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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 18  |  Issue : 3  |  Page : 310-316

Salivary cortisol in adrenal insufficiency in patients with chronic hepatitis C infection


1 Department of Internal Medicine, Al-Azhar University (Boys), Assiut, Egypt
2 Department of Clinical Pathology, Al-Azhar University (Boys), Assiut, Egypt
3 Department of Endocrinology and Metabolism, Al-Azhar University (Girls), Cairo, Egypt

Date of Submission25-May-2020
Date of Decision28-Jun-2020
Date of Acceptance07-Jul-2020
Date of Web Publication30-Oct-2020

Correspondence Address:
Eglal M Kenawy
Department of Internal Medicine, Al-Azhar University (Boys), Assiut, 71511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_81_20

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  Abstract 


Background The assessment of adrenal insufficiency (AI) in cirrhotic patients varies according to the stage of the liver disease. The authors aimed to study the diagnostic role of salivary cortisol (SC) level in the assessment of AI in chronic hepatitis C cirrhotic patients.
Patients and methods A case–controlled study of 50 patients with liver cirrhosis owing to chronic hepatitis C infection and 34 apparently healthy persons was conducted. Fasting serum total cortisol (STC), SC, and corticosteroid-binding globulin (CBG) level assessments, as well as calculation of free cortisol level (CFC) were done.
Results SC (P<0.000), STC (P<0.000), CBG (P<0.000), and CFC (P<0.000) were reduced significantly in patients compared with controls. A total of 11 (22%) patients were diagnosed with AI by reduced STC level, but only five (10%) were diagnosed by reduced SC. In cirrhotic patients, SC (P<0.000), CFC (P<0.000), and CBG (P<0.000) were significantly decreased with the severity of liver cirrhosis according to Child–Pugh classification. High-density lipoprotein level was positively correlated with SC (P<0.000), CFC (P<0.000), and STC (P<0.000) levels. SC was better correlated with CFC than STC, with a significant difference between the two correlations (z score=−2.716 and P<0.003). On receiver operating characteristic curve analysis, SC (at a cutoff value 5.65 ng/dl) had a sensitivity of 76% and specificity of 87.5% compared with 38 and 97.3%, respectively, for STC (at a cutoff value of 12.6 μg/dl).
Conclusion SC correlated well with CFC and is more sensitive than serum total cortisol in the diagnosis of AI in cirrhotic patients.

Keywords: adrenal insufficiency, calculated free cortisol, chronic hepatitis C, cirrhosis, salivary cortisol, total cortisol


How to cite this article:
Bakry AS, Kenawy EM, Abdelmegui MM, Hammad FK. Salivary cortisol in adrenal insufficiency in patients with chronic hepatitis C infection. Al-Azhar Assiut Med J 2020;18:310-6

How to cite this URL:
Bakry AS, Kenawy EM, Abdelmegui MM, Hammad FK. Salivary cortisol in adrenal insufficiency in patients with chronic hepatitis C infection. Al-Azhar Assiut Med J [serial online] 2020 [cited 2020 Nov 25];18:310-6. Available from: http://www.azmj.eg.net/text.asp?2020/18/3/310/299583




  Introduction Top


Patients with liver cirrhosis have many endocrinal abnormalities such as hypogonadism and gynecomastia in males and amenorrhea with infertility in females [1]. Patients with chronic liver disease (CLD) may have alteration in the levels of many hormones such as growth hormone, insulin-like growth factor-1, and thyroid hormones [2]. Adrenal insufficiency (AI) is an endocrine abnormality that is also seen in decompensated cirrhosis [2], which is sometimes called hepatoadrenal syndrome [3]. However, Fede et al. [4] in 2014 suggested that AI is a feature of liver disease per se and not simply related to critical illness. AI has been described in patients with cirrhosis, even in the absence of conditions predisposing to dysfunction of the hypothalamic–pituitary–adrenal axis, such as sepsis or critical illness [5]. There are several hypotheses explaining the mechanisms that lead to AI in patients with liver cirrhosis, such as endotoxemia and abnormalities in the apolipoprotein A-1 level, low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c). Moreover, the release of proinflammatory mediators, damage to the adrenal gland by hemorrhage or infarction, bacterial translocation of enteric organisms, and resistance to glucocorticoid have been suggested [5]. The diagnosis of AI is made by assessing serum total cortisol (STC) level rather than serum free cortisol (FC). Most of circulating cortisol (70%) is bound to corticosteroid-binding globulin (CBG) and 20% is bound to albumin. The biologically active fraction, free or unbound cortisol, constitutes only 10% of the circulating cortisol [4]. The low albumin and CBG concentrations that are seen in liver disease may reduce TC with a concomitant increase in FC levels; thus, AI is overestimated if diagnosed only by measuring STC [6]. FC is measured after mechanical separation of bound and unbound fractions by ultrafiltration or equilibrium dialysis and then measured directly by immunologic assays or tandem mass spectrometry or indirectly via 3H-cortisol dilution [7], which is labor intensive and impractical for every day clinical use [8]. It can be also calculated from total cortisol and CBG using Coolens Method [9].

Several studies were done to diagnose AI in cirrhotic patients, either by using salivary cortisol (SC), STC, or CFC alone [10],[11],[12],[13] or with short Synacthen test, assuming that STC should not be used in the diagnosis of AI in cirrhotic patients as it is affected by alteration in CBG levels, and SC was correlated well with FC in adrenocorticotrophic hormone (ACTH) testing [14],[15]. The aim of this work is to study the diagnostic role of SC level in the assessment of AI in chronic hepatitis C (CHC) cirrhotic patients.


  Patients and methods Top


A case–controlled study of 50 patients with liver cirrhosis due to hepatitis C infection (CHC group) was conducted during a 6-month period from Al-Azhar University Hospital. The study was included 34 apparently healthy age-matched and sex-matched persons free from any liver or endocrinal diseases selected for a control group. The study was done according to the Declaration of Helsinki, 2013 [16], and was approved by the Ethical Committee of the Faculty of Medicine, Al-Azhar University.

Cirrhotic patients included in the study complained of easy fatigability and palpitation and had symptoms of hypotension suspicious to have AI, and the final diagnosis was done by laboratory investigations, as liver cirrhosis per se could give the same picture.

Excluded from the study were patients under 18 years of age, patients with a history of pituitary or adrenal disease, or patients treated with steroids or other drugs known to influence cortisol production or level in the previous 6 months, including etomidate, ketoconazole, antidepressants, antipsychotic drugs and oral contraceptives. Moreover, excluded from the study were patients with severe sepsis, septic or hemorrhagic shock, and those who were administered albumin in the previous 20 days, fresh frozen plasma in the previous 10 days, and terlipressin or glypressin (terlipressin acetate) infusion in the last 6 h before the study. Patients with oral disease like ulcers, gingivitis, or bleeding gums; obese patients (BMI >30 kg/m2); pregnant women; and patients with positive hepatitis B virus infection were also excluded from the study.

Weight and height were recorded, and BMI was calculated. Complete clinical examination and mental status with the grading of hepatic encephalopathy according to the West Haven criteria were done for each patient and controls [17]. Ascites were graded according to the International Ascites Club Grading System [18].

Laboratory workup

Routine investigations were done for each patients and controls, including CBC by Pentra hematology autoanalyzer (HORIBA, France) and liver function and lipid profiles using Mindray BS380 chemistry autoanalyzer (Nanshan, Shenzhen, China). Fasting STC, SC (8:00 a.m.), and CBG by immunoassay were done for each patient and control. Fasting STC assessment was done using competitive binding immunoassay by Cortisol ELIZA Kit, Cat. NO: CAN-C-270 (Diagnostic Biochem, London, Ontario, Canada). The expected normal range of STC is 3.95–27.23 µg/dl. CBG assessment was done using a double-sandwich ELISA technique from MyBiosource (Kit Cat. No. MBS2600955; Southern California, San Diego, USA) according to the manufacturer instructions. The detection range of the kit was from 3.12 to 200 ng/ml, and the minimum detectable human CBG was up to 0.6 ng/ml. SC assay was done as follows: patients were asked to rinse their mouths with water and collect 4–5 ml of saliva into a clean glass tube. Samples were stored at −20°C till assayed. It was measured by competitive binding immunoassay using Cortisol Saliva ELIZA Kit, Cat. No: CAN-C-290 (Diagnostic Biochem Canada). The normal range of SC was 5–21.6 ng/ml. Calculated free cortisol (CFC) was done as follows: we used CFC as an alternative marker for FC measurement. CFC was calculated by Coolens Formula [9] as follows:



where, Z=0.0167+0.182 (CBG-STC).

CFC reference interval lies between 0.0761 and 0.692 μg/dl [7].

Statistical analysis

Data were fed to statistical software SPSS version 16 (IBM Company, USA). The graphs were constructed using Microsoft excel software (Microsoft Corporation, Redmond, Washington, USA). All statistical analysis was done using two-tailed tests and α error of 0.05. A P value less than or equal to 0.05 was considered to be significant. Parametric data were analyzed using independent sample t-test and one-way analysis of variance and nonparametric data using the Mann–Whitney test and Kruskal–Wallis test. Analysis of categorical data was done by Pearson’s χ2 test and Monte Carlo exact test and Fisher’s exact test. Correlation analysis was done by Spearman correlation analysis. To test the difference between two correlations, we used online calculator provided from Free Statistics Calculator (https://www.danielsoper.com/statcalc/calculator.aspx?id=104).


  Results Top


The clinical and laboratory data of the 50 patients and the 34 controls are shown in [Table 1]. Cirrhotic patients were hypotensive (P<0.000) with increased pulse rate than the control group (P<0.000). Serum lipids were significantly reduced, including HDL (P<0.000), than the control. Fasting STC (P<0.000), CBG (P<0.000), CFC (P<0.000), and SC (P<0.000) were statistically decreased in cirrhotic patients than the control group. Eleven (22%) cirrhotic patients were diagnosed as having AI by STC levels, whereas only five (10%) patients of the 11 were diagnosed as having AI when assessed by SC. However, the differences were insignificant between them (P>0.103) ([Table 1]). Stage A Child–Pugh (CP) was found in 12 (24%) patients, stage B in 19 (38%), and stage C in 19 (38%) patients. Comparing Child–Pugh stages (A, B, and C) of chronic liver disease revealed progressively decline in SC [stage A (6.27±0.49) vs stage B (5.59±0.76) vs stage C (4.99±0.87); P<0.000], CBG [stage A (8.83±1.26) vs stage B (5.76±1.52) vs stage C (4.7±1.1); P<0.000] and CFC [stage A (0.12±0.01) vs stage B (0.09±0.02) vs stage C (0.07±0.03), (P<0.000)] with progression of liver disease. Interestingly, the STC level was not significantly decreased with the severity of liver disease, as it did not differ significantly between CP stages B and C (P<0.069) ([Table 2]).
Table 1 Clinical and laboratory data for the 50 patients with liver cirrhosis and the 34 normal controls

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Table 2 Salivary cortisol (SC), serum total cortisol (STC), cortisol-binding globulin (CBG) and calculated free cortisol (CFC) levels in 50 cirrhotic patients according to Child–Pugh classes

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The age of the patients was found to be negatively correlated with SC (r=0.291, P<0.040) and CFC (r=0.335, P<0.018), but it showed insignificant difference with STC (r=0.137, P<0.344). Platelet numbers were positively correlated with SC (P<0.001), CFC (P<0.006), and fasting STC levels (P<0.001). However, HDL levels were positively correlated with SC (P<0.000), CFC (P<0.000), and fasting STC levels (P<0.000)([Table 3]). The CFC was correlated well with SC (r=0.854; P=0.000) and with STC (r=0.611; P<0.000) ([Table 3]). Interestingly we found that SC was better correlated with CFC than STC, and the significant difference between the two correlations showed Z score of −2.716 and P<0.003 ([Table 4]).
Table 3 Correlations between salivary cortisol, serum total cortisol, cortisol-binding globulin, and calculated free cortisol levels in 50 cirrhotic patients

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Table 4 Difference between the correlations of calculated free cortisol (CFC) and both serum total cortisol (STC) and salivary cortisol (SC) levels

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Increase in Child–Paugh score and decrease in albumin level were found to be good predictors of AI diagnosed by either SC or STC. Reduction in HDL level was a predictor for AI diagnosed by SC and not by STC (P =0.002 and 0.205, respectively) ([Table 5]).
Table 5 Linear regression analysis for predictors of AI diagnosed by SC and STC in CHC cirrhotic patients

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SC was the best test to rule out AI in cirrhotic patients than other parameters with high sensitivity (76%) and specificity (87.5%), determining positive predictive value of 90.5% and negative predictive value (NPV) of 70%. CFC had almost the same specificity (87.5%) and positive predictive value (88.9%) as SC, but its sensitivity (64%) and NPV were lower than SC (60.9%). STC had the lowest sensitivity (38%) and lowest NPV among the other parameters (49.2%) but with the highest specificity (93.75%) ([Table 6] and [Figure 1]).
Table 6 Receiver operating characteristic curve between 50 cirrhotic patients and 34 normal controls

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Figure 1 Receiver operating characteristic curve between 50 cirrhotic patients and 34 normal controls.

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  Discussion Top


It is impossible to diagnose AI in critically ill cirrhotic patients on clinical bases as they do not have the typical Addisonian features. The only clinical sign of AI is nonresponding hypotension to vasopressors and fluid resuscitation [19]. The diagnosis of AI in patients with liver cirrhosis is better to be based on laboratory tests [20]. There was a discrepancy in the laboratory criteria used to diagnose AI on measuring FC in severe liver disease [21]. A good correlation was found between both of STC and SC and CFC in our study. However, when we used STC for diagnosis of AI, we found that AI diagnosis is overestimated similar to previously reported studies [22],[23],[24],[25]. This overestimation could be owing to the reduced CBG levels in cirrhotic patients because of the hypoalbuminemia associated with chronic liver disease [12],[26].

The frequency of AI in cirrhotic patients by STC was found to be 22% and by SC to ∼10%. Other studies reported the frequency of AI in cirrhotic patients to be 33 and 38%, respectively, according to STC and 9.1 and 7.2%, respectively, according to SC [13],[25]. This discrepancy could be related to the larger sample size they studied and different methodologies (chemiluminescence and radioimmunoassay) by which they assayed STC, which seems to increase false-positive cases [27].

In this study, low serum albumin and high Child–Pugh score were good predictor of AI diagnosed by either SC or STC. However, low HDL was a predictor of AI diagnosed by SC alone. Mohammed et al. [28] found that low HDL, LDL, and cholesterol; ascites; spontaneous bacterial peritonitis; and high Child and MELD scores were predictors of AI diagnosed by STC. These patients with low HDL require regular evaluation of adrenal function.In the presented study, lipid profile (TG, cholesterol, LDL, and HDL) was decreased in cirrhotic patients than the control group, and this was confirmed previously by other studies, which also found decrease in serum lipid levels improved after liver transplantation and can be used to predict the prognosis of the patients [14],[28],[29],[30],[31]. We found that HDL level decreased significantly with increasing severity of liver cirrhosis and was significantly correlated with STC, CFC, and SC in cirrhotic patients. As demonstrated in other studies, low HDL-c concentration was associated with a low serum level of cortisol and AI in cirrhotic patients [12],[32],[33]. This is because HDL-c brings cholesterol into adrenal glands which are necessary for cortisol synthesis [23].

We found that SC was more sensitive (76%) with higher NPP (70%) followed by CFC and then STC. Ceccato and colleagues found that morning SC value below 7.31 nmol/L can distinguish patients with AI from healthy controls with a sensitivity of 97% and specificity of 93% [34]. The higher sensitivity and specificity described by those authors can be explained by the fact that their patients were not cirrhotic with normal albumin levels.

The measurement of FC is more accurate than STC in diagnosing AI in cirrhotic patients, although it is technically difficult and not routinely performed in clinical laboratories [10]. SC can be assayed daily as it is noninvasive, easy to perform, does not need CBG measurement, is not influenced by alteration in protein concentration [12], and is correlated well with FC and CFC [35].


  Conclusion Top


In conclusion, the presented study demonstrated that SC correlated well with calculated free serum cortisol and is more sensitive than STC in the diagnosis of AI in cirrhotic patients in whom hypoalbuminemia is found. Serial measurements of SC can replace the need for assaying FC or total cortisol in these patients.

Acknowledgements

The authors would like to acknowledge the study participants and the Clinical Pathology technicians for their support in completing the laboratory work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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