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Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients
Arab Journal of Gastroenterology xxx (xxxx) xxx
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Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original article
Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients Mehmet Baysal a,⇑, Yıldız Ortaburun a, Ali Rıza Soylu b, Mustafa Adem Yılmaztepe c, Serap Baysal d, Elif Umit e, Hasan Umit b, Ahmet Tezel b, Ahmet Muzaffer Demir e a
Department of Internal Medicine, Trakya University, Medical Faculty, Edirne, Turkey Department of Gastroenterology, Trakya University, Medical Faculty, Edirne, Turkey Department of Cardiology, Trakya University, Medical Faculty, Edirne, Turkey d Department of Public Health, Trakya University, Medical Faculty, Edirne, Turkey e Department of Haematology, Trakya University, Medical Faculty, Edirne, Turkey b c
a r t i c l e
i n f o
Article history: Received 30 July 2018 Accepted 26 January 2020 Available online xxxx Keywords: Cirrhosis Autonomic dysfunction Diastolic dysfunction Health-related quality of life
a b s t r a c t Background and study aims: Cirrhosis is a multisystem disorder characterized by hyperdynamic circulation which can progress to multiple organ dysfunctions. Recent studies have demonstrated autonomic dysfunction and cirrhotic cardiomyopathy including diastolic dysfunction, systolic dysfunction with electrophysiologic abnormalities in patients with cirrhosis. Due to the long and complicated course of the disease, health related quality of life is affected. We aimed to evaluate the frequency of diastolic dysfunction and autonomic dysfunction in cirrhosis, and the effects on health-related quality of life. Patients and methods: Hundred cirrhotic patients were enrolled in the study. According to the Child-Pugh classification 35 patients were of Child A, 36 of Child B and 29 of Child C. The proportion of autonomic dysfunction was 52%, and diastolic dysfunction 51%. Autonomic dysfunction was diagnosed using bedside maneuvers and tests; diastolic dysfunction was diagnosed using the E/A ratio in echocardiographic findings. Health-related quality of life measurements was obtained from an SF-36 questionnaire. Results: Patients with advanced Child-Pugh classifications were found to have significantly lower healthrelated quality of life values (p < 0.05). Likewise, health-related quality of life values were observed to be significantly lower in patients with autonomic dysfunction (p < 0.05). No significant difference was found in health related quality of life measurements between patients with and without diastolic dysfunction. Conclusion: Our study showed that autonomic dysfunction and diastolic dysfunction are found in patients with cirrhosis. Further studies are needed to assess the effects of autonomic dysfunction and diastolic dysfunction on health-related quality of life. Ó 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Cirrhosis is characterized by decreased peripheral vascular resistance, high cardiac output, increased blood volume and complex cardiovascular abnormalities [1]. Systemic haemodynamic changes in cirrhosis are well known since the 1950s. According to the peripheral arterial vasodilation theory, splanchnic arterial vasodilation occurs as a result of reduced effective blood volume and thus oedema and ascites formation takes place. Activation of neurohumoral pathways, volume and baroreceptors is observed in cirrhosis because of arterial underfilling and systemic hypoten-
⇑ Correspondence author at: Trakya University Faculty of Medicine, Department of Hematology, Balkan Yerleskesi, 22030 Edirne, Turkey. E-mail address: [email protected] (M. Baysal).
sion [2,3]. Autonomic dysfunction and cirrhotic cardiomyopathy can be seen in cirrhotic patients. Autonomic dysfunction was first recognized in patients with alcoholic cirrhosis. Several studies found a similar prevalence of autonomic dysfunction in cirrhotic patients with or without alcohol consumption [4,5]. Bedside tests and maneuvers have been introduced and standardized by Ewing and Clarke [6] to determine autonomic dysfunction or neuropathy. The term cirrhotic cardiomyopathy is well-defined in cirrhotic patients. Diastolic dysfunction, systolic dysfunction and electrophysiological abnormalities are the three components of cirrhotic cardiomyopathy. Diastolic dysfunction results from an increase in the extracellular matrix of the myocardium and myocardial mass, and consequently results in a loss of elastic properties and the occurrence of ventricular stiffness. Thus, as a result of these mechanisms, increased diastolic volume occurs in every diastole
https://doi.org/10.1016/j.ajg.2020.01.003 1687-1979/Ó 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
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M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
and there is also decreased ventricular compliance [7,8]. Diastolic dysfunction is best described as a decreased early-to-atrial wave ratio with conventional echocardiography [9,10]. Despite high cardiac output in cirrhosis, patients with systolic dysfunction are placed within the definition of cirrhotic cardiomyopathy. Despite maintaining adequate blood pressure and cardiac flow the heart cannot supply its own needs. In this case, left ventricular pressure, left ventricular ejection fraction (LVEF) and heart rate were shown to increase during physical exercise [11]. Systolic dysfunction can be recognized in echocardiography by determining LVEF. Hyperdynamic circulation in patients with cirrhosis is characterized by reduced systemic vascular resistance with normal or low arterial blood pressure. Cardiac output is primarily determined by venous return, heart contraction, and heart rate. The mechanisms are controlled by the autonomic nervous system but the vast majority of these physiological mechanisms are impaired in cirrhotic patients [12,13]. The autonomic nervous system consists of the sympathetic, the parasympathetic and the enteric nervous systems, and is responsible for the involuntary control of internal organs, smooth muscles and secretory glands. This system controls arterial pressure, bladder emptying, sweating, gastrointestinal motility, body temperature and many other activities. Since the autonomic nervous system supplies various organs, dysfunctions can be seen in various and multiple disorders and can have negative effects on a patient’s quality of life [14,15]. Autonomic dysfunction in patients with cirrhosis is characterized by abnormal circulatory regulation. Several factors contribute to the development of autonomic dysfunction in this condition. They include ethanol use, changes in lipid metabolism, vitamin E deficiency, immunological pathways and toxic metabolites affecting the nerves. The clinical picture of autonomic dysfunction is broad and symptoms like hypotension, fatigue and gastrointestinal motility changes can be observed. Thus, autonomic dysfunction places a burden on health-related quality of life in cirrhotic patients. However, the importance of autonomic dysfunction in liver cirrhosis, especially clinically, is not fully understood, and this issue is not addressed in clinical practice. At the same time, symptoms such as impaired bowel motility and hypotension in autonomic dysfunction are difficult to treat and are associated with medications such as beta blockers and lactulose, which are commonly used in cirrhotic patients [14,16]. In addition, chronic liver disease patients also suffer from fatigue, reduced self-esteem, difficulty in working, anxiety, depression and other emotional problems, and thus their quality of life and feelings of well-being are deeply affected. Health-related quality of life assesses the effects of a person’s physical condition on psychosocial functions. Health-related quality of life is a broad concept that encompasses many factors. Quality of life is assessed in order to measure health well-being, and in recent years this feature has attracted the attention of researchers at an increasing rate. In order to evaluate health-related quality of life, a number of scales such as WHOQOL (World Health Organization Quality Of Life Scale) and SF-36 (36-item short form) have been developed. There are also disease-specific quality of life scales. For example, CLDQ (Chronic Liver Disease Questionnaire) and LDQOL (Liver Disease Quality Of Life) are specific to chronic liver disease [17]. Studies conducted so far have consistently found that health-related quality of life is significantly lower in patients with chronic liver parenchymal disease. When cirrhosis and advanced liver diseases were evaluated, quality of life was found to be further reduced in cirrhotic patients [18,19]. In our study, we aimed to evaluate the frequency of autonomic dysfunction and cirrhotic cardiomyopathy in cirrhotic patients and its effects on their health-related quality of life.
Patients and methods Our study was performed in Trakya University Faculty of Medicine Department of Internal Medicine, the Department of Gastroenterology and the Department of Cardiology. This study was approved by the Medical Faculty of Trakya University Ethics Committee of non-invasive clinical researches on 05.06.2013. Our study was supported by TUBAP (Trakya University Scientific Research Projects Unit) project no. 2013-114. Informed Consent Forms were signed, which informed each participant about the study and certified that their consent was obtained. A descriptive case series study was conducted with patients diagnosed with cirrhosis admitted to our hospital’s gastroenterology department between 01.09.2013 and 01.09.2014. The diagnosis of liver cirrhosis was made by a histological examination of liver biopsy materials whenever the coagulation parameters of the patients permitted; otherwise by a combination of clinical, biochemical and various imaging techniques. A power analysis was performed to determine the sample size; and with 80% power and an alpha level of 0,05% a total of 100 cirrhotic patients was required for our study. Patients with cirrhosis who were suffering from arterial hypertension (diastolic blood pressure >90-mmHg and/or systolic blood pressure >140-mmHg), congestive heart failure, ischaemic/valvular or other aetiology due to chronic heart disease or diabetes mellitus were excluded. Ejection fraction (EF) was assessed using modified biplane Simpson’s method from the apical two and four chamber view. Corrected QT distance was calculated by drawing a 12-lead ECG of Nihon Kohden 6453 model calibrated in a calm room. Systolic dysfunction was determined by measuring EF on resting transthoracic echocardiography. Diastolic dysfunction was determined through left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-diastolic volume, left ventricular end-systolic volume, left atrium volume, right atrium pressure, early diastolic/atrial filling rate (E/ A), and median pulmonary artery pressure [20]. The short scale form of 36 (SF-36) items was answered by patients in terms of assessing health-related quality of life. Medical outcomes survey SF-36 measures health-related quality of life under eight domains of physical functioning, physical health, emotional functions, vitality, emotional well-being, social functioning, bodily pain, and general health; each of these domains range from 0 (poor health) to 100 (best health). Two summary scores are measured: Physical component summary and mental component summary. To assess parasympathetic functions, heart-rate response to Valsalva maneuver, heart-rate change during deep inspiration (maximum/minimum heart rate), and heart-rate response to standing (30:15 ratio) tests were performed. Blood pressure response to lifting the foot (systolic BP decline) was measured to assess sympathetic functions (Table 1). According to the results, patients were divided into four groups: 1. Normal 2. Early parasympathetic damage: One of three tests was abnormal 3. Definite parasympathetic damage: At least two of the three tests were abnormal 4. Combined sympathetic and parasympathetic damage: One or two sympathetic tests were abnormal Statistical calculations were performed using the software program SPSS PC Ver.22 (IBMÓ SPSS Inc. USA). Descriptive statistics were given as number, percentage and arithmetic mean ± standard deviation (minimum -maximum). The Chi-square test was used in
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
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M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx Table 1 Evaluation of autonomic neuropathy tests.
Tests that reflect parasympathetic functions Heart rate response to Valsalva maneuver Heart rate variability during deep inspiration (minimum maximum heart rate) Heart rate response to standing (30:15 rate) Tests that reflect sympathetic functions Blood pressure response to lifting the foot
Normal
Borderline
Abnormal
1.21 15 bpm
1.11–1.20 11–14 bpm
1.10 10 bpm
1.04
1.01–1.03
1.00
10 mmHg
11–29 mmHg
30 mmHg
the analysis of the cut-off variables for the statistical evaluation made in the analysis of continuous variables; the nonparametric t test (Mann-Whitney U) was used in the independent groups when the variables did not correspond to the normal distribution; nonparametric variance analysis (Kruskal-Wallis) was used in independent groups when the group number was three or more. In the analysis of continuous variables, the parametric t-test (Student T test) was used in independent groups when the variables were of normal distribution. Pearson correlation analysis was used because the data were distributed normally in the evaluation of the relationship among continuous variables. In all tests p < 0.05 was accepted as statistically significant. Results A total of 100 patients with liver cirrhosis were included in the study, 25 of whom were females and 75 were males. 35 patients were found to be of Child A, 36 patients were of Child B, and 29 patients of Child C. Hepatitis B was diagnosed in 46 patients, alcoholic cirrhosis in 22 patients, cryptogenic chronic liver disease in 15 patients and hepatitis C in 5 patients (Table 2). Of the 100 cirrhotic patients, 52 had autonomic dysfunction, 48 were found to be normal, 21 had early parasympathetic damage, and 17 had definite parasympathetic damage. A total of 14 patients had both sympathetic and parasympathetic injuries (Table 3). The SF-36 scores of patients is presented in Table 4. In our study, patients were evaluated for diastolic dysfunction according to E/A ratio. Fifty-one patients with an E/A ratio of less than 1 had diastolic dysfunction diagnosed according to the study, while 49 patients had no diastolic dysfunction (above E/A > 1).
Table 2 Demographic and aetiologic data of the patients. Characteristics
Data
Age (mean ± SD) Sex (female/male) Child-Pugh Score A B C Etiology Hepatitis B Ethanol Cryptogenic Hepatitis C Other causes Mean MELD score (mean ± SD)
59.39 ± 10.1 25/75 n (%) 35 (%35) 36 (%36) 29 (%29) n (%) 46 (%46) 22 (%22) 15 (%15) 6 (%6) 11 (%11) 14.28 ± 5.5
Table 4 SF-36 scores of the patients. Physical Functioning Physical Role Bodily Pain General Health Vitality Social Functioning Emotional Role Mental Health Physical Component Summary Mental Component Summary
± ± ± ± ± ± ± ± ± ±
25.3 34.9 24.3 13.4 19.6 29.9 35.2 20.0 19.4 19.4
Patients with autonomic dysfunction were found to have lower scores for physical functioning, general health, vitality, social functioning, mental health, physical component summary and mental component summary scores of SF-36 subgroups compared with patients with no autonomic dysfunction (Table 5). There was a statistically significant difference in the presence of autonomic dysfunction by Child classification (p < 0.05, Table 6). When the Child-Pugh classification of 48 patients without autonomic dysfunction was examined, it was observed that 24 patients were of Child A, 13 patients of Child B, and 11 patients of Child C. No difference was found in health-related quality of life measurements between patients with and without diastolic dysfunction (Table 7). Table 5 Distribution of patients’ quality of life scores according to autonomic dysfunction. SF-36 Items
Autonomic Dysfunction (N = 52)
Normal (N = 48)
P value
Physical Functioning Physical Role Bodily Pain General Health Vitality Social Functioning Emotional Role Mental Health Physical Component Summary Mental Component Summary
48.08 23.56 60.43 41.25 39.96 53.22 29.48 51.85 43.33 43.63
58.33 36.46 67.03 46.56 49.38 65.94 32.64 59.56 52.10 51.88
0.042 0.065 0.176 0.047 0.016 0.017 0.442 0.018 0.028 0.033
± ± ± ± ± ± ± ± ± ±
25.5 31.9 23.6 10.9 19.1 25.2 35.9 16.6 18.1 19.08
± ± ± ± ± ± ± ± ± ±
24.3 37.2 24.8 15.3 19.2 27.3 34.7 15.4 21.1 19.12
Table 6 Presence of autonomic dysfunction according to the patients’ Child classification.
48 21 17 14
Child A Child B Child C Total
p* value
Autonomic Dysfunction (n = 52)
No Autonomic Dysfunction (n = 48)
Table 3 Results of the patients according to autonomic dysfunction tests. Normal Early parasympathetic injury Severe parasympathetic injury Combined sympathetic and parasympathetic damage
53.00 29.75 63.59 43.80 44.48 59.32 30.99 47.53 47.58 47.58
Number
%
Number
%
24 13 11 48
50 27.1 22.9 100
11 23 18 52
21.2 44.2 34.6 100
0.010
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
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M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
Table 7 Distribution of patients’ quality of life scores according to diastolic dysfunction. SF-36 Items
Diastolic Dysfunction (N = 51) Mean ± SD
Normal (N = 49) Mean ± SD
P value
Physical Functioning Physical Role Bodily Pain General Health Vitality Social Functioning Emotional Role Mental Health Physical Component Summary Mental Component Summary
48.23 29.41 59.90 42.94 41.86 53.97 27.44 53.35 45.12
57.96 30.10 67.45 44.69 47.20 64.90 34.69 57.84 50.05
23.7 37.1 22.0 12.5 15.9 26.2 36.0 14.5 18.6
0.054 0.852 0.120 0.516 0.175 0.088 0.215 0.174 0.220
51.16 ± 17.2
0.072
± ± ± ± ± ± ± ± ±
28.1 33.1 25.9 14.3 22.5 26.6 34.4 17.9 21.1
44.18 ± 21.0
± ± ± ± ± ± ± ± ±
Discussion The autonomic nervous system plays a critical role in regulating cardiac performance and vasomotor activity. In cirrhotic patients, disorders in autonomic cardiovascular reflexes have been shown [21]. The prevalence and severity of autonomic dysfunction was found to increase with the progression of hepatic dysfunction [22]. Up to 80% of patients with advanced cirrhosis had evidence of autonomic dysfunction [23]. The prevalence of autonomic dysfunction was found to be the same in patients with alcoholic cirrhosis and cirrhosis caused by other a etiologies. This finding strongly suggests that autonomic dysfunction is not only due to the toxic effects of ethanol [24,25]. Bajaj et al., in a study with 20 cirrhotic patients, found that 16 of the 20 participants with at least one autonomic dysfunction tested positive for abnormality. Early parasympathetic damage was found in three patients, permanent parasympathetic damage was found in five patients, and in eight patients combined parasympathetic and sympathetic damage was found [4]. Another study by Thuluth et al. found autonomic dysfunction in 43% of cirrhotic patients [26]. In a further study, Hendrickes et al. found vagal neuropathy in 45% of 60 cirrhotic patients [27]. The frequency of autonomic dysfunction in our study was 52%, which is similar to other studies. In addition, statistical analysis comparing autonomic dysfunction with Child classification was statistically significant (p = 0.010). This finding suggests that autonomic dysfunction is more common in advanced stage liver cirrhosis. In the early stages of cirrhosis, the decrease in systemic vascular resistance is compensated for by an increase in heart rate and cardiac output. However, once the disease progresses, peripheral arterial vasodilation increases and the vasodilation neutralizes the cardiac response. In this case a modest decrease in cardiac output is found. This unresponsiveness seen in the myocardium is described as cirrhotic cardiomyopathy. Cirrhotic cardiomyopathy shows normal or increased left ventricular systolic contractility at rest, but there is an increase in serum markers reflecting electrophysiological abnormalities such as decreased systolic or diastolic responses to stress stimulation, corrected QT time elongation, histologic structural changes in the cardiac structure and cardiac stress status [23,28,29]. Cirrhotic cardiomyopathy is manifested by systolic dysfunction, diastolic dysfunction, structural changes in the left side of the heart, electrophysiological abnormalities, autonomic dysfunction and chronotropic incompetence. The main function seen during diastole is the rapid filling of the ventricle with blood; the factors that determine diastolic dysfunction are pressure, volume, and mechanical factors in the ventricle. Normal diastolic filling has both passive and active components. Echocardiographically, these components can be measured by the E wave measurement, which
shows the speed of blood movement during early diastolic filling, and the A wave measurement, which shows atrial contraction during late diastole. As a result, the E/A ratio is frequently used as a parameter to show diastolic dysfunction frequency [9,30–32]. Diastolic dysfunction is the most prominent feature of cirrhotic cardiomyopathy. According to the description at the World Congress of Gastroenterology in 2005, diastolic dysfunction is diagnosed if the E/A ratio is less than 1, E wave is greater than 200 ms (DT) and isovolumetric relaxation time (IVRT) is greater than 80 ms. The prevalence of diastolic dysfunction was reported as 52% and 58% in two recent studies [33,34]. Our results were consistent with these studies, finding 51% of cirrhotic patients with diastolic dysfunction. In another recent study, the frequency of cirrhotic cardiomyopathy was found to be 39.32% of cirrhotic patients and diastolic dysfunction was present in all patients with cirrhotic cardiomyopathy [35]. In a recent study by Ruiz-del-Arbol et al., diastolic dysfunction was related to the severity of liver disease [36]. In our study autonomic dysfunction is associated with the degree of severity of liver disease, but not diastolic dysfunction. This may be due to the limited sample size. In many studies, it has been argued that cirrhotic cardiomyopathy may arise as a response to the stress state, and the prognosis for patients with asymptomatic cardiac insufficiency has yet to be determined. In this context, we evaluated the systolic and diastolic dysfunction of cirrhotic cardiomyopathy without stress response. Due to the long course of cirrhosis and the prevalence of symptoms that seriously affect the quality of life as the disease progresses, the measurement of quality of life in patients with cirrhosis is crucial to the understanding the nature of the disease and its impact on individuals. In addition, understanding the factors that lead to a deterioration of quality of life in terms of new treatment approaches is beneficial in revealing the points that can be a potential target for attention, and in revealing whether health-service provision is sufficient. Studies in chronic liver disease have clearly demonstrated that health-related quality of life is lower in both cirrhotic and non-cirrhotic patients compared with control or normal populations [37]. A number of studies have been conducted to evaluate the impact of the severity of the disease on health-related quality of life. These studies have revealed that as health conditions deteriorates, health-related quality of life scores decrease. In a cohort of 1300 patients with chronic liver disease, patients with cirrhosis Child class B and C were found to have lower SF-36 scores than those with Child A class. This has also been shown in other studies. In addition, three studies showed only low physical health status and its sub-titles in the Child B and C groups compared with the Child A group. It is noteworthy that these three studies were conducted with a lower number of patients than the other studies [17,38,39]. In our study, it was observed that all quality of life scores of patients decreased as the Child class increased. In order to demonstrate autonomic dysfunction and neuropathy, five tests were first described by Ewing and Clarke, and four of these were used in our study. For technical reasons, the bloodpressure response to palm squeezing could not be used when we were working. E/A ratio, E wave deceleration time (DT) and isovolumetric relaxation time (IVRT) were defined in 2005 as echocardiographic parameters in order to demonstrate echocardiographic diastolic dysfunction and cirrhotic cardiomyopathy. In our study, only the E/A ratio was evaluated from these parameters. These two conditions stand as a limitation of our work. In conclusion, cirrhotic patients with autonomic dysfunction were found to have lower physical function, general health status, vitality, social function, mental health, physical health status and mental health status. In the literature, no studies evaluating the health-related quality of life effects of autonomic dysfunction in cirrhotic patients have been found. Our study has shown that autonomic dysfunction and diastolic dysfunction are frequently found
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
in patients with cirrhosis. Both conditions are important and masked in cirrhotic patients in normal situations. In particular, autonomic dysfunction can be associated with quality of life impairments, and further comprehensive studies are needed to assess the health-related quality of life effects of autonomous dysfunction.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original article
Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients Mehmet Baysal a,⇑, Yıldız Ortaburun a, Ali Rıza Soylu b, Mustafa Adem Yılmaztepe c, Serap Baysal d, Elif Umit e, Hasan Umit b, Ahmet Tezel b, Ahmet Muzaffer Demir e a
Department of Internal Medicine, Trakya University, Medical Faculty, Edirne, Turkey Department of Gastroenterology, Trakya University, Medical Faculty, Edirne, Turkey Department of Cardiology, Trakya University, Medical Faculty, Edirne, Turkey d Department of Public Health, Trakya University, Medical Faculty, Edirne, Turkey e Department of Haematology, Trakya University, Medical Faculty, Edirne, Turkey b c
a r t i c l e
i n f o
Article history: Received 30 July 2018 Accepted 26 January 2020 Available online xxxx Keywords: Cirrhosis Autonomic dysfunction Diastolic dysfunction Health-related quality of life
a b s t r a c t Background and study aims: Cirrhosis is a multisystem disorder characterized by hyperdynamic circulation which can progress to multiple organ dysfunctions. Recent studies have demonstrated autonomic dysfunction and cirrhotic cardiomyopathy including diastolic dysfunction, systolic dysfunction with electrophysiologic abnormalities in patients with cirrhosis. Due to the long and complicated course of the disease, health related quality of life is affected. We aimed to evaluate the frequency of diastolic dysfunction and autonomic dysfunction in cirrhosis, and the effects on health-related quality of life. Patients and methods: Hundred cirrhotic patients were enrolled in the study. According to the Child-Pugh classification 35 patients were of Child A, 36 of Child B and 29 of Child C. The proportion of autonomic dysfunction was 52%, and diastolic dysfunction 51%. Autonomic dysfunction was diagnosed using bedside maneuvers and tests; diastolic dysfunction was diagnosed using the E/A ratio in echocardiographic findings. Health-related quality of life measurements was obtained from an SF-36 questionnaire. Results: Patients with advanced Child-Pugh classifications were found to have significantly lower healthrelated quality of life values (p < 0.05). Likewise, health-related quality of life values were observed to be significantly lower in patients with autonomic dysfunction (p < 0.05). No significant difference was found in health related quality of life measurements between patients with and without diastolic dysfunction. Conclusion: Our study showed that autonomic dysfunction and diastolic dysfunction are found in patients with cirrhosis. Further studies are needed to assess the effects of autonomic dysfunction and diastolic dysfunction on health-related quality of life. Ó 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Cirrhosis is characterized by decreased peripheral vascular resistance, high cardiac output, increased blood volume and complex cardiovascular abnormalities [1]. Systemic haemodynamic changes in cirrhosis are well known since the 1950s. According to the peripheral arterial vasodilation theory, splanchnic arterial vasodilation occurs as a result of reduced effective blood volume and thus oedema and ascites formation takes place. Activation of neurohumoral pathways, volume and baroreceptors is observed in cirrhosis because of arterial underfilling and systemic hypoten-
⇑ Correspondence author at: Trakya University Faculty of Medicine, Department of Hematology, Balkan Yerleskesi, 22030 Edirne, Turkey. E-mail address: [email protected] (M. Baysal).
sion [2,3]. Autonomic dysfunction and cirrhotic cardiomyopathy can be seen in cirrhotic patients. Autonomic dysfunction was first recognized in patients with alcoholic cirrhosis. Several studies found a similar prevalence of autonomic dysfunction in cirrhotic patients with or without alcohol consumption [4,5]. Bedside tests and maneuvers have been introduced and standardized by Ewing and Clarke [6] to determine autonomic dysfunction or neuropathy. The term cirrhotic cardiomyopathy is well-defined in cirrhotic patients. Diastolic dysfunction, systolic dysfunction and electrophysiological abnormalities are the three components of cirrhotic cardiomyopathy. Diastolic dysfunction results from an increase in the extracellular matrix of the myocardium and myocardial mass, and consequently results in a loss of elastic properties and the occurrence of ventricular stiffness. Thus, as a result of these mechanisms, increased diastolic volume occurs in every diastole
https://doi.org/10.1016/j.ajg.2020.01.003 1687-1979/Ó 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
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M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
and there is also decreased ventricular compliance [7,8]. Diastolic dysfunction is best described as a decreased early-to-atrial wave ratio with conventional echocardiography [9,10]. Despite high cardiac output in cirrhosis, patients with systolic dysfunction are placed within the definition of cirrhotic cardiomyopathy. Despite maintaining adequate blood pressure and cardiac flow the heart cannot supply its own needs. In this case, left ventricular pressure, left ventricular ejection fraction (LVEF) and heart rate were shown to increase during physical exercise [11]. Systolic dysfunction can be recognized in echocardiography by determining LVEF. Hyperdynamic circulation in patients with cirrhosis is characterized by reduced systemic vascular resistance with normal or low arterial blood pressure. Cardiac output is primarily determined by venous return, heart contraction, and heart rate. The mechanisms are controlled by the autonomic nervous system but the vast majority of these physiological mechanisms are impaired in cirrhotic patients [12,13]. The autonomic nervous system consists of the sympathetic, the parasympathetic and the enteric nervous systems, and is responsible for the involuntary control of internal organs, smooth muscles and secretory glands. This system controls arterial pressure, bladder emptying, sweating, gastrointestinal motility, body temperature and many other activities. Since the autonomic nervous system supplies various organs, dysfunctions can be seen in various and multiple disorders and can have negative effects on a patient’s quality of life [14,15]. Autonomic dysfunction in patients with cirrhosis is characterized by abnormal circulatory regulation. Several factors contribute to the development of autonomic dysfunction in this condition. They include ethanol use, changes in lipid metabolism, vitamin E deficiency, immunological pathways and toxic metabolites affecting the nerves. The clinical picture of autonomic dysfunction is broad and symptoms like hypotension, fatigue and gastrointestinal motility changes can be observed. Thus, autonomic dysfunction places a burden on health-related quality of life in cirrhotic patients. However, the importance of autonomic dysfunction in liver cirrhosis, especially clinically, is not fully understood, and this issue is not addressed in clinical practice. At the same time, symptoms such as impaired bowel motility and hypotension in autonomic dysfunction are difficult to treat and are associated with medications such as beta blockers and lactulose, which are commonly used in cirrhotic patients [14,16]. In addition, chronic liver disease patients also suffer from fatigue, reduced self-esteem, difficulty in working, anxiety, depression and other emotional problems, and thus their quality of life and feelings of well-being are deeply affected. Health-related quality of life assesses the effects of a person’s physical condition on psychosocial functions. Health-related quality of life is a broad concept that encompasses many factors. Quality of life is assessed in order to measure health well-being, and in recent years this feature has attracted the attention of researchers at an increasing rate. In order to evaluate health-related quality of life, a number of scales such as WHOQOL (World Health Organization Quality Of Life Scale) and SF-36 (36-item short form) have been developed. There are also disease-specific quality of life scales. For example, CLDQ (Chronic Liver Disease Questionnaire) and LDQOL (Liver Disease Quality Of Life) are specific to chronic liver disease [17]. Studies conducted so far have consistently found that health-related quality of life is significantly lower in patients with chronic liver parenchymal disease. When cirrhosis and advanced liver diseases were evaluated, quality of life was found to be further reduced in cirrhotic patients [18,19]. In our study, we aimed to evaluate the frequency of autonomic dysfunction and cirrhotic cardiomyopathy in cirrhotic patients and its effects on their health-related quality of life.
Patients and methods Our study was performed in Trakya University Faculty of Medicine Department of Internal Medicine, the Department of Gastroenterology and the Department of Cardiology. This study was approved by the Medical Faculty of Trakya University Ethics Committee of non-invasive clinical researches on 05.06.2013. Our study was supported by TUBAP (Trakya University Scientific Research Projects Unit) project no. 2013-114. Informed Consent Forms were signed, which informed each participant about the study and certified that their consent was obtained. A descriptive case series study was conducted with patients diagnosed with cirrhosis admitted to our hospital’s gastroenterology department between 01.09.2013 and 01.09.2014. The diagnosis of liver cirrhosis was made by a histological examination of liver biopsy materials whenever the coagulation parameters of the patients permitted; otherwise by a combination of clinical, biochemical and various imaging techniques. A power analysis was performed to determine the sample size; and with 80% power and an alpha level of 0,05% a total of 100 cirrhotic patients was required for our study. Patients with cirrhosis who were suffering from arterial hypertension (diastolic blood pressure >90-mmHg and/or systolic blood pressure >140-mmHg), congestive heart failure, ischaemic/valvular or other aetiology due to chronic heart disease or diabetes mellitus were excluded. Ejection fraction (EF) was assessed using modified biplane Simpson’s method from the apical two and four chamber view. Corrected QT distance was calculated by drawing a 12-lead ECG of Nihon Kohden 6453 model calibrated in a calm room. Systolic dysfunction was determined by measuring EF on resting transthoracic echocardiography. Diastolic dysfunction was determined through left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-diastolic volume, left ventricular end-systolic volume, left atrium volume, right atrium pressure, early diastolic/atrial filling rate (E/ A), and median pulmonary artery pressure [20]. The short scale form of 36 (SF-36) items was answered by patients in terms of assessing health-related quality of life. Medical outcomes survey SF-36 measures health-related quality of life under eight domains of physical functioning, physical health, emotional functions, vitality, emotional well-being, social functioning, bodily pain, and general health; each of these domains range from 0 (poor health) to 100 (best health). Two summary scores are measured: Physical component summary and mental component summary. To assess parasympathetic functions, heart-rate response to Valsalva maneuver, heart-rate change during deep inspiration (maximum/minimum heart rate), and heart-rate response to standing (30:15 ratio) tests were performed. Blood pressure response to lifting the foot (systolic BP decline) was measured to assess sympathetic functions (Table 1). According to the results, patients were divided into four groups: 1. Normal 2. Early parasympathetic damage: One of three tests was abnormal 3. Definite parasympathetic damage: At least two of the three tests were abnormal 4. Combined sympathetic and parasympathetic damage: One or two sympathetic tests were abnormal Statistical calculations were performed using the software program SPSS PC Ver.22 (IBMÓ SPSS Inc. USA). Descriptive statistics were given as number, percentage and arithmetic mean ± standard deviation (minimum -maximum). The Chi-square test was used in
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
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M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx Table 1 Evaluation of autonomic neuropathy tests.
Tests that reflect parasympathetic functions Heart rate response to Valsalva maneuver Heart rate variability during deep inspiration (minimum maximum heart rate) Heart rate response to standing (30:15 rate) Tests that reflect sympathetic functions Blood pressure response to lifting the foot
Normal
Borderline
Abnormal
1.21 15 bpm
1.11–1.20 11–14 bpm
1.10 10 bpm
1.04
1.01–1.03
1.00
10 mmHg
11–29 mmHg
30 mmHg
the analysis of the cut-off variables for the statistical evaluation made in the analysis of continuous variables; the nonparametric t test (Mann-Whitney U) was used in the independent groups when the variables did not correspond to the normal distribution; nonparametric variance analysis (Kruskal-Wallis) was used in independent groups when the group number was three or more. In the analysis of continuous variables, the parametric t-test (Student T test) was used in independent groups when the variables were of normal distribution. Pearson correlation analysis was used because the data were distributed normally in the evaluation of the relationship among continuous variables. In all tests p < 0.05 was accepted as statistically significant. Results A total of 100 patients with liver cirrhosis were included in the study, 25 of whom were females and 75 were males. 35 patients were found to be of Child A, 36 patients were of Child B, and 29 patients of Child C. Hepatitis B was diagnosed in 46 patients, alcoholic cirrhosis in 22 patients, cryptogenic chronic liver disease in 15 patients and hepatitis C in 5 patients (Table 2). Of the 100 cirrhotic patients, 52 had autonomic dysfunction, 48 were found to be normal, 21 had early parasympathetic damage, and 17 had definite parasympathetic damage. A total of 14 patients had both sympathetic and parasympathetic injuries (Table 3). The SF-36 scores of patients is presented in Table 4. In our study, patients were evaluated for diastolic dysfunction according to E/A ratio. Fifty-one patients with an E/A ratio of less than 1 had diastolic dysfunction diagnosed according to the study, while 49 patients had no diastolic dysfunction (above E/A > 1).
Table 2 Demographic and aetiologic data of the patients. Characteristics
Data
Age (mean ± SD) Sex (female/male) Child-Pugh Score A B C Etiology Hepatitis B Ethanol Cryptogenic Hepatitis C Other causes Mean MELD score (mean ± SD)
59.39 ± 10.1 25/75 n (%) 35 (%35) 36 (%36) 29 (%29) n (%) 46 (%46) 22 (%22) 15 (%15) 6 (%6) 11 (%11) 14.28 ± 5.5
Table 4 SF-36 scores of the patients. Physical Functioning Physical Role Bodily Pain General Health Vitality Social Functioning Emotional Role Mental Health Physical Component Summary Mental Component Summary
± ± ± ± ± ± ± ± ± ±
25.3 34.9 24.3 13.4 19.6 29.9 35.2 20.0 19.4 19.4
Patients with autonomic dysfunction were found to have lower scores for physical functioning, general health, vitality, social functioning, mental health, physical component summary and mental component summary scores of SF-36 subgroups compared with patients with no autonomic dysfunction (Table 5). There was a statistically significant difference in the presence of autonomic dysfunction by Child classification (p < 0.05, Table 6). When the Child-Pugh classification of 48 patients without autonomic dysfunction was examined, it was observed that 24 patients were of Child A, 13 patients of Child B, and 11 patients of Child C. No difference was found in health-related quality of life measurements between patients with and without diastolic dysfunction (Table 7). Table 5 Distribution of patients’ quality of life scores according to autonomic dysfunction. SF-36 Items
Autonomic Dysfunction (N = 52)
Normal (N = 48)
P value
Physical Functioning Physical Role Bodily Pain General Health Vitality Social Functioning Emotional Role Mental Health Physical Component Summary Mental Component Summary
48.08 23.56 60.43 41.25 39.96 53.22 29.48 51.85 43.33 43.63
58.33 36.46 67.03 46.56 49.38 65.94 32.64 59.56 52.10 51.88
0.042 0.065 0.176 0.047 0.016 0.017 0.442 0.018 0.028 0.033
± ± ± ± ± ± ± ± ± ±
25.5 31.9 23.6 10.9 19.1 25.2 35.9 16.6 18.1 19.08
± ± ± ± ± ± ± ± ± ±
24.3 37.2 24.8 15.3 19.2 27.3 34.7 15.4 21.1 19.12
Table 6 Presence of autonomic dysfunction according to the patients’ Child classification.
48 21 17 14
Child A Child B Child C Total
p* value
Autonomic Dysfunction (n = 52)
No Autonomic Dysfunction (n = 48)
Table 3 Results of the patients according to autonomic dysfunction tests. Normal Early parasympathetic injury Severe parasympathetic injury Combined sympathetic and parasympathetic damage
53.00 29.75 63.59 43.80 44.48 59.32 30.99 47.53 47.58 47.58
Number
%
Number
%
24 13 11 48
50 27.1 22.9 100
11 23 18 52
21.2 44.2 34.6 100
0.010
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
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M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
Table 7 Distribution of patients’ quality of life scores according to diastolic dysfunction. SF-36 Items
Diastolic Dysfunction (N = 51) Mean ± SD
Normal (N = 49) Mean ± SD
P value
Physical Functioning Physical Role Bodily Pain General Health Vitality Social Functioning Emotional Role Mental Health Physical Component Summary Mental Component Summary
48.23 29.41 59.90 42.94 41.86 53.97 27.44 53.35 45.12
57.96 30.10 67.45 44.69 47.20 64.90 34.69 57.84 50.05
23.7 37.1 22.0 12.5 15.9 26.2 36.0 14.5 18.6
0.054 0.852 0.120 0.516 0.175 0.088 0.215 0.174 0.220
51.16 ± 17.2
0.072
± ± ± ± ± ± ± ± ±
28.1 33.1 25.9 14.3 22.5 26.6 34.4 17.9 21.1
44.18 ± 21.0
± ± ± ± ± ± ± ± ±
Discussion The autonomic nervous system plays a critical role in regulating cardiac performance and vasomotor activity. In cirrhotic patients, disorders in autonomic cardiovascular reflexes have been shown [21]. The prevalence and severity of autonomic dysfunction was found to increase with the progression of hepatic dysfunction [22]. Up to 80% of patients with advanced cirrhosis had evidence of autonomic dysfunction [23]. The prevalence of autonomic dysfunction was found to be the same in patients with alcoholic cirrhosis and cirrhosis caused by other a etiologies. This finding strongly suggests that autonomic dysfunction is not only due to the toxic effects of ethanol [24,25]. Bajaj et al., in a study with 20 cirrhotic patients, found that 16 of the 20 participants with at least one autonomic dysfunction tested positive for abnormality. Early parasympathetic damage was found in three patients, permanent parasympathetic damage was found in five patients, and in eight patients combined parasympathetic and sympathetic damage was found [4]. Another study by Thuluth et al. found autonomic dysfunction in 43% of cirrhotic patients [26]. In a further study, Hendrickes et al. found vagal neuropathy in 45% of 60 cirrhotic patients [27]. The frequency of autonomic dysfunction in our study was 52%, which is similar to other studies. In addition, statistical analysis comparing autonomic dysfunction with Child classification was statistically significant (p = 0.010). This finding suggests that autonomic dysfunction is more common in advanced stage liver cirrhosis. In the early stages of cirrhosis, the decrease in systemic vascular resistance is compensated for by an increase in heart rate and cardiac output. However, once the disease progresses, peripheral arterial vasodilation increases and the vasodilation neutralizes the cardiac response. In this case a modest decrease in cardiac output is found. This unresponsiveness seen in the myocardium is described as cirrhotic cardiomyopathy. Cirrhotic cardiomyopathy shows normal or increased left ventricular systolic contractility at rest, but there is an increase in serum markers reflecting electrophysiological abnormalities such as decreased systolic or diastolic responses to stress stimulation, corrected QT time elongation, histologic structural changes in the cardiac structure and cardiac stress status [23,28,29]. Cirrhotic cardiomyopathy is manifested by systolic dysfunction, diastolic dysfunction, structural changes in the left side of the heart, electrophysiological abnormalities, autonomic dysfunction and chronotropic incompetence. The main function seen during diastole is the rapid filling of the ventricle with blood; the factors that determine diastolic dysfunction are pressure, volume, and mechanical factors in the ventricle. Normal diastolic filling has both passive and active components. Echocardiographically, these components can be measured by the E wave measurement, which
shows the speed of blood movement during early diastolic filling, and the A wave measurement, which shows atrial contraction during late diastole. As a result, the E/A ratio is frequently used as a parameter to show diastolic dysfunction frequency [9,30–32]. Diastolic dysfunction is the most prominent feature of cirrhotic cardiomyopathy. According to the description at the World Congress of Gastroenterology in 2005, diastolic dysfunction is diagnosed if the E/A ratio is less than 1, E wave is greater than 200 ms (DT) and isovolumetric relaxation time (IVRT) is greater than 80 ms. The prevalence of diastolic dysfunction was reported as 52% and 58% in two recent studies [33,34]. Our results were consistent with these studies, finding 51% of cirrhotic patients with diastolic dysfunction. In another recent study, the frequency of cirrhotic cardiomyopathy was found to be 39.32% of cirrhotic patients and diastolic dysfunction was present in all patients with cirrhotic cardiomyopathy [35]. In a recent study by Ruiz-del-Arbol et al., diastolic dysfunction was related to the severity of liver disease [36]. In our study autonomic dysfunction is associated with the degree of severity of liver disease, but not diastolic dysfunction. This may be due to the limited sample size. In many studies, it has been argued that cirrhotic cardiomyopathy may arise as a response to the stress state, and the prognosis for patients with asymptomatic cardiac insufficiency has yet to be determined. In this context, we evaluated the systolic and diastolic dysfunction of cirrhotic cardiomyopathy without stress response. Due to the long course of cirrhosis and the prevalence of symptoms that seriously affect the quality of life as the disease progresses, the measurement of quality of life in patients with cirrhosis is crucial to the understanding the nature of the disease and its impact on individuals. In addition, understanding the factors that lead to a deterioration of quality of life in terms of new treatment approaches is beneficial in revealing the points that can be a potential target for attention, and in revealing whether health-service provision is sufficient. Studies in chronic liver disease have clearly demonstrated that health-related quality of life is lower in both cirrhotic and non-cirrhotic patients compared with control or normal populations [37]. A number of studies have been conducted to evaluate the impact of the severity of the disease on health-related quality of life. These studies have revealed that as health conditions deteriorates, health-related quality of life scores decrease. In a cohort of 1300 patients with chronic liver disease, patients with cirrhosis Child class B and C were found to have lower SF-36 scores than those with Child A class. This has also been shown in other studies. In addition, three studies showed only low physical health status and its sub-titles in the Child B and C groups compared with the Child A group. It is noteworthy that these three studies were conducted with a lower number of patients than the other studies [17,38,39]. In our study, it was observed that all quality of life scores of patients decreased as the Child class increased. In order to demonstrate autonomic dysfunction and neuropathy, five tests were first described by Ewing and Clarke, and four of these were used in our study. For technical reasons, the bloodpressure response to palm squeezing could not be used when we were working. E/A ratio, E wave deceleration time (DT) and isovolumetric relaxation time (IVRT) were defined in 2005 as echocardiographic parameters in order to demonstrate echocardiographic diastolic dysfunction and cirrhotic cardiomyopathy. In our study, only the E/A ratio was evaluated from these parameters. These two conditions stand as a limitation of our work. In conclusion, cirrhotic patients with autonomic dysfunction were found to have lower physical function, general health status, vitality, social function, mental health, physical health status and mental health status. In the literature, no studies evaluating the health-related quality of life effects of autonomic dysfunction in cirrhotic patients have been found. Our study has shown that autonomic dysfunction and diastolic dysfunction are frequently found
Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003
M. Baysal et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx
in patients with cirrhosis. Both conditions are important and masked in cirrhotic patients in normal situations. In particular, autonomic dysfunction can be associated with quality of life impairments, and further comprehensive studies are needed to assess the health-related quality of life effects of autonomous dysfunction.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Please cite this article as: M. Baysal, Y. Ortaburun, A. R. Soylu et al., Autonomic and diastolic dysfunction association with quality of life impairment in cirrhotic patients, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2020.01.003