Abstract
Objecive
Patients with autoimmune hepatitis (AIH) reportedly have an impaired quality of life (QOL), mainly due to depression, even during remission. In addition, hypozincaemia has been demonstrated in patients with chronic liver disease, including AIH, and is known to be related to depression. Corticosteroids are known to cause mental instability. We therefore investigated the longitudinal association between zinc supplementation and changes in the mental status among AIH patients treated with corticosteroids.
Materials
This study enrolled 26 patients with serological remission of AIH routinely treated at our facility after excluding 15 patients who either discontinued polaprezinc (150 mg/day) within 24 months or interrupted treatment. Two questionnaires, the Chronic Liver Disease Questionnaire (CLDQ) and SF-36, were adopted to evaluate the QOL before and after zinc supplementation.
Results
Serum zinc levels were significantly elevated after zinc supplementation (p＜0.0001). The CLDQ worry subscale significantly improved after zinc supplementation (p=0.017), but none of the SF-36 subscales was affected. Multivariate analyses demonstrated that daily prednisolone dosing was inversely related to both the CLDQ worry domain score (p=0.036) and the SF-36 mental health component (p=0.031). There was a significant negative correlation between the changes in the daily steroid dose and the CLDQ worry domain scores before and after zinc supplementation (p=0.006). No serious adverse events occurred during the observation period.
Conclusion
Zinc supplementation safely and efficiently improved mental impairment, possibly caused by continuous treatment with corticosteroids, in patients with AIH.
Keywords: autoimmune hepatitis, CLDQ, chronic liver disease questionnaire, corticosteroid, quality of life, serum zinc
Introduction
According to a Japanese nationwide survey, the incidence of autoimmune hepatitis (AIH) has been increasing (1) similar to worldwide trends (2), but there are no drugs that can ‘cure’ this disease (3). As a tentative treatment, the current practice guidelines of the Japanese intractable hepato-biliary disease study group and the American Association for the Study of the Liver recommend corticosteroids and azathioprine as the first-line treatment for patients with AIH (4,5).
However, long-term administration of corticosteroids is widely known to be associated with physical adverse events, such as osteoporosis and opportunistic infection (6,7), as well as with mental adverse events, such as depression (8). It is generally known that AIH predominantly occurs in women, who develop depression at almost twice the frequency in men (9,10). It is therefore reasonable that depression and anxiety are more prevalent in patients with AIH than in the general population (11,12). To quantify the overall quality of life (QOL), including depression, anxiety and other emotions, a number of QOL measurement scales have been developed since the 1990s, mainly in Europe and the United States (13,14).
Janik et al. reported that patients with AIH had a significantly impaired health-related QOL, and depression seemed to be a dominant symptom affecting their well-being (15). Similar results were demonstrated even among children and adolescents by a Brazilian research group (16). In Japan, it was also reported that patients with AIH had an impaired health-related QOL and that doctors should be aware of the risk when prescribing steroids (17). In addition, Takahashi et al. demonstrated that even patients with AIH in remission showed an impaired health-related QOL associated with disease duration (18).
Nishikawa et al. analysed the results of questionaries from over 300 patients with chronic liver disease and revealed that those at a greater risk of depression tended to have lower serum zinc levels than those at a lower risk of depression (19). They concluded that the serum zinc level could be a useful marker for a decreased health-related QOL in patients with chronic liver diseases. Pereira et al. reported that serum zinc levels were significantly lower in young patients with AIH than in controls (20). Several randomized control trials (RCTs) have reported that zinc supplementation improved depression (21-23), although the associated molecular mechanism was not clearly elucidated. However, there have been no reports on the effect of zinc supplementation on the impaired health-related QOL in patients with AIH in remission.
The present study therefore explored whether or not polaprezinc could improve the impaired QOL in AIH patients in clinical remission.
Materials and Methods
Patients
Of the 84 patients with histologically proven AIH at Nara Medical University Hospital, 41 agreed to participate in this study between October 2015 and October 2017. The inclusion criteria were as follows: (i) patients in clinical remission for AIH; (ii) patients with continuous supplementation of polaprezinc for over two years; and (iii) patients who provided valid responses to the specified QOL questionnaire. Clinical remission in this study was defined as a serum alanine aminotransferase (ALT) level below its normal upper limit and below the concomitant aspartate transaminase (AST) level for at least six months. The exclusion criteria were as follows: (i) not in clinical remission of AIH; (ii) presence of decompensated cirrhosis; (iii) positive for hepatitis C virus (HCV), hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV); (iv) presence of another liver disease; (v) taking hepatotoxic drugs; (vi) presence of renal failure and heart failure; and (vii) pregnant or lactating.
The participants were prescribed polaprezinc (75 mg, twice per day) for 2 years, and their QOL before and after supplementation of polaprezinc was assessed using two different questionnaires: the Chronic Liver Disease Questionnaire (CLDQ) and SF-36. We excluded 15 patients for the following reasons: treatment with polaprezinc for ＜2 years (n=11) and treatment interruption (n=4). Finally, the changes in the QOL of the remaining 26 patients who had successfully taken polaprezinc for over 2 years were assessed (Fig. 1).
Figure 1.
Flow chart of the study patients.
Questionnaires for evaluating the QOL in patients with AIH
The SF-36 is a comprehensive, scientific, reliable, and validated instrument for measuring the health-related QOL (13) and has been used extensively after a thorough investigation from its conception to quantitative psychometric evaluations. This QOL rating scale is based on the following eight health concepts: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional, and 8) mental health. Based on these subscales, the physical component summary (PCS) score, mental component summary (MCS) score, and role/social component summary (RCS) score were also calculated.
The CLDQ, a QOL scale specific to liver disease developed by Younossi et al. in 1999, consists of 29 items and assesses the QOL over the previous 2 weeks (14). This subscale consists of 6 domains, including abdominal symptoms (items 1, 5, 17), fatigue (items 2, 4, 8, 11, 13), systemic symptoms (items 3, 6, 21, 23, 27), activity (items 7, 9, 14), the emotional function (items 10, 12, 15, 16, 19, 20, 24, 26), and worry (items 18, 22, 25, 28, 29), with higher scores indicating a better QOL.
In the present study, the correlations between the SF-36 subscale scores and clinical backgrounds as well as those between the CLDQ subscale and the clinical parameters of the AIH patients were evaluated.
Statistical analyses and ethical issues
Numerical variables were expressed as the median and quartiles. The McNemar test and Wilcoxon matched-pairs signed-rank test were used to compare the patient characteristics, clinical test values, and scores of the two questionaries before and after zinc supplementation. Correlation was assessed using Spearman's rank correlation coefficients. Unrelated categorical variables were examined using Pearson's chi-square test. To investigate the independent associations between the QOL and predictors, such as the age, dosage of prednisolone, and albumin level, we used a multivariable linear regression model that included these three predictors as independent variables simultaneously. Values of p＜0.05 were considered to be indicative of statistical significance. The JMP version 14.3 (SAS Institute, Cary, USA) software program and EZR software program, which is a graphical user interface for the R statistical computing and graphics environment (24), were used for the statistical analyses.
The Ethics Committee of Nara Medical University Hospital approved this study (approval #15-003 and #1116), which was conducted according to the ethical principles in the Japanese ethics guideline for epidemiological research [https://www.mhlw.go.jp/content/000757566.pdf Accessed on July 05, 2021]. This study was conducted according to the Declaration of Helsinki, and written informed consent was obtained from all patients.
Results
Clinical and demographic data
The clinical profiles of patients with AIH before and after zinc supplementation are shown in Table 1. Twenty-three (88.5%) out of 26 patients were women (median age: 66.5 years old). There were 3 (11.5%) cirrhotic patients in this study, and the median disease duration of the participants was 8.0 years. As all of the patients in this study were well-treated with prednisolone and/or ursodeoxycholic acid, their serum transaminase levels were within normal limits. The median doses of prednisolone and ursodeoxycholic acid were 3.3 and 600 mg, respectively.
Table 1.
Characteristics of the Patients with AIH.
| Zinc supplementation | p | ||
|---|---|---|---|
| Before (n=26) | After (n=26) | ||
| BMI (kg/m2) | 22.8 (20.1-25.2) | 23.9 (20.1-25.2) | 0.205 |
| AST (U/L) | 21 (19-28) | 22 (19-30) | 0.433 |
| ALT (U/L) | 14 (11-24) | 16 (11-25) | 0.863 |
| ALP (U/L) | 194 (158-262) | 223 (191-244) | 0.148 |
| GGT (U/L) | 19 (14-29) | 20 (15-26) | 0.720 |
| Total bilirubin (mg/dL) | 0.7 (0.6-1.0) | 0.6 (0.6-0.8) | 0.150 |
| Albumin (g/dL) | 4.2 (4.0-4.3) | 4.2 (4.1-4.3) | 0.226 |
| IgG (mg/dL) | 1,308 (1,066-1,565) | 1,268 (1,109-1,507) | 0.618 |
| Zinc (μg/dL) | 74 (70-79) | 92 (80-101) | <0.0001 |
| Copper (μg/dL) | 126.0 (101.5-133.5) | 107.0 (93.5-120.5) | 0.021 |
| Hyaluronic acid (ng/mL) | 61 (33-115) | 46 (36-105) | 0.468 |
| Procollagen type III (U/mL) | 0.6 (0.4-0.6) | 0.4 (0.4-0.6) | 0.055 |
| Collagen type IV 7S (ng/mL) | 3.8 (3.0-5.8) | 3.9 (3.5-4.3) | 0.907 |
| Plt (×104/μl) | 19.1 (16.6-23.4) | 21.1 (17.7-24.5) | 0.001 |
| Elastography (kPa) | 1.4 (1.3-1.7) | 1.5 (1.3-1.7) | 0.222 |
| Use of PSL (%) | 61.5 (16/26) | 57.7 (15/26) | 0.739 |
| Dose of PSL (mg/day) | 3.3 (0.0-5.8) | 2.5 (0.0-5.0) | 0.380 |
| Use of UDCA (%) | 96.2 (25/26) | 96.2 (25/26) | 1.000 |
| Dose of UDCA (mg/day) | 600 (600-600) | 600 (600-600) | 0.406 |
| Cirrhosis (case) | 11.5% (3/26) | 11.5% (3/26) | 1.000 |
| Hypertension (case) | 15.4% (4/26) | 19.2% (5/26) | 0.317 |
| Diabetes (case) | 15.4% (4/26) | 19.2% (5/26) | 0.317 |
| Osteoporosis (case) | 15.4% (4/26) | 15.4% (4/26) | 1.000 |
Data are median (interquartile range) for continuous variables, percentage values for categorical variables. AIH: autoimmune hepatitis, BMI: body mass index, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, Plt: platelet, PSL: prednisolone, UDCA: ursodeoxycholic acid
Serum zinc levels were significantly elevated after zinc supplementation for 2 years (before, 74 μg/dL; after, 92 μg/dL; p＜0.0001). Serum copper levels were significantly decreased during the observation period (before, 126 μg/dL; after, 107 μg/dL; p=0.021), but the serum copper levels in all patients after zinc supplementation stayed within the normal range. All other parameters except for the patient age, disease duration, and platelet count, were not significantly changed.
In the group with increased serum zinc levels (n=21) during the follow-up period, 23.8% (5/21) of the AIH patients needed to have their daily prednisolone dosage increased in order to maintain clinical remission. In contrast, in the group with decreased serum zinc levels (n=5), the rate of patients with increased daily dosages of prednisolone was as high as 40.0% (2/5), although a statistically significant differences could not be detected due to the insufficient number of patients in the analysis (p=0.463).
SF-36 and CLDQ domain scores
None of the SF-36 subscales were affected by the zinc supplementation, but the CLDQ worry subscale was significantly improved after zinc supplementation (before, 5.5; after, 5.8; p=0.017, Table 2). Regarding the correlation between the clinical background characteristics and the subscale scores of SF-36 and CLDQ, the prednisolone dosage, age, and serum albumin level were not correlated with any components or any summary scores of the SF-36 or CLDQ before zinc supplementation (Supplementary material 1). In contrast, however, the prednisolone dosage was negatively correlated with the SF-36 mental health component (p=0.031) and the CLDQ worry component (p=0.036) after zinc supplementation, independent of potential confounders, such as the age and albumin level (Table 3). Furthermore, neither the patient's age nor serum albumin level were correlated with any other components of the questionnaires. To exclude the possibility of a sex-based difference in the effects, we also analysed the correlations of these parameters only in women with AIH and obtained similar results (Supplementary material 2).
Table 2.
CLDQ and SF-36 Scores among Patients with AIH.
| Zinc supplementation | p | ||
|---|---|---|---|
| Before (n=26) | After (n=26) | ||
| SF-36 | |||
| Physical functioning | 90.0 (70.0-95.0) | 85.0 (70.0-95.0) | 0.465 |
| Role physical | 93.8 (71.9-100.0) | 93.8 (76.6-100.0) | 0.566 |
| Bodily pain | 84.0 (62.0-100.0) | 79.0 (61.3-100.0) | 0.655 |
| General health | 52.0 (50.0-67.0) | 53.5 (45.5-67.0) | 0.133 |
| Vitality | 71.9 (56.3-79.7) | 68.8 (56.3-79.7) | 0.095 |
| Social functioning | 87.5 (75.0-100.0) | 100.0 (75.0-100.0) | 0.472 |
| Role emotion | 91.7 (77.1-100.0) | 100.0 (75.0-100.0) | 0.720 |
| Mental Health | 75.0 (70.0-88.8) | 77.5 (70.0-90.0) | 0.646 |
| PCS | 47.7 (37.5-51.8) | 47.0 (31.6-51.0) | 0.055 |
| MCS | 54.9 (50.0-56.9) | 53.0 (48.0-58.7) | 0.319 |
| RCS | 49.3 (44.4-56.3) | 53.1 (45.2-59.5) | 0.895 |
| CLDQ | |||
| Overall | 6.3 (5.7-6.7) | 6.1 (5.5-6.5) | 0.643 |
| Abdominal | 6.3 (5.7-6.9) | 6.2 (5.4-6.7) | 0.315 |
| Fatigue | 5.6 (5.0-6.2) | 5.7 (5.4-6.2) | 0.803 |
| Systemic | 5.7 (5.2-6.4) | 5.8 (5.2-6.2) | 0.774 |
| Activity | 6.0 (5.4-6.7) | 6.0 (5.7-6.7) | 0.362 |
| Emotions | 5.8 (5.2-6.1) | 5.9 (5.5-6.2) | 0.401 |
| Worry | 5.5 (4.8-6.2) | 5.8 (5.1-6.4) | 0.017 |
Data are shown as median (interquartile range). CLDQ: Chronic Liver Disease Questionnaire, SF-36: 36-Item Short Form Survey, AIH: autoimmune hepatitis, PCS: physical component summary, MCS: mental component summary, RCS: role/social component summary
Table 3.
Association between QOL and Patients' Characteristics (Age, PSL Dose, & Albumin).
| Outcomes | Predictors | Unadjusted β coefficient* (95%CI) | p value |
|---|---|---|---|
| Worry of CLDQ | Age | 1.70×10-7 [-2.45×10-7, 5.85×10-7] | 0.405 |
| PSL dose | -0.14 [-0.27, -0.01] | 0.033 | |
| Albumin | -1.57 [-4.02, 0.96] | 0.213 | |
| Predictors | Adjusted β coefficient† (95%CI) | p value | |
| Age | -2.06×10-8 [-4.34×10-7, 3.93×10-7] | 0.919 | |
| PSL dose | -0.15 [-0.28, -0.01] | 0.036 | |
| Albumin | -1.72 [-4.16, 0.73] | 0.157 | |
| Outcomes | Predictors | Unadjusted β coefficient* (95%CI) | p value |
| Mental health of SF36 | Age | -4.25×10-7 [-3.40×10-6, 2.55×10-6] | 0.770 |
| PSL dose | -0.81 [-1.74, 0.12] | 0.085 | |
| Albumin | -12.46 [-30.22, 5.30] | 0.161 | |
| Predictors | Adjusted β coefficient† (95%CI) | p value | |
| Age | -1.89×10-6 [-4.77×10-6, 9.89×10-7] | 0.187 | |
| PSL dose | -1.05 [-2.00, -0.10] | 0.031 | |
| Albumin | -15.56 [-32.57, 1.45] | 0.071 |
* β coefficient represent the change of outcome variables associated with 1 unit increase of predictors. † Adjsuted for age, PSL dose, and albumin. CI: confidence interval, CLDQ: chronic liver disease questionary, PSL: prednisolone, QOL: quality of life
Relationship between the prednisolone dosage and CLDQ worry domain score
To examine the influence of prednisolone on the mental health of the patients with AIH, we assessed the direct relationship between the daily dosage of prednisolone and the CLDQ worry domain score, which showed a significant corelation according to a multivariate analysis after zinc supplementation. During the two-year observation period in this study, there were seven cases of AIH relapse for which reinduction therapy with a transiently increased dose of prednisolone was adopted. Therefore, the prednisolone dose at the end of the observation period was higher in these patients than at the beginning of the observation period. As shown in Fig. 2, there was a significant negative correlation between the change in daily steroid dose and change in the worry domain scores of CLDQ before and after zinc supplementation (p=0.006). The results of these analyses were very similar to those of the studies restricted to women (Supplementary material 3).
Figure 2.
Associations between prednisolone dosage and the Chronic Liver Disease Questionnaire (CLDQ) worry domain score. Changes in the CLDQ worry domain score after the observation period were also negatively correlated with those in the daily dosage of prednisolone (p=0.006).
Relationship between the serum zinc concentration and CLDQ worry domain score
To examine the influence of zinc administration on CLDQ worry domain score, all subjects were analysed for the correlation between changes in each worry domain score of the CLDQ and the serum zinc concentrations before and after polaprezinc administration. Unfortunately, no significant positive correlation was found between increased serum zinc levels and improved worry domain scores of the CLDQ (data not shown). However, in the group with worsened worry domain scores of the CLDQ over the 2-year observation period (n=5), the median serum zinc concentration at the end of the observation and the median change in the serum zinc concentration after the observation period were 83.0 and 10.0 μg/dL, respectively; in contrast, these values were higher in the group without worsened worry domain scores of the CLDQ (n=21), at 92.5 μg/dL and 19.9 μg/dL, respectively.
Discussion
In the present study, a comparison of the QOL before and after zinc supplementation for two years among patients with AIH showed an improvement in the QOL related to depressive symptoms after zinc supplementation. This appears to be the first longitudinal study to have found a significant association between zinc supplementation and the mental domain of the QOL among patients with AIH. Based on these results, we gained new theoretical insight into the association between the serum zinc concentration and health-related QOL in patients with AIH. Our findings suggest that both hypozincaemia and impairment of the CLDQ worry domain are associated with depression.
The health-related QOL has come to be regarded as one of the major targets for clinical research and practice (25,26), and many clinicians have begun focusing on patients' QOL, especially in the last decade (27,28). Concerning AIH, cirrhosis is already present in about 30% of adults at the initial diagnosis (5,29), and even low doses of corticosteroids, which have been recommended as first-line therapeutic agents, frequently lead to serious adverse events (30). Cirrhotic patients have been known to have a generally impaired QOL (31,32), and hypozincaemia has also been identified in patients with such chronic liver diseases, as well as depression (19,33,34). Although the efficacy of zinc supplementation for other liver diseases has been shown (35,36), there have been no reports on AIH. Consequently, this is the first study to demonstrate the benefits of zinc supplementation in AIH patients.
Based on our basic research findings, we believe that the study results can be explained by three mechanisms: 1) excessive steroids can cause depressive symptoms associated with zinc deficiency, and zinc supplementation may contribute to the reduction in the maintenance dosage of steroid in patients with AIH and subsequently improve their depressive symptoms; 2) zinc deficiency can cause organ inflammation through the cytokine-mediated signalling cascade; and 3) hepatocytes may have a self-protective effect through the enhanced expression of antioxidant factors induced by zinc supplementation.
In the basic research field, it has been shown that serum corticosteroid levels are markedly increased in highly depressed, zinc-deficient mice (37) and that abnormal secretion of glucocorticoid impairs the hippocampus and increases the risk of developing depression (38). In addition, it has been recently suggested that dysfunction of the zinc receptor GPR39 may be related to depression (39). Furthermore, basic studies using mice deficient in metallothionein, which binds zinc intracellularly, have confirmed pathological exacerbation with increased production of proinflammatory cytokines [interferon-gamma (IFN-γ) and interleukin-17 (IL-17)] from macrophages (40), suggesting that IFN-γ- and IL-17-dependent inflammation are exacerbated in the absence of intracellular zinc signalling. Recently, Ghosh et al. analysed circulating T cells in patients with major depressive disorder by flow cytometry and demonstrated an elevated circulating T helper (Th) 17 cell percentage and increased Th17 cells-to-regulatory T (Treg) cells ratio as well as IFN-γ-positive Th17 cell subsets, which secreted more IL-17 in some patients than in others (41). Th17 cells have attracted attention as effector cells for hepatocellular damage in AIH, and increased serum levels of IL-17 and intrahepatic Th17 cells have previously been observed in AIH (42). Th17 cells are inhibited by IFN-γ, which is produced by Th1 cells, whereas IL-6 coexistence in the presence of TGF-β induces Th17 cells, and IL-6 absence induces Treg cells. These results suggest that the Th17/Treg balance may contribute to the pathogenesis of the disease. In addition, Th1-stimulated M1 macrophages may exacerbate the inflammatory pathology by increasing Th17 cells via the high expression of IL-23.
Thus, an increasing number of interesting findings are being reported regarding liver disease and zinc. Zinc has been said to contribute to tissue protection by increasing the expression of haeme-oxygenase (HO-1), a stress response protein (43,44), and recent basic research suggests that HO-1-mediated signalling is important for disease activity in AIH, suggesting that this signalling pathway may also be a therapeutic target (45,46).
As briefly mentioned in the Introduction, AIH occurs disproportionately in women, and since adrenal steroids are the first-line treatment, it is not difficult to imagine that the incidence of depressive symptoms may be relatively high in this disease. Therefore, the findings of this study are novel, practical, and interesting, as they show that correcting hypozincaemia in chronic liver diseases, including AIH, with zinc supplementation can result in suppression of proinflammatory cytokines, such as IFN-γ and IL-17, which, together with the enhanced expression of antioxidant factors, can help improve both physical and psychological conditions.
Of note, hypocupraemia, which is said to occur with excessively elevated serum zinc levels, was not observed in any cases during the two-year observation period of this study, so there is no need to be overly concerned about the safety of this approach. Zinc preparations have been used in daily practice as a treatment for overt hepatic encephalopathy along with synthetic disaccharides and non-absorbable antibacterial agents, but recent studies have shown that even covert encephalopathy worsens the QOL of patients with chronic liver disease (47,48). Given these findings, the use of zinc preparations to correct hypozincaemia, which is caused by a decrease in not only the dietary intake but also albumin synthesis in the liver and the use of diuretics, is a realistic treatment option and should not be limited to end-stage conditions, such as liver failure.
Several limitations associated with this study warrant mention. First, this was a single-centre study, and its sample size was quite small, although all of the patients were analysed for a set of parameters assessed before and after zinc supplementation. Subsequently, the lack of power due to the small sample size may have prevented us from definitively concluding that clinicians might be able to taper the maintenance dosage of prednisolone during the period of zinc supplementation. To overcome this issue, a further study with an increased sample size is needed. Second, we failed to set comparative controls without zinc supplementation in this study due to the limited number of patients with AIH, although it was shown that there had been no significant change in the clinical factors that might affect the patient QOL after zinc supplementation. Third, serum zinc levels can easily change with not only circadian rhythm but also fasting and haemolysis (49,50). Fourth, as Nishikawa et al. mentioned, whether a decreased QOL causes hypozincaemia or whether hypozincaemia causes an impaired QOL is unclear (19).
However, despite these limitations, we were able to demonstrate a favourable effect of zinc supplementation on improvement in the QOL (especially in the worry domain) in patients with AIH in this study, so this therapy might be beneficial both mentally and physically.
The authors state that they have no Conflict of Interest (COI).
Financial Support
The study was supported in part by a grant-in-aid from Mylan, Mitsubishi Tanabe Pharma, and JIMRO, as well as a grant-in-aid for research from Nara Medical University.
Supplementary Material
Changes in the CLDQ worry domain score before and after the observation period were also negatively corelated with those in the daily dosage of prednisolone (P = 0.002).
Acknowledgement
We thank all of the participating patients for providing their personal information.
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Associated Data
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Supplementary Materials
Changes in the CLDQ worry domain score before and after the observation period were also negatively corelated with those in the daily dosage of prednisolone (P = 0.002).