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Association of apoptotic marker cytokeratin18 with blood pressure in non-alcoholic fatty liver disease patients.

Byline: Benash Altaf, Shireen Jawed and Rana Muhammad Tahir Salam

Keywords: CVS, CK18, DBP, HTN, MS, NAFLD, SBP.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is an emerging health issue worldwide affecting both obese and non-obese individuals.1 It is an evolving epidemic in western as well as Asian population. Its prevalence is continuously increasing and affecting 15%-20% of the Asian population.1

It involves multisystem regulatory pathways including hepatic and extra hepatic tissues such as Cardiovascular System (CVS) and renal system.1 Abnormalities in these systems are the leading cause of many metabolic disorders like dyslipidaemia, insulin resistance, diabetes mellitus type-2 (T2DM) and hypertension (HTN). Dyslipidaemia associated with NAFLD is due to excess production of atherogenic lipoprotein and it is characterized by increased levels of serum triglycerides, decreased levels of HDL cholesterol and excess release of pro-inflammatory mediators. These markers are the contributing factors for atherosclerosis, hypertension (HTN) and cardiovascular diseases (CVD). HTN and CVD have poor prognosis and said to be the one of the major causes of morbidity and mortality in NAFLD patients.2,3

Cytokeratin (CK18) is a well-known marker for apoptosis and inflammation. It is not normally found in vascular smooth muscle but is highly expressed during the formation of atherosclerotic plaques and found to be raised in hypertensive NAFLD patients.4 Evidences are available showing correlation of (CK18) with BP and has reported its pivotal role in pathophysiology of these disorders.4,5

Association between liver enzymes like serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Gamma-glutamyl transferase (GGT) and hypertension is well established. Many previous researchers have documented positive association of these enzymes with HTN in NAFLD.3 Very few epidemiological studies focused on the relationship of CK18 with HTN and reported varying results.6 Some have reported positive correlation between CK18 and systolic blood pressure (SBP),7 rebutted to this, some did not find any significant association between CK18 and BP.8 Due to these inconsistent results, association between these parameters is still to be hypothesised and required new researches to focus their relationship.

The current study was aimed to explore the association of CK18 with Blood Pressure in NAFLD patients as no documentations concerning relationship between these parameters are available in Pakistan to the best of authors' knowledge.

Methodology

The current descriptive cross sectional study comprising of 100 patients was conducted at King Edward Medical University (K.E.M.U), working in collaboration with Mayo Hospital, Lady Willingdon Hospital, Lady Aitchison Hospital, Kot Khawaja Saeed Hospital, Shahdara Hospital, and Govt Syed Mitha teaching Hospital Lahore affiliated to it. Sample size of 100 cases was estimated by using prevalence of B.P, confidence interval 95%, 80% power of test and [alpha] 5%.

After approval from ethical review committee, 100 NAFLD patients from radiology OPD of Mayo hospital by convenient sampling technique were enrolled. The inclusion criteria were Nondiabetics with age ranging between 40-60 years with fatty liver both male and female. Subjects with Fatty liver were diagnosed on the basis of high echogenicity textured liver on ultrasound. However subjects with hepatitis B and C and known diabetics were excluded from the study. Informed written consent was taken from each patient and confidentiality was assured. All the relevant demographic information and history were taken on a pre-designed Performa. Physical examination was done and blood pressure was measured with mercury sphygmomanometer by auscultatory method. Triplicate readings were taken in the sitting position, after relaxing the patient for 5 minutes an average were entered in the data.9

Blood pressure cut off points for hypertensive patients were taken according to the new guidelines 2017 for hypertension provided by American Heart Association and the American College of Cardiology.10

According to the new criteria, normal BP and elevated blood pressure are 80 mm Hg, respectively. Blood pressure 130-139/80-89 mm Hg and >140/>90 mm Hg were taken as stage I and II hypertension.10

After taking informed consent, 5 ml of blood samples were taken and serum was separated in a centrifuge machine for 30 minutes to determine the level of CK18M30 in both groups by sandwich ELISA (Elabscience, Catalog No. E-EL-H2073 in Pathology lab of KEMU. Microtiter plate Elisa plate was pre-coated with CK18M30 antibody. Standards or samples were added to ELISA microwells and the target antigen binds to capture the antibody. This is followed by addition and incubation of Avidin-Horseradish Peroxidase and biotinylated antibody specific for CK18M30. Substrate solution was added after washing. After adding stop solution optical density at 450nm was noted by ELISA reader plate.

Statistical analysis was done using SPPS 21.0. Descriptive variables are presented as frequencies, while mean and standard deviation for continuous variables. Categorical variables are presented as percentages. Association was analyzed by regression analysis.

Table-1: Descriptive of studied subject (n= 100).

Variables###Mean###Standard Deviation (SD)

Age (years)###43.8###5.34

Height (m)###1.59###0.063

Weight (kg)###78.2###11.17

Body mass index (BMI) kg/m2###30.5###4.07

Systolic Blood Pressure (SBP) mmHg###125.09###17.5

Diastolic blood pressure (DBP) mmHg###88.62###14.21

Table-2: Association between CK18 and blood pressure.

Blood pressure###?###S.E###r###P value###95% C.I

Systolic blood pressure (SBP)###0.045###0.075###0.06###0.55###0.014-0.195

Diastolic blood pressure (DBP)###0.05###0.06###0.09###0.37###0.066-0.176

Results

This study included 100 NAFLD patients of mean +-SD age of 43.8 +- 5.34. Descriptive statistics of study is presented in Table-1. Out of total NAFLD population, 24 were normotensive and 76 subjects were hypertensive. Figure-1 is showing the comparison of blood pressure among study groups. Mean +- SD SBP and DBP of normotensive subjects were 106+-12.8 and 72+-12.8 mmHg, respectively. SBP and DBP of hypertensive subject were 131+-14.1 and 94+-10.2 mmHg, which was significantly different from normotensive subjects (P value 0.001*).

Figure-2 shows that CK18 is higher in hypertensive than normotensive subjects (18.3+-2.8 v/s 10.5+- 5.6) and difference was statistically significant with (p = 0.016*), However Regression analysis did not show significant association of CK18 with systolic (p = 0.55) and diastolic blood pressure, (p = 0.37) (Table-2).

Discussion

NAFLD is becoming the major health burden in Western, American as well as in Asian population. It is also considered as hepatic manifestation of metabolic syndrome (MS).11

Patients with NAFLD have probability for developing co-morbidities including hypertension,12 atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus and chronic renal diseases.13 Associated factors like obesity, atherogenic dyslipidaemia, and greater carotid intima-media thickness followed by atherosclerosis, a prothrombotic and a proinflammatory state are greater contributor in developing deteriorating consequences.12

All these proinflammatory conditions result in inflammation and elevation of inflammatory markers like CK18. Framingham et al documented that, high BP due to decline in HDL level is the most common element of NAFLD.14 On the other hand, hypertension is attributed to an inflammatory disease by various researchers.12

The objective of the current study is to enlighten the significant association between CK18 and BP for early detection, and effective management of hypertension, which is key determinant of cardiovascular risk and leading cause of morbidity, disability and mortality in NAFLD worldwide.3 Strong evidences showed that the rise in 20mmHg systolic blood pressure (SBP) and 10 mm Hg diastolic blood pressure (DBP) are contributing towards doubling of the risk of mortality from stroke and cardio vascular diseases.10

In current study, individuals with 131+-14.1 and 94+-10.2mmHg SBP and DBP were considered as hypertensive as per new guide lines by American Heart Association.10 Speliotes etal have reported that NAFLD patients showed higher SBP, which is supporting our results.14 Qian LY et. al's study is also in agreement with our results as they also reported higher limits of blood pressure in NAFLD patients and they further considered blood pressure as the independent risk factor of NAFLD.12 Some previous studies are also in favour of our results documenting higher BP in NAFLD patients.15,16

One of the previous evidences revealed that NAFLD with raised levels of the emerging inflammatory biomarker CK18 is an independent risk factor for hypertension.7 In the present study, we analyzed the association of blood pressure with serum CK18 by regression analysis. It was found to be higher in hypertensive than normotensive NAFLD patients (p =0.016*) but no significant association of CK18 was found with SBP (p = 0.55) and DSB (p =0.37) as it requires a larger number of individuals, while small sample size is the limitation of this study. However, present study is in line with Mattey DL who did not find any significant association between CK18 and BP in European population.8

The concern of this study was to highlight the association between CK18 and BP, though significant association was not observed. However elevated CK18 in hypertensives may emulate damage of cells having CK18 in cardiac vasculature and atherosclerotic plaques. It might be a useful surrogate marker for the identification of patients at risk of developing hypertension and subsequent IHD and targeted management to prevent life threatening morbidities and disabilities.

Effective screening strategies including new biomarkers like CK18 should be recommended for early detection of co-morbidities of NAFLD to prevent harmful consequences and promoting healthy life style.

Conclusion

Most of the NAFLD patients were hypertensives associated with raised inflammatory biomarker CK18.

Limitation

Small sample size is the limitation of study because significant association requires sample size on a broader scale.

This is a cross sectional study so we could not establish a casual association between BP and elevated CK18levels in NAFLD patients.

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

References

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3. Patel S, Lawlor DA, Ferreira DL, Hughes AD, Chaturvedi N, Callaway M, et al. The association of nonalcoholic fatty liver disease with central and peripheral blood pressure in adolescence: findings from a cross-sectional study. J Hypertens. 2015; 33:546-52.

4. Bar H, Bea F, Blessing E, Watson L, Wende P, Kreuzer J, et al. Phosphorylation of cytokeratin 8 and 18 in human vascular smooth muscle cells of atherosclerotic lesions and umbilical cord vessels. Basic Res Cardiol. 2001; 96:50-8.

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6. Wu G, Li H, Fang Q, Zhang J, Zhang M, Zhang L, et al. Complementary Role of Fibroblast Growth Factor 21 and Cytokeratin 18 in Monitoring the Different Stages of Nonalcoholic Fatty Liver Disease. Sci Rep. 2017; 7:5095.

7. Kwak DS, Jun DW, Cho YK, Lee SM, Lee SH, Jung IS, et al. Clinical Correlation between Serum Cytokeratin-18 and Metabolic Parameters in Patients with Sonographic Non-alcoholic FattyLiver Disease. Korean J Gastroenterol. 2014; 64:206-12.

8. Mattey DL, Dawes PT, Nixon NB, Goh L, Banks MJ, Kitas GD. Increased levels of antibodies to cytokeratin 18 in patients with rheumatoid arthritis and ischemic heart disease. Ann Rheum Dis. 2004; 63:420-5.

9. Jawed S, Zia S, Tariq S. Frequency of different blood groups and its association with BMI and blood pressure among the female medical students of Faisalabad. J Pak Med Assoc. 2017; 67:1132-7.

10. Paul K Whelton, Robert M Carey, Wilbert S Aronow, Donald E Casey Jr, Karen J Collins, Cheryl Dennison Himmelfarb, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018; 71:1269-324.

11. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001; 50:1844-50.

12. Qian LY, Tu JF, Ding YH, Pang J, Che XD, Zou H, etal. Association of blood pressure level with nonalcoholic fatty liver disease in non-hypertensive population: Normal is not the new normal. Medicine (Baltimore). 2016; 95:e4293.

13. Paschos P, Paletas K. Nonalcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009; 13:9-19

14. Speliotes EK, Massaro JM, Hoffmann U, Vasan RS, Meigs JB, Sahani DV, et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham heart study. Hepatology. 2010; 51:1979-87.

15. Singh GK, Vitola BE, Holland MR, Sekarski T, Patterson BW, Magkos F, et al. Alterations in ventricular structure and function in obese adolescents with nonalcoholic fatty liver disease. J Pediatr. 2013; 162:1160-8.

16. Alp H, Karaarslan S, Selver Eklioglu B, Atabek ME, Altin H, Baysal T. Association between nonalcoholic fatty liver disease and cardiovascular risk in obese children and adolescents. Can J Cardiol. 2013; 29:1118-25.
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Author:Altaf, Benash; Jawed, Shireen; Salam, Rana Muhammad Tahir
Publication:Journal of Pakistan Medical Association
Article Type:Report
Geographic Code:9PAKI
Date:Dec 31, 2020
Words:2317
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