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Curcumin ameliorates health-related quality of life in patients with liver cirrhosis: A randomized, double-blind placebo-controlled trial
Complementary Therapies in Medicine 49 (2020) 102351
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Curcumin ameliorates health-related quality of life in patients with liver cirrhosis: A randomized, double-blind placebo-controlled trial
T
Masoud Nouri-Vaskeha,b, Hossein Afshanc, Aida Malek Mahdavib,1,*, Leila Alizadehc,1,**, Xiude Fand,e, Mohammad Zareif,g a
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran c Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Infectious Diseases, The First Affiliated Hospital of Xi 'an Jiaotong University, Xi’an, 710061 China e Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, 44195, USA f Departrment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA g Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Curcumin Curcuma Quality of life End stage liver disease Liver cirrhosis
Objectives: Current study aimed to find the effects of curcumin on quality of life (QoL) in liver cirrhotic patients. Design: In this randomized double-masked placebo-controlled trial, 70 cases with liver cirrhosis aged 20–70 years were randomly divided into two groups to receive 1000 mg/day curcumin (n = 35) or placebo (n = 35) for 12 weeks. The health-related QoL (HRQoL) was assessed by CLDQ, LDSI 2.0, and SF-36. Results: Fifty-eight patients (28 in curcumin and 30 in placebo groups) finished the research. Compared with baseline, overall scores as well as most of CLDQ domains (e.g. Fatigue, Emotional Function, Worry, Abdominal Symptoms, and Systemic Symptoms) and the Physical and Mental health (Total) scores and most of SF-36 domains (e.g. Physical Functioning, Bodily Pain, Vitality, Social Functioning, and Mental Health) increased considerably (P < 0.05) after curcumin administration. Furthermore, curcumin reduced most of LDSI 2.0 domains (e.g. Itch, Joint pain, Pain in the right upper abdomen, Sleeping during the day, Decreased appetite, Depression, Fear of complication, Jaundice, Hindrance in Financial Affairs, Change in use of time, Decreased sexual interest, and Decreased sexual activity) significantly (P < 0.05). Significant differences were noticed between two groups in CLDQ domains and overall scores, LDSI 2.0 domains and overall scores, SF-36 Physical and Mental health (total) scores and all its domains scores (P < 0.05), adjusting for baseline values and disease duration. Conclusions: Curcumin improved QoL in liver cirrhotic patients according to CLDQ, LDSI 2.0, and SF-36 domains. Additional studies are warranted to consider curcumin as a safe, accessible, and low-cost complementary therapeutic option in cirrhosis.
1. Introduction Liver cirrhosis is the final outcome of various liver disorders associated with hepatic encephalopathy, ascites, peritonitis and gastrointestinal bleeding.1 Cirrhosis has become more prevalent in recent decades and it is a common cause of mortality all over the world.2 Liver cirrhosis has a progressive nature and coincides with physical and mental signs, thereby exerting a remarkable negative influence on quality of life (QoL).3–5 QoL, a concept that presents positive and negative features of a person’s life, has become important in various
gastrointestinal diseases including liver cirrhosis.3 The health-related QoL (HRQoL) is a multi-dimensional conception that contains self-reported physical and mental health measurements and social well-being, thereby becomes more significant in patients with cirrhosis.6 Various tools such as Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life Questionnaire (LDQOL), Liver Disease Symptom Index 2.0 (LDSI 2.0), and 36-Item Short Form Health Survey (SF-36) have been proposed to assess the impact of liver cirrhosis on HRQoL.7 According to the recent research, HRQoL is diminished in liver cirrhotic patients compared with healthy individuals.8–12 Thus, evaluating
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Corresponding author at: Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran. Corresponding author at: Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran. E-mail addresses: [email protected] (A. Malek Mahdavi), [email protected] (L. Alizadeh). 1 These authors contributed equally to this work. ⁎⁎
https://doi.org/10.1016/j.ctim.2020.102351 Received 21 December 2019; Received in revised form 16 February 2020; Accepted 18 February 2020 Available online 19 February 2020 0965-2299/ © 2020 Elsevier Ltd. All rights reserved.
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Fig. 1. Study Flow Diagram.
among individuals with primary sclerosing cholangitis (PSC) reported that curcumin was not associated with significant improvements in cholestasis or symptoms.38 Since HRQoL has become as one of the major points in current medicine and considering the importance of HRQoL for subjects with chronic liver ailments like cirrhosis and because no study exists regarding the curcumin and QoL in cases with liver cirrhosis, this research was carried out as the first investigation to find out the consequences of curcumin supplement on HRQoL in liver cirrhotic patients.
HRQoL is necessary in these patients and improving HRQoL is considered as a main part of disease management and has been shown to increase long-term survival in these patients.13 Furthermore, it has been indicated that appropriate therapy of ascites and encephalopathy can ameliorate HRQoL and augments the life span.3,14 Currently, there are no approved agents accessible for treatment of liver fibrosis as well as cirrhosis and conventional treatments usually have poor outcomes and impose great expenses for both families and societies; therefore, herbal therapies have recently been proposed as a potential useful therapy for cirrhosis. Curcumin, the main bioactive component of Curcuma longa L., has a variety of biological and pharmacological functions such as anti-inflammatory, antioxidant, anticarcinogenic, anti-angiogenic, antithrombotic, and etc. and has become the main topic of research in recent years.15,16 Curcumin is extensively used as a medicinal herb in different areas due to its safety and tolerability.17 It has gained attention as a promising agent for prevention and treatment of different hepatic ailments including liver fibrosis. Based on previous animal and in vitro research, curcumin had beneficial effects in liver injury and cirrhosis.18–27 It suppresses the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and inhibits inflammation, diminishes oxidative stress, and inhibiting angiogenesis, thereby can inhibit liver cirrhosis.28,29 Although no previous studies have been conducted regarding curcumin consumption and HRQoL in liver cirrhosis, there are some reports indicating that curcumin can improve QoL in various conditions like irritable bowel syndrome (IBS), chronic pulmonary problems, and cancer.30–34 Furthermore, there are some investigations stating that curcumin can improve hepatic steatosis and fibrosis in non-alcoholic fatty liver disease (NAFLD).35–37Another study
2. Patients and methods 2.1. Study design & subjects In a randomized, double-masked, placebo-controlled trial, seventy volunteer cases with liver cirrhosis aged 20–70 years with model for end-stage liver disease (MELD) score > 11 and arterial oxygen pressure > 60 mmHg were selected from gastroenterology outpatient clinic of Tabriz University of Medical Sciences between October 2018 and July 2019. Subjects with any history of malignancy, hepatopulmonary syndrome, pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg), hyperoxaluria, cystic fibrosis with FEV1 < 40 %, gallstones and/or bladder stones, use of anti-platelet and/or anti-coagulant medications and taking polyphenol supplements within three months before trial were not included. Our research protocol was accepted by the Medical Ethics Committee of Tabriz University of Medical Sciences (registration code: IR.TBZMED.REC.1397.660) and registered on the Iranian Registry of Clinical Trials (IRCT, registration code: IRCT20180802040678N1). 2
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Wilcoxon signed rank test were applied for within-group comparisons. Between-group comparisons were made by Chi square test, independent sample t-test, or Mann-Whitney U test, as appropriate. Analysis of covariance (ANCOVA) was used to find any differences between the two groups after the study. P < 0.05 was defined as statistical significance.
Study patients were informed about the research and signed a written consent. Qualified patients were randomly divided into intervention and placebo groups using a block randomization method (block size = 2), that matched cases to per block according to age, sex, and MELD score. To keep masking, an investigator with no involvement in the trial conducted the distribution. Moreover, participants and researchers were kept blind throughout the trial. Patients in the intervention group (n = 35) received an oral dose of 1000 mg/day (2 equal dosages of one 500 mg capsule) curcumin for 12 weeks (curcumin, Karen Pharmaceutical & Nutrilife Co., Yazd, Iran). The control group (n = 35) received placebo according to the same protocol (placebo, Karen Pharmaceutical & Nutrilife Co., Yazd, Iran). Placebo capsules comprised inactive ingredients with no curative property and were similar to supplements in shape and color. Subjects were advised to take the supplements with breakfast and dinner meals. Subjects were also requested to maintain their routine diet and physical activity throughout the trial. Subjects were followed-up every week for any unfavorable outcomes of curcumin consumption. Fig. 1 depicts a flowchart of research.
3. Results From 70 patients who enrolled to the trial, seven cases in the curcumin group and five cases in the placebo group were removed due to lost to follow-up and mortality. It should be mentioned that the cause of mortality was due to the severity of liver cirrhosis. Furthermore, lost to follow-up was due to the reasons irrelevant to the treatment (i.e., personel reason, being on vacation, having changed their location and thus not accessible). Thus, information was presented for 58 patients (28 in curcumin group and 30 in placebo group). Both groups did not differ significantly in terms of primary causes of liver cirrhosis and/or ingest of hepatoprotective substances. No adverse effect was declared with using curcumin or placebo throughout the trial. The means ± SD age and duration of liver cirrhosis were 46.21 ± 11.72 and 4.25 ± 2.98 years, respectively. Thirty subjects (52 %) were males and 28 (48 %) were females. As demonstrated in Table 1, baseline characteristics did not differ between two groups (P > 0.05).
2.2. HRQoL assessment At the beginning and at the end of trial, HRQoL was assessed by CLDQ, LDSI 2.0, and SF-36 questionnaires. The CLDQ is the primary liver-specific self-reported questionnaire with 29 items in six main domains named abdominal symptoms, fatigue, systemic symptoms, activity, emotional function and worry.39 All items were assessed on a 1–7 scale with “1’’ representing “all of the time’’ and “7’’ representing “none of the time’’, and higher scores indicated better HRQoL.39 Mahmoudi et al.40 translated CLDQ into Persian language which was a valid and reliable measurement of HRQoL (convergent validity: 100 %, discriminant validity: 95.8 %, and the Cronbach’s alpha coefficient: 0.650.89). The symptoms experienced by patients and undesirable consequences of these symptoms on daily activities were assessed using LDSI 2.0.41 The LDSI 2.0 was originated in Netherlands and included 24 items classified into two subscales including severity of symptoms and how symptoms affect persons’ daily and social functions. All items were assessed on a five-point Likert-type measure from 0 ‘not at all’ to 4 ‘to a high extent’. The total and subscales scores were computed by summing the subject’s answers (0–60 for the severity of signs, 0–36 for the impediment of symptoms and 0–96 for the overall). Higher scores indicated increasing symptoms severity and impediment.41 Saffari et al.41 translated LDSI 2.0 into Persian language which was a reliable and valid measure of HRQOL (the Cronbach’s alpha coefficients for total scale and subscales of symptom index were 0.896 and between 0.5910.821, respectively). SF-36 is another widely used scale for HRQOL which contains 8 subcategories: (a) Physical Functioning (10 items), (b) Social Functioning (2 items), (c) Role Physical (4 items), (d) Role Emotional (3 items), (e) Mental Health (5 items), (f) Vitality (4 items), (g) Bodily Pain (2 items), (h) General Health (5 items).3 Likert scale was used for rating all items except the third and fourth. The third and fourth items were yes or no questions. The scores given to each category ranged from 0 to 100, where 0 and 100 depicted the lowest and highest QoL, respectively.3 Montazeri et al.42 translated SF-36 into Persian language which was a reliable and valid measure of HRQoL (the Cronbach’s alpha coefficient: 0.77-0.90 and convergent validity: 0.58 to 0.95).
Table 1 Baseline characteristics of participants. Characteristics
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Age (years) Duration of liver cirrhosis (years) Sex, n (%) Male Female Causes of liver cirrhosis, n (%) Cryptogenic Autoimmune HBV HCV PSC PVT Alcoholic Fatty liver BMI (kg/m2), n (%) 18.5-24.9 25.0-29.9 30.0-34.9 ALT (IU/L), n (%) ≤40 > 40 AST (IU/L), n (%) ≤34 > 34 MELD Score classification, n (%) ≤9 10-19 20-29 Child Pugh score classification, n (%) A B C
46.00 ± 12.99 4.39 ± 2.86 14 (50) 14 (50)
46.40 ± 10.62 4.12 ± 3.13 16 (53) 14 (47)
0.898 0.728 0.800
10 (35.7) 8 (28.6) 3 (10.7) 2 (7.1) 2 (7.1) 2 (7.1) 1 (3.6) 0 (0.0)
7 8 4 2 2 2 3 2
(23.3) (26.7) (13.3) (6.7) (6.7) (6.7) (10.0) (6.7)
0.824
14 (50) 13 (46.4) 1 (3.6)
16 (53.3) 12 (40) 2 (6.7)
0.803
17 (60.7) 11 (39.3)
15 (50) 15 (50)
0.412
11 (39.3) 17 (60.7)
11 (36.7) 19 (63.3)
0.837
0 (0.0) 26 (92.9) 2 (7.1)
5 (16.7) 24 (80.0) 1 (3.3)
0.069
11 (39.3) 15 (53.6) 2 (7.1)
17 (56.7) 12 (40.0) 1 (3.3)
0.390
HBV, Hepatitis B virus; HCV, Hepatitis C virus; PSC, Primary sclerosing cholangitis; PVT, Portal vein thrombosis; BMI, Body mass index; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; MELD, Model for end-stage liver disease. Continuous variables were reported as mean ± SD while categorical variables were expressed as frequency (percentage). P < 0.05 was considered significant. * P values indicate comparison between groups (Independent-sample t-test or Chi square, as appropriate).
2.3. Statistical analysis Data were analyzed via SPSS software version 16.0 (SPSS Inc., Chicago, IL). Kolmogorov-Smirnov test was used for normality evaluation. Qualitative, normally, and non-normally quantitative parameters were stated as numbers (percentages), means ± SD, and median (Min-Max), respectively. Paired t-test and or non-parametric 3
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Table 2 Comparison of CLDQ domains and overall scores in treatment groups before and after study.
Table 3 Comparison of LDSI 2.0 domains scores in treatment groups before and after study.
Domain
Measurement Period
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Domain
Measurement Period
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Fatigue
Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P**
3.33 ± 0.94 3.86 ± 0.99 < 0.001 4.64 ± 0.76 4.87 ± 0.85 0.035 5.46 ± 0.83 5.77 ± 0.87 0.013 3.22 ± 1.26 3.95 ± 1.44 < 0.001 4.95 ± 0.82 4.99 ± 0.86 0.212 4.58 ± 0.90 5.15 ± 0.98 < 0.001 4.36 ± 0.69 4.76 ± 0.80 < 0.001
3.36 ± 0.87 3.10 ± 0.71 < 0.001 4.67 ± 0.75 4.36 ± 0.72 < 0.001 5.41 ± 0.85 4.96 ± 0.74 < 0.001 3.23 ± 1.19 2.79 ± 1.03 < 0.001 4.93 ± 0.81 4.54 ± 0.80 < 0.001 4.58 ± 0.81 4.29 ± 0.84 < 0.001 4.36 ± 0.64 4.01 ± 0.59 < 0.001
0.897 < 0.001
Itch
Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P**
1.48 ± 0.93 1.07 ± 1.02 0.003
1.45 ± 0.0.72 1.82 ± 0.56 < 0.001
0.874 < 0.001
0.42 ± 0.64 0.28 ± 0.55 0.030
0.26 ± 0.43 0.46 ± 0.64 0.063
0.272 0.017
2.44 ± 0.88 1.89 ± 0.78 < 0.001
2.36 ± 0.82 2.81 ± 0.70 < 0.001
0.723 < 0.001
1.89 ± 0.91 1.35 ± 0.65 < 0.001
1.88 ± 0.77 2.23 ± 0.69 < 0.001
0.966 < 0.001
1.03 ± 0.67 0.96 ± 0.68 0.161
0.95 ± 0.71 1.21 ± 0.91 0.027
0.641 0.009
1.69 ± 0.65 1.12 ± 0.72 < 0.001
1.66 ± 0.64 1.85 ± 0.71 0.005
0.863 < 0.001
1.64 ± 0.55 1.37 ± 0.55 0.011
1.66 ± 0.71 2.16 ± 0.71 < 0.001
0.888 < 0.001
1.46 ± 0.88 1.14 ± 0.59 0.010
1.40 ± 0.67 1.66 ± 0.71 0.003
0.755 < 0.001
0.31 ± 0.43 0.12 ± 0.39 0.005
0.31 ± 0.40 0.48 ± 0.44 0.002
0.906 < 0.001
………. ………. ……….
………. ………. ……….
………. ……….
………. ………. ……….
………. ………. ……….
………. ……….
1.75 ± 0.58 1.50 ± 0.74 0.017
1.76 ± 0.56 2.06 ± 0.58 0.001
0.913 < 0.001
1.85 ± 0.70 1.21 ± 1.06 < 0.001
1.70 ± 0.75 2.03 ± 0.81 0.001
0.415 < 0.001
1.57 ± 0.95 1.14 ± 1.01 0.001
1.66 ± 0.92 1.93 ± 0.78 0.003
0.701 < 0.001
1.57 ± 0.95 0.75 ± 0.92 < 0.001
1.56 ± 0.93 1.63 ± 0.88 0.161
0.985 < 0.001
Emotional Function Worry
Abdominal Symptoms Activity
Systemic Symptoms CLDQ Overall score
weeks
weeks
weeks
weeks
weeks
weeks
weeks
0.883 < 0.001
Joint Pain
0.807 < 0.001 0.980 < 0.001
Pain in the Right Upper Abdomen
0.950 < 0.001
Sleeping During the Day
0.997 < 0.001
Worry About Family Situation
0.999 < 0.001
Decreased Appetite
CLDQ: Chronic Liver Disease Questionnaire. Values are means ± SD. P < 0.05 was considered significant. * P values indicate comparison between groups (independent sample t-test at baseline and ANCOVA test, adjusted for baseline values and duration of liver cirrhosis, after 12 weeks). ** P values indicate comparison within groups (paired t-test).
Depression
Fear of Complication
Table 2 presents CLDQ domains and overall scores in treatment groups before and after trial. CLDQ domains and overall scores did not differ significantly between study groups at baseline (P > 0.05). As noted in Table 2, overall score as well as most of CLDQ domains including Fatigue, Emotional Function, Worry, Abdominal Symptoms, and Systemic Symptoms increased significantly after curcumin supplementation (P < 0.001), whereas in the placebo group, significant decrease was noticed in CLDQ domains and overall scores after 12 weeks (P < 0.001). After trial, differences in CLDQ domains and overall scores were significant between two groups (P < 0.001). Table 3 shows LDSI 2.0 domains in treatment groups before and after study. At baseline, LDSI 2.0 domains did not differ significantly between two groups (P > 0.05). As indicated in Table 3, curcumin supplementation caused significant reduction in most of LDSI 2.0 domains including Itch (P = 0.003), Joint pain (P = 0.030), Pain in the right upper abdomen (P < 0.001), Sleeping during the day (P < 0.001), Decreased appetite (P < 0.001), Depression (P = 0.011), Fear of Complication (P = 0.010), Jaundice (P = 0.005), Hindrance in Financial Affairs (P = 0.017), Change in use of time (P < 0.001), Decreased sexual interest (P = 0.001), and Decreased sexual activity (P < < 0.001), whereas in the placebo group, considerable increase was noticed in most of LDSI 2.0 domains after 12 weeks (P < 0.05). After trial, significant changes were noticed in LDSI 2.0 domains and overall scores between two groups (P < 0.05). Table 4 shows SF-36 domains and overall scores in treatment groups. No remarkable differences were observed between two groups regarding SF-36 domains and overall scores at baseline (P > 0.05). As stated in Table 4, the Physical and Mental health (total) scores (P < 0.001) and most of SF-36 domains including Physical Functioning (P < 0.001), Bodily Pain (P < 0.001), Vitality (P < 0.001), Social Functioning (P < 0.001), and Mental Health (P = 0.019) enhanced significantly after curcumin supplementation, whereas in the placebo group, significant decrease was noticed in Physical and Mental health (total) scores (P < 0.001) and most of SF-36 domains including
Jaundice
Memory problems
Change of Personality
Hindrance in Financial Affairs Change in Use of Time
Decreased Sexual Interest
Decreased Sexual Activity
LDSI 2.0: Liver Disease Symptom Index 2.0. Values are means ± SD. P < 0.05 was considered significant. * P values indicate comparison between groups (independent sample t-test at baseline and ANCOVA test, adjusted for baseline values and duration of liver cirrhosis, after 12 weeks). ** P values indicate comparison within groups (paired t-test).
4
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manipulating patients’ QoL can ameliorate long-term survival in liver cirrhosis.47 Improving liver biochemistry is thrilling for clinicians, but from the patients’ view does not indicate much if it is not linked with better QoL. Some therapies may improve the liver tests but at the same time have no effects or even negative effects on patients’ well-being. Taking into consideration the importance of liver cirrhosis as a persistent condition and its undesirable consequences on QoL, current investigation was conducted to find if curcumin can change the QoL in patients with liver cirrhosis. Our findings indicated that compared to baseline and placebo, curcumin supplement significantly improved QoL (assessed by CLDQ, LDSI 2.0, and SF-36) in patients with liver cirrhosis. QoL measurement tools (e.g. CLDQ and SF-36) can complete clinical outcomes, such as the Child-Pugh classification, liver enzymes, histological phase, and mortality rates, thereby assisting to merge the biomedical and the psychosocial patterns of health. This combined method to the study of liver cirrhosis will catch the overall influence of disease on patients’ health and well-being. Based on previous in vivo and in vitro investigations, curcumin had advantageous properties in liver injury and cirrhosis.18–27 However, to our knowledge, there was no research examining the consequences of curcumin supplement on QoL in liver cirrhosis. Current study was consistent with previous investigations conducted in different ailments such as IBS,30–32 chronic pulmonary problems,33 and cancer.34 Similar to our study, Portincasa et al.30 demonstrated that curcumin significantly improved symptoms and QoL in IBS patients after one month intervention. Di Ciaulaa et al.31 also indicated a significant reduction in the severity index and an improvement in both symptoms and QoL following two-month curcumin treatment in IBS subjects. Furthermore, curcumin (72−144 mg daily for 8 weeks) was found to reduce the extent of abdominal pain and to improve QoL in IBS patients.32 In another research in subjects with chronic pulmonary problems, Panahi et al.33 reported advantages of curcuminoids in alleviating signs and improving the HRQoL. Moreover, curcuminoid supplementation was associated with a significantly greater improvement in QoL in cancer patients.34 It has been demonstrated that curcumin can modulate various molecules (i.e., cell cycle proteins, transcription factors, enzymes, cytokines, and adhesion molecules), thereby exerting anti-inflammatory and therapeutic functions.48 Anti-inflammatory and immune-modulating activities of curcumin are predominantly due to the ability to suppress NF-κB, inducible nitric oxide synthase, cyclooxygenase-2, lipoxygenase, and proinflammatory cytokines.49–54 Curcumin could also neutralize oxidative stress via multiple mechanisms such as scavenging free radicals, increasing intracellular glutathione levels and inhibition of lipid peroxidation. Furthermore, curcumin could activate antioxidant enzymes such as glutathione peroxidase, glutathione transferase, superoxide dismutase, catalase, heme-oxygenase-1, and thioredoxin reductase.55 These activities together with an anti-apoptotic function contribute curcumin to be considered as a potential therapy for multiple chronic problems including liver cirrhosis.56 The limitation of present study was that we used self-report measures to evaluate patients’ QoL; thus, a recall bias might have influenced the responses. The main strength of current research was that it was the first randomized, double-masked placebo-controlled trial to understand the therapeutic properties of curcumin on QoL in cirrhotic patients. Also, a relatively large number of patients and long duration of intervention as well as monitoring patients’ status by a telephone conversations and high acceptation of curcumin in cases were supposed as additional strengths of current research. As a conclusion, in spite of observed significant positive effects of curcumin supplement in improving QoL in cirrhotic patients, additional studies are warranted to consider curcumin as a safe, accessible, and low-cost complementary therapeutic option in these patients.
Table 4 Comparison of SF-36 domains scores in treatment groups before and after intervention. Domain
Measurement Period
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Physical Functioning
Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P**
38.04 ± 16.68 49.18 ± 20.56 < 0.001
40.67 ± 15.57 35.33 ± 15.47 < 0.001
0.537 < 0.001
0.0 (0.0-0.5) 0.0 (0.0–1.0) 0.065
0.0 (0.0-0.50) 0.0 (0.0-0.25) 0.046
0.500 0.018
48.93 ± 12.06 57.57 ± 12.64 < 0.001
49.50 ± 10.27 47.33 ± 9.69 < 0.001
0.846 < 0.001
28.57 ± 12.97 31.96 ± 15.47 0.062
28.67 ± 12.79 24.83 ± 11.78 < 0.001
0.978 < 0.001
35.00 ± 16.33 46.79 ± 19.82 < 0.001
36.50 ± 16.40 28.83 ± 13.8 < 0.001
0.729 < 0.001
43.89 ± 15.34 55.82 ± 17.22 < 0.001
44.03 ± 13.44 39.90 ± 12.54 < 0.001
0.971 < 0.001
0.0 (0.0-0.67) 0.0 (0.0–1.0) 0.111
0.0 (0.0-0.67) 0.0 (0.0-0.33) 0.705
0.630 0.059
57.86 ± 8.60 60.29 ± 7.29 0.019
60.07 ± 7.05 57.87 ± 8.32 0.101
0.288 0.014
30.44 ± 9.37 38.85 ± 14.97 < 0.001
31.58 ± 7.45 27.92 ± 6.71 < 0.001
0.609 < 0.001
35.67 ± 8.52 47.16 ± 18.66 < 0.001
36.26 ± 7.60 30.89 ± 6.65 < 0.001
0.782 < 0.001
Role Physical
Bodily Pain
General Health
Vitality
Social Functioning
Role Emotional
Mental Health
Physical Health
Mental Health (Total)
SF-36: Short Form-36 Quality of Life. Values are means ± SD or median (Min–Max). P < 0.05 was considered significant. * P values indicate comparison between groups (independent sample t-test or Mann-Whitney U test for normally and non-normally distributed variables, respectively at baseline and ANCOVA test, adjusted for baseline values and duration of liver cirrhosis, after 12 weeks). ** P values indicate comparison within groups (paired t-test or Wilcoxon signed rank test for normally and non-normally distributed variables, respectively).
Physical Functioning (P < 0.001), Role Physical (P = 0.046), Bodily Pain (P < 0.001), General Health (P < 0.001), Vitality (P < 0.001), and Social Functioning (P < 0.001) after 12 weeks. After trial, significant changes were noticed in the SF-36 Physical and Mental health (total) scores and all its domains scores between groups (P < 0.001). 4. Discussion HRQoL is one of the major subjects in medicine and its measurement is crucial as a necessary component of health consequences. HRQoL which represents subject’s subjective measure of physical, intellectual and civic aspects of well-being and social functioning is supposed a thorough and noteworthy outcome assessment.40 According to previous reports, HRQoL was considerably disturbed in cirrhotic patients compared with healthy individuals.8–12,43–45In addition, significant association was noticed between liver cirrhosis and poor HRQoL assessed by either CLDQ or SF-36.45,46It seems that 5
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Curcumin decreased oxidative stress, inhibited NF-kappaB activation, and improved liver pathology in ethanolinduced liver injury in rats. J Biomed Biotechnol. 2009;2009:981963. 28. Cai Y, Lu D, Zou Y, et al. Curcumin protects against intestinal origin endotoxemia in rat liver cirrhosis by targeting PCSK9. J Food Sci. 2017;82(3):772–780. 29. Zhang F, Zhang Z, Chen L, et al. Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells. J Cell Mol Med. 2014;18(7):1392–1406. 30. Portincasa P, Bonfrate L, Scribano M, et al. Curcumin and fennel essential oil improve symptoms and quality of life in patients with irritable bowel syndrome. J Gastrointestin Liver Dis. 2016;25(2):151–157. 31. Di Ciaula A, Portincasa P, Maes N, Albert A. Efficacy of bio-optimized extracts of turmeric and essential fennel oil on the quality of life in patients with irritable bowel syndrome. Ann Gastroenterol. 2018;31(6):685–691. 32. Bundy R, Walker AF, Middleton RW, Booth J. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: A pilot study. J Altern Complement Med. 2004;10(6):1015–1018. 33. Panahi Y, Ghanei M, Hajhashemi A, Sahebkar A. Effects of curcuminoids-piperine combination on systemic oxidative stress, clinical symptoms and quality of life in subjects with chronic pulmonary complications due to sulfur mustard: A randomized controlled trial. J Diet Suppl. 2016;13(1):93–105. 34. Panahi Y, Saadat A, Beiraghdar F, Sahebkar A. Adjuvant therapy with bioavailabilityboosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: A randomized double-blind placebocontrolled trial. Phytother Res. 2014;28(10):1461–1467. 35. Saadati S, Hekmatdoost A, Hatami B, et al. Comparing different non-invasive methods in assessment of the effects of curcumin on hepatic fibrosis in patients with non-alcoholic fatty liver disease. Gastroenterol Hepatol Bed Bench. 2018;11(Suppl. 1):S8–S13. 36. Saadati S, Hatami B, Yari Z, et al. The effects of curcumin supplementation on liver enzymes, lipid profile, glucose homeostasis, and hepatic steatosis and fibrosis in patients with non-alcoholic fatty liver disease. Eur J Clin Nutr. 2019;73(3):441–449. 37. Saadati S, Sadeghi A, Mansour A, et al. Curcumin and inflammation in nonalcoholic fatty liver disease: A randomized, placebo controlled clinical trial. BMC Gastroenterol. 2019;19(1):133–138. 38. Eatona J, Nelsona K, Gossarda A, et al. Efficacy and safety of curcumin in primary sclerosing cholangitis: An open label pilot study. Scand J Gastroenterol. 2019;54(5):633–639. 39. Younossi ZM, Guyatt G, Kiwi M, Boparai N, King D. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. GUT. 1999;45(2):295–300. 40. Mahmoudi H, Jafari P, Alizadeh-Naini M, Gholami S, Malek-Hosseini SA, Ghaffaripour S. Validity and reliability of Persian version of chronic liver disease questionnaire (CLDQ). Qual Life Res. 2012;21(8):1479–1485. 41. Saffari M, Alavian SM, Naderi MK, Pakpour AH, Al Zaben F, Koenig HG. Cross-cultural adaptation and psychometric assessment of the liver disease symptom index 2.0 to measure health-related quality of life among iranian patients with chronic hepatitis B. J Transcult Nurs. 2016;27(5):496–508. 42. Montazeri A, Goshtasebi A, Vahdaninia M, Gandek B. The Short Form Health Survey (SF-36): Translation and validation study of the Iranian version. Qual Life Res. 2005;14(3) pp. 82–75. 43. Svirtlih N, Pavic S, Terzic D, et al. Reduced quality of life in patients with chronic viral liver disease as assessed by SF12 questionnaire. J Gastrointestin Liver Dis. 2008;17(4):405–409. 44. Younossi ZM, Boparai N, McCormick M, Price LL, Guyatt G. Assessment of utilities and health-related quality of life in patients with chronic liver disease. Am J Gastroenterol. 2001;96(7):579–583. 45. Bao ZJ, Qiu DK, Ma X, et al. Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy. World J Gastroenterol. 2007;13(21):3003–3008. 46. Afendy A, Kallman JB, Stepanova M, et al. Predictors of health-related quality of life in patients with chronic liver disease. Aliment Pharmacol Ther. 2009;30(5):469–476. 47. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatolo. 2006;44(1):217–231. 48. Shishodia S, Sethi G, Aggarwal BB. Curcumin: Getting back to the roots. Ann N Y Acad Sci. 2005;1056:206–217. 49. Venkataranganna MV, Rafiq M, Gopumadhavan S, Peer G, Babu UV, Mitra SK. NCB02 (standardized Curcumin preparation) protects dinitrochlorobenzene- induced colitis through downregulation of NFkappa-B and iNOS. World J Gastroenterol. 2007;13(7):1103–1107. 50. Rajasekaran SA. Therapeutic potential of curcumin in gastrointestinal diseases. World J Gastrointest Pathophysiol. 2011;2(1):1–14.
CRediT authorship contribution statement Masoud Nouri-Vaskeh: Conceptualization, Methodology, Validation, Investigation, Data curation, Writing - original draft, Visualization. Hossein Afshan: Investigation, Data curation. Aida Malek Mahdavi: Conceptualization, Methodology, Formal analysis, Writing original draft, Supervision. Leila Alizadeh: Conceptualization, Methodology, Validation, Investigation, Visualization, Supervision, Funding acquisition. Xiude Fan: Writing review & editing. Mohammad Zarei: Writing - review & editing. Declaration of Competing Interest None was declared. Acknowledgments The findings of our manuscript are come from the MD dissertation of Hossein Afshan approved in Tabriz University of Medical Sciences, Tabriz, Iran. We are so grateful to the Liver and Gastrointestinal Diseases Research Center of Tabriz University of Medical Sciences, Tabriz, Iran for funding this research. We are also grateful to the patients for cooperation in current project. References 1. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838–851. 2. Moon AM, Singal AG, Tapper EB. Contemporary epidemiology of chronic liver disease and cirrhosis. Clin Gastroenterol Hepatol. 2019 pii: S1542-3565(19)30849-3. [Epub ahead of print]. 3. Loria A, Escheik C, Gerber NL, Younossi ZM. Quality of life in cirrhosis. Curr Gastroenterol Rep. 2013;15(1):301. 4. Kalaitzakis E. Quality of life in liver cirrhosis. In: V.R Preedy, R.R Watson, eds. Handbook of disease burdens and quality of life measures. New York: Springer; 2010:2239–2254. 5. Orr JG, Homer T, Ternent L, et al. Health-related quality of life in people with advanced chronic liver disease. J Hepatol. 2014;61(5):1158–1165. 6. van der Plas SM, Hansen BE, de Boer JB, et al. Generic and disease-specific health related quality of life of liver patients with various aetiologies: A survey. Qual Life Res. 2007;16(3):375–388. 7. Younossi Z, Henry L. Overall health-related quality of life in patients with end-stage liver disease. Clin Liver Dis. 2015;6(1):9–14. 8. Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterol. 2001;120(1):170–178. 9. Martin LM, Sheridan MJ, Younossi ZM. The impact of liver disease on health-related quality of life: A review of the literature. Curr Gastroenterol Rep. 2002;4(1):79–83. 10. Tapper E, Kanwal F, Asrani S, et al. Patient reported outcomes in cirrhosis: A scoping review of the literature. Hepatology. 2018;67(6):2375–2383. 11. Les I, Doval E, Flavia M, et al. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroen Hepat. 2010;22(2):221–227. 12. Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci. 2003;48(8):1622–1626. 13. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol. 2006;44(1):217–231. 14. Sanyal A, Younossi ZM, Bass NM, et al. Randomised clinical trial: Rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011;34(8):853–861. 15. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as ‘Curecumin’: From kitchen to clinic. Biochem Pharmacol. 2008;75(4):787–809. 16. Epstein J, Sanderson IR, Macdonald TT. Curcumin as a therapeutic agent: The evidence from in vitro, animal and human studies. Br J Nutr. 2010;103(11):1545–1557. 17. Lao CD, Ruffin MT, Normolle D. Dose escalation of a curcuminoid formulation. BMC Complem Altern Med. 2006;6(10):1–4. 18. Wu P, Huang R, Xiong YL, Wu C. Protective effects of curcumin against liver fibrosis through modulating DNA methylation. Chin J Nat Medicines. 2016;14(4):255–264. 19. Rivera-Espinoza Y, Muriel P. Pharmacological actions of curcumin in liver diseases or damage. Liver Int. 2009;29(10):1457–1466. 20. Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin protects the rat liver from CCl4caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol. 2008;73(2):399–409. 21. Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int. 2007;27(3):373–383. 22. Bisht S, Khan MA, Bekhit M, et al. A polymeric nanoparticle formulation of curcumin (NanoCurc) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest. 2011;91(9):1383–1395.
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ulcerative colitis: Preclinical and clinical observations. Food Funct. 2012;3(11):1109–1117. 54. Hanai H, Sugimoto K. Curcumin has bright prospects for the treatment of inflammatory bowel disease. Curr Pharm Des. 2009;15(18):2087–2094. 55. Panahi Y, Sahebkar A, Amiri M, et al. Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant status by curcumin: Results of a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2012;108:1272–1279. 56. O’Connell MA, Rushworth SA. Curcumin: potential for hepatic fibrosis therapy? Br J Pharmacol. 2008;153(3):403–405.
51. Plummer SM, Holloway KA, Manson MM, et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene. 1999;18(44):6013–6020. 52. Koeberle A, Muñoz E, Appendino GB, et al. SAR studies on curcumin’s pro-inflammatory targets: Discovery of prenylated pyrazolocurcuminoids as potent and selective novel inhibitors of 5-lipoxygenase. J Med Chem. 2014;57(13):5638–5648. 53. Baliga MS, Joseph N, Venkataranganna MV, Saxena A, Ponemone V, Fayad R. Curcumin, an active component of turmeric in the prevention and treatment of
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Complementary Therapies in Medicine journal homepage: www.elsevier.com/locate/ctim
Curcumin ameliorates health-related quality of life in patients with liver cirrhosis: A randomized, double-blind placebo-controlled trial
T
Masoud Nouri-Vaskeha,b, Hossein Afshanc, Aida Malek Mahdavib,1,*, Leila Alizadehc,1,**, Xiude Fand,e, Mohammad Zareif,g a
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran c Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Infectious Diseases, The First Affiliated Hospital of Xi 'an Jiaotong University, Xi’an, 710061 China e Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, 44195, USA f Departrment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA g Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Curcumin Curcuma Quality of life End stage liver disease Liver cirrhosis
Objectives: Current study aimed to find the effects of curcumin on quality of life (QoL) in liver cirrhotic patients. Design: In this randomized double-masked placebo-controlled trial, 70 cases with liver cirrhosis aged 20–70 years were randomly divided into two groups to receive 1000 mg/day curcumin (n = 35) or placebo (n = 35) for 12 weeks. The health-related QoL (HRQoL) was assessed by CLDQ, LDSI 2.0, and SF-36. Results: Fifty-eight patients (28 in curcumin and 30 in placebo groups) finished the research. Compared with baseline, overall scores as well as most of CLDQ domains (e.g. Fatigue, Emotional Function, Worry, Abdominal Symptoms, and Systemic Symptoms) and the Physical and Mental health (Total) scores and most of SF-36 domains (e.g. Physical Functioning, Bodily Pain, Vitality, Social Functioning, and Mental Health) increased considerably (P < 0.05) after curcumin administration. Furthermore, curcumin reduced most of LDSI 2.0 domains (e.g. Itch, Joint pain, Pain in the right upper abdomen, Sleeping during the day, Decreased appetite, Depression, Fear of complication, Jaundice, Hindrance in Financial Affairs, Change in use of time, Decreased sexual interest, and Decreased sexual activity) significantly (P < 0.05). Significant differences were noticed between two groups in CLDQ domains and overall scores, LDSI 2.0 domains and overall scores, SF-36 Physical and Mental health (total) scores and all its domains scores (P < 0.05), adjusting for baseline values and disease duration. Conclusions: Curcumin improved QoL in liver cirrhotic patients according to CLDQ, LDSI 2.0, and SF-36 domains. Additional studies are warranted to consider curcumin as a safe, accessible, and low-cost complementary therapeutic option in cirrhosis.
1. Introduction Liver cirrhosis is the final outcome of various liver disorders associated with hepatic encephalopathy, ascites, peritonitis and gastrointestinal bleeding.1 Cirrhosis has become more prevalent in recent decades and it is a common cause of mortality all over the world.2 Liver cirrhosis has a progressive nature and coincides with physical and mental signs, thereby exerting a remarkable negative influence on quality of life (QoL).3–5 QoL, a concept that presents positive and negative features of a person’s life, has become important in various
gastrointestinal diseases including liver cirrhosis.3 The health-related QoL (HRQoL) is a multi-dimensional conception that contains self-reported physical and mental health measurements and social well-being, thereby becomes more significant in patients with cirrhosis.6 Various tools such as Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life Questionnaire (LDQOL), Liver Disease Symptom Index 2.0 (LDSI 2.0), and 36-Item Short Form Health Survey (SF-36) have been proposed to assess the impact of liver cirrhosis on HRQoL.7 According to the recent research, HRQoL is diminished in liver cirrhotic patients compared with healthy individuals.8–12 Thus, evaluating
⁎
Corresponding author at: Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran. Corresponding author at: Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran. E-mail addresses: [email protected] (A. Malek Mahdavi), [email protected] (L. Alizadeh). 1 These authors contributed equally to this work. ⁎⁎
https://doi.org/10.1016/j.ctim.2020.102351 Received 21 December 2019; Received in revised form 16 February 2020; Accepted 18 February 2020 Available online 19 February 2020 0965-2299/ © 2020 Elsevier Ltd. All rights reserved.
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Fig. 1. Study Flow Diagram.
among individuals with primary sclerosing cholangitis (PSC) reported that curcumin was not associated with significant improvements in cholestasis or symptoms.38 Since HRQoL has become as one of the major points in current medicine and considering the importance of HRQoL for subjects with chronic liver ailments like cirrhosis and because no study exists regarding the curcumin and QoL in cases with liver cirrhosis, this research was carried out as the first investigation to find out the consequences of curcumin supplement on HRQoL in liver cirrhotic patients.
HRQoL is necessary in these patients and improving HRQoL is considered as a main part of disease management and has been shown to increase long-term survival in these patients.13 Furthermore, it has been indicated that appropriate therapy of ascites and encephalopathy can ameliorate HRQoL and augments the life span.3,14 Currently, there are no approved agents accessible for treatment of liver fibrosis as well as cirrhosis and conventional treatments usually have poor outcomes and impose great expenses for both families and societies; therefore, herbal therapies have recently been proposed as a potential useful therapy for cirrhosis. Curcumin, the main bioactive component of Curcuma longa L., has a variety of biological and pharmacological functions such as anti-inflammatory, antioxidant, anticarcinogenic, anti-angiogenic, antithrombotic, and etc. and has become the main topic of research in recent years.15,16 Curcumin is extensively used as a medicinal herb in different areas due to its safety and tolerability.17 It has gained attention as a promising agent for prevention and treatment of different hepatic ailments including liver fibrosis. Based on previous animal and in vitro research, curcumin had beneficial effects in liver injury and cirrhosis.18–27 It suppresses the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and inhibits inflammation, diminishes oxidative stress, and inhibiting angiogenesis, thereby can inhibit liver cirrhosis.28,29 Although no previous studies have been conducted regarding curcumin consumption and HRQoL in liver cirrhosis, there are some reports indicating that curcumin can improve QoL in various conditions like irritable bowel syndrome (IBS), chronic pulmonary problems, and cancer.30–34 Furthermore, there are some investigations stating that curcumin can improve hepatic steatosis and fibrosis in non-alcoholic fatty liver disease (NAFLD).35–37Another study
2. Patients and methods 2.1. Study design & subjects In a randomized, double-masked, placebo-controlled trial, seventy volunteer cases with liver cirrhosis aged 20–70 years with model for end-stage liver disease (MELD) score > 11 and arterial oxygen pressure > 60 mmHg were selected from gastroenterology outpatient clinic of Tabriz University of Medical Sciences between October 2018 and July 2019. Subjects with any history of malignancy, hepatopulmonary syndrome, pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg), hyperoxaluria, cystic fibrosis with FEV1 < 40 %, gallstones and/or bladder stones, use of anti-platelet and/or anti-coagulant medications and taking polyphenol supplements within three months before trial were not included. Our research protocol was accepted by the Medical Ethics Committee of Tabriz University of Medical Sciences (registration code: IR.TBZMED.REC.1397.660) and registered on the Iranian Registry of Clinical Trials (IRCT, registration code: IRCT20180802040678N1). 2
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Wilcoxon signed rank test were applied for within-group comparisons. Between-group comparisons were made by Chi square test, independent sample t-test, or Mann-Whitney U test, as appropriate. Analysis of covariance (ANCOVA) was used to find any differences between the two groups after the study. P < 0.05 was defined as statistical significance.
Study patients were informed about the research and signed a written consent. Qualified patients were randomly divided into intervention and placebo groups using a block randomization method (block size = 2), that matched cases to per block according to age, sex, and MELD score. To keep masking, an investigator with no involvement in the trial conducted the distribution. Moreover, participants and researchers were kept blind throughout the trial. Patients in the intervention group (n = 35) received an oral dose of 1000 mg/day (2 equal dosages of one 500 mg capsule) curcumin for 12 weeks (curcumin, Karen Pharmaceutical & Nutrilife Co., Yazd, Iran). The control group (n = 35) received placebo according to the same protocol (placebo, Karen Pharmaceutical & Nutrilife Co., Yazd, Iran). Placebo capsules comprised inactive ingredients with no curative property and were similar to supplements in shape and color. Subjects were advised to take the supplements with breakfast and dinner meals. Subjects were also requested to maintain their routine diet and physical activity throughout the trial. Subjects were followed-up every week for any unfavorable outcomes of curcumin consumption. Fig. 1 depicts a flowchart of research.
3. Results From 70 patients who enrolled to the trial, seven cases in the curcumin group and five cases in the placebo group were removed due to lost to follow-up and mortality. It should be mentioned that the cause of mortality was due to the severity of liver cirrhosis. Furthermore, lost to follow-up was due to the reasons irrelevant to the treatment (i.e., personel reason, being on vacation, having changed their location and thus not accessible). Thus, information was presented for 58 patients (28 in curcumin group and 30 in placebo group). Both groups did not differ significantly in terms of primary causes of liver cirrhosis and/or ingest of hepatoprotective substances. No adverse effect was declared with using curcumin or placebo throughout the trial. The means ± SD age and duration of liver cirrhosis were 46.21 ± 11.72 and 4.25 ± 2.98 years, respectively. Thirty subjects (52 %) were males and 28 (48 %) were females. As demonstrated in Table 1, baseline characteristics did not differ between two groups (P > 0.05).
2.2. HRQoL assessment At the beginning and at the end of trial, HRQoL was assessed by CLDQ, LDSI 2.0, and SF-36 questionnaires. The CLDQ is the primary liver-specific self-reported questionnaire with 29 items in six main domains named abdominal symptoms, fatigue, systemic symptoms, activity, emotional function and worry.39 All items were assessed on a 1–7 scale with “1’’ representing “all of the time’’ and “7’’ representing “none of the time’’, and higher scores indicated better HRQoL.39 Mahmoudi et al.40 translated CLDQ into Persian language which was a valid and reliable measurement of HRQoL (convergent validity: 100 %, discriminant validity: 95.8 %, and the Cronbach’s alpha coefficient: 0.650.89). The symptoms experienced by patients and undesirable consequences of these symptoms on daily activities were assessed using LDSI 2.0.41 The LDSI 2.0 was originated in Netherlands and included 24 items classified into two subscales including severity of symptoms and how symptoms affect persons’ daily and social functions. All items were assessed on a five-point Likert-type measure from 0 ‘not at all’ to 4 ‘to a high extent’. The total and subscales scores were computed by summing the subject’s answers (0–60 for the severity of signs, 0–36 for the impediment of symptoms and 0–96 for the overall). Higher scores indicated increasing symptoms severity and impediment.41 Saffari et al.41 translated LDSI 2.0 into Persian language which was a reliable and valid measure of HRQOL (the Cronbach’s alpha coefficients for total scale and subscales of symptom index were 0.896 and between 0.5910.821, respectively). SF-36 is another widely used scale for HRQOL which contains 8 subcategories: (a) Physical Functioning (10 items), (b) Social Functioning (2 items), (c) Role Physical (4 items), (d) Role Emotional (3 items), (e) Mental Health (5 items), (f) Vitality (4 items), (g) Bodily Pain (2 items), (h) General Health (5 items).3 Likert scale was used for rating all items except the third and fourth. The third and fourth items were yes or no questions. The scores given to each category ranged from 0 to 100, where 0 and 100 depicted the lowest and highest QoL, respectively.3 Montazeri et al.42 translated SF-36 into Persian language which was a reliable and valid measure of HRQoL (the Cronbach’s alpha coefficient: 0.77-0.90 and convergent validity: 0.58 to 0.95).
Table 1 Baseline characteristics of participants. Characteristics
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Age (years) Duration of liver cirrhosis (years) Sex, n (%) Male Female Causes of liver cirrhosis, n (%) Cryptogenic Autoimmune HBV HCV PSC PVT Alcoholic Fatty liver BMI (kg/m2), n (%) 18.5-24.9 25.0-29.9 30.0-34.9 ALT (IU/L), n (%) ≤40 > 40 AST (IU/L), n (%) ≤34 > 34 MELD Score classification, n (%) ≤9 10-19 20-29 Child Pugh score classification, n (%) A B C
46.00 ± 12.99 4.39 ± 2.86 14 (50) 14 (50)
46.40 ± 10.62 4.12 ± 3.13 16 (53) 14 (47)
0.898 0.728 0.800
10 (35.7) 8 (28.6) 3 (10.7) 2 (7.1) 2 (7.1) 2 (7.1) 1 (3.6) 0 (0.0)
7 8 4 2 2 2 3 2
(23.3) (26.7) (13.3) (6.7) (6.7) (6.7) (10.0) (6.7)
0.824
14 (50) 13 (46.4) 1 (3.6)
16 (53.3) 12 (40) 2 (6.7)
0.803
17 (60.7) 11 (39.3)
15 (50) 15 (50)
0.412
11 (39.3) 17 (60.7)
11 (36.7) 19 (63.3)
0.837
0 (0.0) 26 (92.9) 2 (7.1)
5 (16.7) 24 (80.0) 1 (3.3)
0.069
11 (39.3) 15 (53.6) 2 (7.1)
17 (56.7) 12 (40.0) 1 (3.3)
0.390
HBV, Hepatitis B virus; HCV, Hepatitis C virus; PSC, Primary sclerosing cholangitis; PVT, Portal vein thrombosis; BMI, Body mass index; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; MELD, Model for end-stage liver disease. Continuous variables were reported as mean ± SD while categorical variables were expressed as frequency (percentage). P < 0.05 was considered significant. * P values indicate comparison between groups (Independent-sample t-test or Chi square, as appropriate).
2.3. Statistical analysis Data were analyzed via SPSS software version 16.0 (SPSS Inc., Chicago, IL). Kolmogorov-Smirnov test was used for normality evaluation. Qualitative, normally, and non-normally quantitative parameters were stated as numbers (percentages), means ± SD, and median (Min-Max), respectively. Paired t-test and or non-parametric 3
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Table 2 Comparison of CLDQ domains and overall scores in treatment groups before and after study.
Table 3 Comparison of LDSI 2.0 domains scores in treatment groups before and after study.
Domain
Measurement Period
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Domain
Measurement Period
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Fatigue
Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P** Baseline After 12 P**
3.33 ± 0.94 3.86 ± 0.99 < 0.001 4.64 ± 0.76 4.87 ± 0.85 0.035 5.46 ± 0.83 5.77 ± 0.87 0.013 3.22 ± 1.26 3.95 ± 1.44 < 0.001 4.95 ± 0.82 4.99 ± 0.86 0.212 4.58 ± 0.90 5.15 ± 0.98 < 0.001 4.36 ± 0.69 4.76 ± 0.80 < 0.001
3.36 ± 0.87 3.10 ± 0.71 < 0.001 4.67 ± 0.75 4.36 ± 0.72 < 0.001 5.41 ± 0.85 4.96 ± 0.74 < 0.001 3.23 ± 1.19 2.79 ± 1.03 < 0.001 4.93 ± 0.81 4.54 ± 0.80 < 0.001 4.58 ± 0.81 4.29 ± 0.84 < 0.001 4.36 ± 0.64 4.01 ± 0.59 < 0.001
0.897 < 0.001
Itch
Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P**
1.48 ± 0.93 1.07 ± 1.02 0.003
1.45 ± 0.0.72 1.82 ± 0.56 < 0.001
0.874 < 0.001
0.42 ± 0.64 0.28 ± 0.55 0.030
0.26 ± 0.43 0.46 ± 0.64 0.063
0.272 0.017
2.44 ± 0.88 1.89 ± 0.78 < 0.001
2.36 ± 0.82 2.81 ± 0.70 < 0.001
0.723 < 0.001
1.89 ± 0.91 1.35 ± 0.65 < 0.001
1.88 ± 0.77 2.23 ± 0.69 < 0.001
0.966 < 0.001
1.03 ± 0.67 0.96 ± 0.68 0.161
0.95 ± 0.71 1.21 ± 0.91 0.027
0.641 0.009
1.69 ± 0.65 1.12 ± 0.72 < 0.001
1.66 ± 0.64 1.85 ± 0.71 0.005
0.863 < 0.001
1.64 ± 0.55 1.37 ± 0.55 0.011
1.66 ± 0.71 2.16 ± 0.71 < 0.001
0.888 < 0.001
1.46 ± 0.88 1.14 ± 0.59 0.010
1.40 ± 0.67 1.66 ± 0.71 0.003
0.755 < 0.001
0.31 ± 0.43 0.12 ± 0.39 0.005
0.31 ± 0.40 0.48 ± 0.44 0.002
0.906 < 0.001
………. ………. ……….
………. ………. ……….
………. ……….
………. ………. ……….
………. ………. ……….
………. ……….
1.75 ± 0.58 1.50 ± 0.74 0.017
1.76 ± 0.56 2.06 ± 0.58 0.001
0.913 < 0.001
1.85 ± 0.70 1.21 ± 1.06 < 0.001
1.70 ± 0.75 2.03 ± 0.81 0.001
0.415 < 0.001
1.57 ± 0.95 1.14 ± 1.01 0.001
1.66 ± 0.92 1.93 ± 0.78 0.003
0.701 < 0.001
1.57 ± 0.95 0.75 ± 0.92 < 0.001
1.56 ± 0.93 1.63 ± 0.88 0.161
0.985 < 0.001
Emotional Function Worry
Abdominal Symptoms Activity
Systemic Symptoms CLDQ Overall score
weeks
weeks
weeks
weeks
weeks
weeks
weeks
0.883 < 0.001
Joint Pain
0.807 < 0.001 0.980 < 0.001
Pain in the Right Upper Abdomen
0.950 < 0.001
Sleeping During the Day
0.997 < 0.001
Worry About Family Situation
0.999 < 0.001
Decreased Appetite
CLDQ: Chronic Liver Disease Questionnaire. Values are means ± SD. P < 0.05 was considered significant. * P values indicate comparison between groups (independent sample t-test at baseline and ANCOVA test, adjusted for baseline values and duration of liver cirrhosis, after 12 weeks). ** P values indicate comparison within groups (paired t-test).
Depression
Fear of Complication
Table 2 presents CLDQ domains and overall scores in treatment groups before and after trial. CLDQ domains and overall scores did not differ significantly between study groups at baseline (P > 0.05). As noted in Table 2, overall score as well as most of CLDQ domains including Fatigue, Emotional Function, Worry, Abdominal Symptoms, and Systemic Symptoms increased significantly after curcumin supplementation (P < 0.001), whereas in the placebo group, significant decrease was noticed in CLDQ domains and overall scores after 12 weeks (P < 0.001). After trial, differences in CLDQ domains and overall scores were significant between two groups (P < 0.001). Table 3 shows LDSI 2.0 domains in treatment groups before and after study. At baseline, LDSI 2.0 domains did not differ significantly between two groups (P > 0.05). As indicated in Table 3, curcumin supplementation caused significant reduction in most of LDSI 2.0 domains including Itch (P = 0.003), Joint pain (P = 0.030), Pain in the right upper abdomen (P < 0.001), Sleeping during the day (P < 0.001), Decreased appetite (P < 0.001), Depression (P = 0.011), Fear of Complication (P = 0.010), Jaundice (P = 0.005), Hindrance in Financial Affairs (P = 0.017), Change in use of time (P < 0.001), Decreased sexual interest (P = 0.001), and Decreased sexual activity (P < < 0.001), whereas in the placebo group, considerable increase was noticed in most of LDSI 2.0 domains after 12 weeks (P < 0.05). After trial, significant changes were noticed in LDSI 2.0 domains and overall scores between two groups (P < 0.05). Table 4 shows SF-36 domains and overall scores in treatment groups. No remarkable differences were observed between two groups regarding SF-36 domains and overall scores at baseline (P > 0.05). As stated in Table 4, the Physical and Mental health (total) scores (P < 0.001) and most of SF-36 domains including Physical Functioning (P < 0.001), Bodily Pain (P < 0.001), Vitality (P < 0.001), Social Functioning (P < 0.001), and Mental Health (P = 0.019) enhanced significantly after curcumin supplementation, whereas in the placebo group, significant decrease was noticed in Physical and Mental health (total) scores (P < 0.001) and most of SF-36 domains including
Jaundice
Memory problems
Change of Personality
Hindrance in Financial Affairs Change in Use of Time
Decreased Sexual Interest
Decreased Sexual Activity
LDSI 2.0: Liver Disease Symptom Index 2.0. Values are means ± SD. P < 0.05 was considered significant. * P values indicate comparison between groups (independent sample t-test at baseline and ANCOVA test, adjusted for baseline values and duration of liver cirrhosis, after 12 weeks). ** P values indicate comparison within groups (paired t-test).
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manipulating patients’ QoL can ameliorate long-term survival in liver cirrhosis.47 Improving liver biochemistry is thrilling for clinicians, but from the patients’ view does not indicate much if it is not linked with better QoL. Some therapies may improve the liver tests but at the same time have no effects or even negative effects on patients’ well-being. Taking into consideration the importance of liver cirrhosis as a persistent condition and its undesirable consequences on QoL, current investigation was conducted to find if curcumin can change the QoL in patients with liver cirrhosis. Our findings indicated that compared to baseline and placebo, curcumin supplement significantly improved QoL (assessed by CLDQ, LDSI 2.0, and SF-36) in patients with liver cirrhosis. QoL measurement tools (e.g. CLDQ and SF-36) can complete clinical outcomes, such as the Child-Pugh classification, liver enzymes, histological phase, and mortality rates, thereby assisting to merge the biomedical and the psychosocial patterns of health. This combined method to the study of liver cirrhosis will catch the overall influence of disease on patients’ health and well-being. Based on previous in vivo and in vitro investigations, curcumin had advantageous properties in liver injury and cirrhosis.18–27 However, to our knowledge, there was no research examining the consequences of curcumin supplement on QoL in liver cirrhosis. Current study was consistent with previous investigations conducted in different ailments such as IBS,30–32 chronic pulmonary problems,33 and cancer.34 Similar to our study, Portincasa et al.30 demonstrated that curcumin significantly improved symptoms and QoL in IBS patients after one month intervention. Di Ciaulaa et al.31 also indicated a significant reduction in the severity index and an improvement in both symptoms and QoL following two-month curcumin treatment in IBS subjects. Furthermore, curcumin (72−144 mg daily for 8 weeks) was found to reduce the extent of abdominal pain and to improve QoL in IBS patients.32 In another research in subjects with chronic pulmonary problems, Panahi et al.33 reported advantages of curcuminoids in alleviating signs and improving the HRQoL. Moreover, curcuminoid supplementation was associated with a significantly greater improvement in QoL in cancer patients.34 It has been demonstrated that curcumin can modulate various molecules (i.e., cell cycle proteins, transcription factors, enzymes, cytokines, and adhesion molecules), thereby exerting anti-inflammatory and therapeutic functions.48 Anti-inflammatory and immune-modulating activities of curcumin are predominantly due to the ability to suppress NF-κB, inducible nitric oxide synthase, cyclooxygenase-2, lipoxygenase, and proinflammatory cytokines.49–54 Curcumin could also neutralize oxidative stress via multiple mechanisms such as scavenging free radicals, increasing intracellular glutathione levels and inhibition of lipid peroxidation. Furthermore, curcumin could activate antioxidant enzymes such as glutathione peroxidase, glutathione transferase, superoxide dismutase, catalase, heme-oxygenase-1, and thioredoxin reductase.55 These activities together with an anti-apoptotic function contribute curcumin to be considered as a potential therapy for multiple chronic problems including liver cirrhosis.56 The limitation of present study was that we used self-report measures to evaluate patients’ QoL; thus, a recall bias might have influenced the responses. The main strength of current research was that it was the first randomized, double-masked placebo-controlled trial to understand the therapeutic properties of curcumin on QoL in cirrhotic patients. Also, a relatively large number of patients and long duration of intervention as well as monitoring patients’ status by a telephone conversations and high acceptation of curcumin in cases were supposed as additional strengths of current research. As a conclusion, in spite of observed significant positive effects of curcumin supplement in improving QoL in cirrhotic patients, additional studies are warranted to consider curcumin as a safe, accessible, and low-cost complementary therapeutic option in these patients.
Table 4 Comparison of SF-36 domains scores in treatment groups before and after intervention. Domain
Measurement Period
Curcumin group (n = 28)
Placebo group (n = 30)
P*
Physical Functioning
Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P** Baseline After 12 weeks P**
38.04 ± 16.68 49.18 ± 20.56 < 0.001
40.67 ± 15.57 35.33 ± 15.47 < 0.001
0.537 < 0.001
0.0 (0.0-0.5) 0.0 (0.0–1.0) 0.065
0.0 (0.0-0.50) 0.0 (0.0-0.25) 0.046
0.500 0.018
48.93 ± 12.06 57.57 ± 12.64 < 0.001
49.50 ± 10.27 47.33 ± 9.69 < 0.001
0.846 < 0.001
28.57 ± 12.97 31.96 ± 15.47 0.062
28.67 ± 12.79 24.83 ± 11.78 < 0.001
0.978 < 0.001
35.00 ± 16.33 46.79 ± 19.82 < 0.001
36.50 ± 16.40 28.83 ± 13.8 < 0.001
0.729 < 0.001
43.89 ± 15.34 55.82 ± 17.22 < 0.001
44.03 ± 13.44 39.90 ± 12.54 < 0.001
0.971 < 0.001
0.0 (0.0-0.67) 0.0 (0.0–1.0) 0.111
0.0 (0.0-0.67) 0.0 (0.0-0.33) 0.705
0.630 0.059
57.86 ± 8.60 60.29 ± 7.29 0.019
60.07 ± 7.05 57.87 ± 8.32 0.101
0.288 0.014
30.44 ± 9.37 38.85 ± 14.97 < 0.001
31.58 ± 7.45 27.92 ± 6.71 < 0.001
0.609 < 0.001
35.67 ± 8.52 47.16 ± 18.66 < 0.001
36.26 ± 7.60 30.89 ± 6.65 < 0.001
0.782 < 0.001
Role Physical
Bodily Pain
General Health
Vitality
Social Functioning
Role Emotional
Mental Health
Physical Health
Mental Health (Total)
SF-36: Short Form-36 Quality of Life. Values are means ± SD or median (Min–Max). P < 0.05 was considered significant. * P values indicate comparison between groups (independent sample t-test or Mann-Whitney U test for normally and non-normally distributed variables, respectively at baseline and ANCOVA test, adjusted for baseline values and duration of liver cirrhosis, after 12 weeks). ** P values indicate comparison within groups (paired t-test or Wilcoxon signed rank test for normally and non-normally distributed variables, respectively).
Physical Functioning (P < 0.001), Role Physical (P = 0.046), Bodily Pain (P < 0.001), General Health (P < 0.001), Vitality (P < 0.001), and Social Functioning (P < 0.001) after 12 weeks. After trial, significant changes were noticed in the SF-36 Physical and Mental health (total) scores and all its domains scores between groups (P < 0.001). 4. Discussion HRQoL is one of the major subjects in medicine and its measurement is crucial as a necessary component of health consequences. HRQoL which represents subject’s subjective measure of physical, intellectual and civic aspects of well-being and social functioning is supposed a thorough and noteworthy outcome assessment.40 According to previous reports, HRQoL was considerably disturbed in cirrhotic patients compared with healthy individuals.8–12,43–45In addition, significant association was noticed between liver cirrhosis and poor HRQoL assessed by either CLDQ or SF-36.45,46It seems that 5
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CRediT authorship contribution statement Masoud Nouri-Vaskeh: Conceptualization, Methodology, Validation, Investigation, Data curation, Writing - original draft, Visualization. Hossein Afshan: Investigation, Data curation. Aida Malek Mahdavi: Conceptualization, Methodology, Formal analysis, Writing original draft, Supervision. Leila Alizadeh: Conceptualization, Methodology, Validation, Investigation, Visualization, Supervision, Funding acquisition. Xiude Fan: Writing review & editing. Mohammad Zarei: Writing - review & editing. Declaration of Competing Interest None was declared. Acknowledgments The findings of our manuscript are come from the MD dissertation of Hossein Afshan approved in Tabriz University of Medical Sciences, Tabriz, Iran. We are so grateful to the Liver and Gastrointestinal Diseases Research Center of Tabriz University of Medical Sciences, Tabriz, Iran for funding this research. We are also grateful to the patients for cooperation in current project. References 1. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838–851. 2. Moon AM, Singal AG, Tapper EB. Contemporary epidemiology of chronic liver disease and cirrhosis. Clin Gastroenterol Hepatol. 2019 pii: S1542-3565(19)30849-3. [Epub ahead of print]. 3. Loria A, Escheik C, Gerber NL, Younossi ZM. Quality of life in cirrhosis. Curr Gastroenterol Rep. 2013;15(1):301. 4. Kalaitzakis E. Quality of life in liver cirrhosis. In: V.R Preedy, R.R Watson, eds. Handbook of disease burdens and quality of life measures. New York: Springer; 2010:2239–2254. 5. Orr JG, Homer T, Ternent L, et al. Health-related quality of life in people with advanced chronic liver disease. J Hepatol. 2014;61(5):1158–1165. 6. van der Plas SM, Hansen BE, de Boer JB, et al. Generic and disease-specific health related quality of life of liver patients with various aetiologies: A survey. Qual Life Res. 2007;16(3):375–388. 7. Younossi Z, Henry L. Overall health-related quality of life in patients with end-stage liver disease. Clin Liver Dis. 2015;6(1):9–14. 8. Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterol. 2001;120(1):170–178. 9. Martin LM, Sheridan MJ, Younossi ZM. The impact of liver disease on health-related quality of life: A review of the literature. Curr Gastroenterol Rep. 2002;4(1):79–83. 10. Tapper E, Kanwal F, Asrani S, et al. Patient reported outcomes in cirrhosis: A scoping review of the literature. Hepatology. 2018;67(6):2375–2383. 11. Les I, Doval E, Flavia M, et al. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroen Hepat. 2010;22(2):221–227. 12. Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci. 2003;48(8):1622–1626. 13. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol. 2006;44(1):217–231. 14. Sanyal A, Younossi ZM, Bass NM, et al. Randomised clinical trial: Rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011;34(8):853–861. 15. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as ‘Curecumin’: From kitchen to clinic. Biochem Pharmacol. 2008;75(4):787–809. 16. Epstein J, Sanderson IR, Macdonald TT. Curcumin as a therapeutic agent: The evidence from in vitro, animal and human studies. Br J Nutr. 2010;103(11):1545–1557. 17. Lao CD, Ruffin MT, Normolle D. Dose escalation of a curcuminoid formulation. BMC Complem Altern Med. 2006;6(10):1–4. 18. Wu P, Huang R, Xiong YL, Wu C. Protective effects of curcumin against liver fibrosis through modulating DNA methylation. Chin J Nat Medicines. 2016;14(4):255–264. 19. Rivera-Espinoza Y, Muriel P. Pharmacological actions of curcumin in liver diseases or damage. Liver Int. 2009;29(10):1457–1466. 20. Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin protects the rat liver from CCl4caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol. 2008;73(2):399–409. 21. Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int. 2007;27(3):373–383. 22. Bisht S, Khan MA, Bekhit M, et al. A polymeric nanoparticle formulation of curcumin (NanoCurc) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest. 2011;91(9):1383–1395.
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