Insufficiency | Number of Participants Who Received Liver Transplantation at 90 Days | 5 Participants |
Secondary
Number of Participants With Low Free Cortisol
Patients will have their free cortisol levels measured to assess for deficiency.
Time frame: 24 hours
Population: 1 patient from normal adrenal response group was missing free cortisol data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants With Low Free Cortisol | 6 Participants |
| Relative Adrenal Insufficiency | Number of Participants With Low Free Cortisol | 1 Participants |
Secondary
Number of Participants With Relative Adrenal Insufficiency (RAI)
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Adrenal Response | Number of Participants With Relative Adrenal Insufficiency (RAI) | 37 Participants |