|Year : 2021 | Volume
| Issue : 4 | Page : 197-202
Nonalcoholic fatty liver disease among long-term hospitalized patients with schizophrenia in a public psychiatric hospital
Tai- Chi Lee1, Bo- Jian Wu2, Chuan- Hsun Yu3, Tso- Jen Wang3
1 Department of Family Medicine, Yuli Hospital, Ministry of Welfare and Health, Yuli Township, Hualien County, Taiwan
2 Department of Psychiatry, Yuli Hospital, Ministry of Welfare and Health, Yuli Township, Hualien County; Department of Psychiatry, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan City, Taiwan
3 Department of Psychiatry, Yuli Hospital, Ministry of Welfare and Health, Yuli Township, Hualien County, Taiwan
|Date of Submission||22-Sep-2021|
|Date of Decision||07-Oct-2021|
|Date of Acceptance||08-Oct-2021|
|Date of Web Publication||21-Dec-2021|
M.D., Ph.D Tso- Jen Wang
448 Chung-Hua Road, Yuli Township, Hualien County 981
Source of Support: None, Conflict of Interest: None
Objectives: Nonalcoholic fatty liver disease (NAFLD) is a notable chronic liver disease due to metabolic syndrome, which has yet to be explored in long-term hospitalized patients with schizophrenia. In this study, we intended to study the prevalence of NAFLD and related risk factors for patients with schizophrenia who were long-term hospitalized. Methods: All of 182 patients with schizophrenia were recruited from a public psychiatric hospital in Taiwan. Abdomen ultrasonography was carried out for all patients. In addition to age and sex, covariates including medical diagnoses (e.g., hypertension, hypertriglyceridemia, hypercholesterolemia, and diabetes), obesity, one-year cumulative dose of antipsychotics before the entry of this study, and abnormal liver function were included in the logistic regression model. Results: The mean age ± standard deviation (SD) was 50.3 ± 9.2 years. The mean duration ± SD of hospitalization was 8.7 ± 5.0 years. Males accounted for 60.4% (110/182). The percentage of NAFLD was 70.8% (129/182). In multivariate logistic regression, patients' odd ratios (OR) (95% confidence interval [CI]) for a diagnosis of hypertriglyceridemia were 4.3 (1.11–16.7, p < 0.05) and for a finding of obesity 15.8 (3.82–65.6, p < 0.01), were significantly to have NAFLD. But patients with chronic hepatitis B were not significant to have NAFLD (OR [95% CI] = 0.17 [0.05–0.6]). Conclusion: The prevalence of NAFLD was high in patients with long-term hospitalized patients with schizophrenia in this study. We suggest that patients with schizophrenia and with long-term hospitalization need to receive timely, comprehensive, and prompt assessments for the presence of NAFLD as well as that intervention for their NAFLD is mandatory for maintaining well-being and quality of life in them.
Keywords: chronic hepatitis B infection, medications for psychosis, steatosis of liver, Taiwan
|How to cite this article:|
Lee TC, Wu BJ, Yu CH, Wang TJ. Nonalcoholic fatty liver disease among long-term hospitalized patients with schizophrenia in a public psychiatric hospital. Taiwan J Psychiatry 2021;35:197-202
|How to cite this URL:|
Lee TC, Wu BJ, Yu CH, Wang TJ. Nonalcoholic fatty liver disease among long-term hospitalized patients with schizophrenia in a public psychiatric hospital. Taiwan J Psychiatry [serial online] 2021 [cited 2022 Aug 12];35:197-202. Available from: http://www.e-tjp.org/text.asp?2021/35/4/197/332967
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury, and 20%–30% of NAFLDs are caused by nonalcoholic steatohepatitis, which may lead to cirrhosis, hepatic failure, and hepatocellular carcinoma . The definition of NAFLD includes (a) evidence of steatosis of the liver revealed by imaging study or histology and (b) exclusion of steatosis secondary to other factors, such as alcohol use, chronic hepatitis C (especially genotype 3), genetic disease, or medicine, which may lead to fatty liver (e.g., valproate) .
Compared to those without NAFLD, patients with NAFLD have a higher prevalence of mortality, cardiovascular diseases, cancers, and liver diseases with the rank of the first, second, and third, respectively, among those with NAFLD . The prevalence of NAFLD is about 23% in the United States of America , 23.3% in China , and 11.5%–42.6% in Taiwan ,. The risk factors of NAFLDs include obesity, diabetes, hyperlipidemia, and hypertension ,,,. In the general population in Taiwan, factors related to NAFLD are elevated serum levels of alanine aminotransferase (ALT), hyperuricemia, and metabolic syndromes, such as hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, and obesity ,. Because the incidence of viral hepatitis has decreased due to the promotion of public health, NAFLD has become an important topic of liver disease in the future.
For patients with schizophrenia, owing to the use of antipsychotics, especially the second-generation (atypical) antipsychotics (SGAs), the prevalence of medical comorbidities such as diabetes mellitus, hypertension, hyperlipidemia, and obesity, is remarkably higher than those in the general population . In addition, disadvantageous dietary habits, negative symptoms, lower social functioning, and a lack of exercise are more common in patients with schizophrenia . Possibly due to unhealthy lifestyles and metabolic comorbidity, patients with schizophrenia are at increased risk for NAFLD . A study enrolling 180 antipsychotic-naive patients with schizophrenia revealed that about a quarter of enrollees developed NAFLD after having received SGAs for three years . A cross-sectional study recruiting 202 young male patients with schizophrenia showed that the prevalence of NAFLD is about 50% .
In the viewpoint of public health, patients with schizophrenia are a vulnerable population who tend to have chronic liver disease that needs further prevention and treatment , especially for those who continue the use of a large amount of antipsychotics which may have a marked effect on lipid deposition in the liver ,. Long-term hospitalized patients with schizophrenia have more severe positive and negative symptoms, which may need more amount of antipsychotics and a lack of leisure activities for exercise than those in the community . Therefore, to postulate that patients with schizophrenia in the long-stay wards are more prone to have a liver disease such as NAFLD is reasonable.
To our knowledge, no studies exist to have explored the prevalence and risk factors of NAFLD among long-term hospitalized patients with schizophrenia who may have a longer time of exposure to antipsychotic treatment and subsequently may have a higher risk for NAFLD. In this cross-sectional study, we intended to study the prevalence of NAFLD and related risk factors for long-term hospitalized patients with schizophrenia.
| Methods|| |
We screened 238 subjects in a public psychiatric hospital, Yuli Hospital, the Ministry of Health and Welfare, Taiwan. The inclusion criteria were patients (a) who met the diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and (b) who were hospitalized longer than two years. The exclusion criteria were those with (a) previous history of alcohol use disorder, (b) current use of valproate, (c) presence of chronic hepatitis C or cirrhosis of the liver, (d) refusal to be evaluated, and (e) acute psychosis requiring a transfer to acute wards. Fifty-six patients were excluded – 31 had chronic hepatitis C, 29 were on valproate, as well as 6 had chronic hepatitis C and were on valproate. Ultimately, 182 patients were recruited.
The study protocol was approved by the institutional review board of Yuli Hospital (protocol number = YLH03-2012, date of approval = December 12, 2012) with the stipulation of obtaining signed informed consent from all the study participants. The study began in January 2013 and was completed in June 2013.
For each patient, the cumulative dose of antipsychotics during one year before the entry of this study was converted to an approximate dose of chlorpromazine . The antipsychotics were categorized into SGAs, nonclozapine SGAs, clozapine, combined use of first-generation (typical) antipsychotics (FGAs) and SGAs, and combined use of nonclozapine SGAs as well as clozapine . Body mass index (BMI) was calculated for each patient. Obesity was defined as BMI greater than or equal to 27. Blood was collected for fasting blood glucose, total cholesterol, triglyceride, and ALT. A high blood level of ALT was defined as ALT greater than 40 U/L. We coded diagnoses of hypertension, diabetes, hypercholesterolemia, and hypertriglyceridemia from the electronic medical record.
The abdomen ultrasonography was carried out by a senior and certified family medicine physician, TCL, using 3.5 MHz color ultrasonography. The diagnosis of NAFLD was made by the diagnostic criteria for NAFLD provided by the American Gastroenterology Association .
To explore the differences between NAFLD and non-NAFLD groups, we did univariate analysis with an independent t-test for continuous variables and a Chi-square test for categorical variables. In addition to age and sex, covariates including the medical diagnoses (e.g., hypertension, hypertriglyceridemia, hypercholesterolemia, and diabetes), obesity, high blood level of ALT ,, type of antipsychotics, one-year cumulative dose of antipsychotics , and comorbid chronic  hepatitis B  were included in the logistic regression model. The adequate sample size of the current study was 110, which was fewer than the number of participants (n = 182) and was sufficient for a logistic regression model according to a calculation formula proposed by a number of researchers .
We computed all study data with International Business Machine Statistical Package of Social Science software version 19 for Windows (IBM SPSS Company, Armonk, New York, USA). The differences between the groups were considered significant if p-values were smaller than 0.05 (two-tailed).
| Results|| |
Demographic data and other measured outcomes
[Table 1] presents demographic data and other measured outcomes. The age of patients with schizophrenia was 50.3 ± 9.2 (mean ± standard deviation [SD]) years. The duration of hospitalization was 8.7 ± 5.0 (mean ± SD) years. Male patients accounted for 60.4% (110/182). The percentage of NAFLD was 70.8% (129/182).
|Table 1: Differences in variables between groups of nonalcoholic fatty liver disease and non-nonalcoholic fatty liver disease|
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We found that our majority of patients with schizophrenia (n = 152) received a single category of antipsychotic alone. For those who received a single category of antipsychotic, the percentage of categories of antipsychotics were as follows – FGAs (n = 56, 36.8 %), clozapine (n = 55, 36.7%), risperidone (n = 19, 12.5%), amisulpride (n = 9, 5.9%), quetiapine (n = 5, 3.3%), zotepine (n = 4, 2.6%), olanzapine (n = 2, 1.3%), and aripiprazole (n = 1, 0.7%). Significant differences were found between NAFLD and non-NAFLD groups in a number of metabolic factors such as BMI (p < 0.01), the blood level of triglyceride (p < 0.01), fasting blood glucose (p < 0.01), the presence of hypertriglyceridemia (p < 0.01), hypercholesterolemia (p < 0.05), diabetes (p < 0.01), hypertension (p < 0.01), high blood level of ALT (p < 0.05), and obesity (p < 0.01).
Factors related to nonalcoholic fatty liver disease
[Table 2] displays the results of the logistic regression models, in which multicollinearity did not exist because the absolute values of bivariate correlation coefficients were all less than 0.7 . In multivariate logistic regression, patients' odd ratios (OR) (95% confidence interval [CI]) for a diagnosis of hypertriglyceridemia were 4.3 (1.11–16.7, p < 0.05) and for a finding of obesity 15.8 (3.82–65.6, p < 0.01), were significantly to have NAFLD. But, patients with chronic hepatitis B were not significant to have NAFLD (OR [95% CI] = 0.17 [0.05–0.6]).
|Table 2: Logistic regression model for exploring factors related to nonalcoholic fatty liver disease|
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| Discussion|| |
To our knowledge, this is the first study to explore the prevalence of NALFD in long-term hospitalized patients with schizophrenia. Our current study showed that a high prevalence of NAFLD – up to 70% – was found among hospitalized patients with schizophrenia with an average of 8.7 years of length of stay [Table 1]. In addition, multivariate logistic regression revealed that hypertriglyceridemia (p < 0.05 in multivariate analysis) and obesity (p < 0.01 in multivariate analysis) were significant risk factors of NAFLD, and chronic hepatitis B is a protective factor against NAFLD for these patients [Table 2].
The prevalence of NAFLD in our study is much higher than in the general population ,,,. The prevalence of NAFLD in this current study is also much higher than in drug-naïve patients with schizophrenia receiving SGAs for three years (prevalence = 25%)  and 202 male patients with schizophrenia receiving antipsychotics at least for one month (prevalence = 50%) . The most important reason for the disparity in the prevalence of NAFLD is due to the differences in the participants in our study from those in the other two studies. The higher prevalence of NAFLD in ours may be partly explained by the fact that patients with schizophrenia in the long-stay wards have more marked negative symptoms, which lead to a lack of leisure activities including regular exercise . Moreover, patients with obesity (p < 0.01 in both univariate and multivarate analyses) and hypertriglyceridemia (p < 0.01 and p < 0.05 in univariate and multivarate analyses, respectivley) were more significantly to have NAFLD in this current study [Table 2]. Those findings are compatible with those in studies for the general population [6, 7, 11] and in a study enrolling male patients with schizophrenia .
A study recruiting 876 people with metabolic syndrome in the general population in Taiwan revealed that women are 4.2 times more likely than men to have NAFLD . But in this study [Table 2], we did not find an association between sex and NAFLD. This might be accounted for by the fact that the target population in this study was hospitalized patients with schizophrenia whose lifestyles, including medication and eating and exercise patterns, were predominantly affected by institutionalization, so gender effects on NAFLD are to be offset. In addition, after controlling for many confounders, our study did not reveal any association between diabetes and NAFLD [Table 2], which is not in accordance with the findings in other studies [6, 7, 11]. In line with our study, a study exploring 202 male patients with schizophrenia does not show any association between fasting glucose level and NAFLD, either . The possible reasons may be due to differences in characteristics of subjects among various studies (schizophrenia vs. general population) and sample size (smaller sizes in the current study and in Yan et al.'s study vs. larger sizes in other studies).
Our study did not show that patients with SGAs or combined use of FGAs and SGAs were more to have NAFLD than those who used FGAs alone [Table 2]. For further analysis, in multivariate logistic regression, we excluded patients with combined use of antipsychotics and found that users of different types of SGAs, i.e., risperidone, zotepine, amisulpride, aripiprazole, clozapine, olanzapine, and quetiapine, did not have a significant association with NAFLD in comparisons with FGAs users (data not shown). But patients on SGAs are considered to be more likely than those on FGAs to have NAFLD . In addition, one study also showed that combined antipsychotic treatment and a higher antipsychotic dose can increase the risk of NAFLD in male patients with schizophrenia . The disparity in results between our study and the latter may be explained in part due to the differences in demographic factors (e.g., both sexes vs. males, civilian patients vs. veterans, older vs. younger in the current study, and long-term hospitalization vs. unknown duration of hospitalization). Besides, there was a smaller size in our current study, which led to an insufficient statistical power to detect the effect of various types of antipsychotics on the occurrence of NAFLD.
Notably, our study was found that patients with chronic hepatitis B were not likely to have NAFLD [Table 2]. The finding of our study is compatible with that of many studies ,,,. A study conducted in Hong Kong showed that chronic hepatitis B infection is associated with a lower risk of NAFLD in the general population; among patients with chronic hepatitis B, the e antigen of hepatitis B, viral genotypes, and hepatitis B DNA levels are not associated with NAFLD . But a meta-analysis comprising 17 studies revealed that the occurrence of hepatic steatosis is negatively associated with the viral load of chronic hepatitis B, suggesting a possible mechanism that a higher viral load of chronic hepatitis B may have protective effects against NAFLD . Our finding warrants further investigation of the rôle of chronic hepatitis B on NAFLD, which could shed light on exploring novel treatment modalities for NAFLD in the future.
Finally, significant differences (p < 0.05) existed in the length of stay between those with NAFLD and those without [Table 1]. But for further analysis in the multivariate logistic regression [Table 2], no significant association was found between the length of stay and NAFLD (data not shown). Further studies about the association between the length of stay and the occurrence of NAFLD for patients with schizophrenia may be warranted.
Our study found that patients with hypertriglyceridemia and obesity were at risk for NAFLD. Hence, for inpatients with schizophrenia, detecting the occurrence of obesity and hypertriglyceridemia by means of a regular monitor of blood triglyceride level and BMI is important. For patients with a high risk for NAFLD, prudent use of some types of SGAs, (e.g., clozapine, olanzapine, or quetiapine), which may be more likely to cause metabolic syndrome ,. In addition, for the prevention of occurrence of NAFLD and treatment of pre-existing NAFLD, psychiatrists, psychiatric nurses, occupational therapists, and dietitians in hospitals should arrange integrative programs including psychoeducation, diet, and physical interventions to maintain physicical fitness in inpatients with schizophrenia ,.
Furthermore, to incorporate general practitioners or gastroenterologists for integrated care for the early detection of NALFD is pivotal for psychiatrists for inpatients with schizophrenia and with obesity and metabolic syndrome. The regular arrangement of abdomen ultrasonography and liver function tests should be done to patients at high risk for NAFLD. Concerning those who have pre-existing NAFLD, for the prevention of the development of cirrhosis, hepatic failure, and hepatocellular carcinoma, close monitoring and intensive treatment are needed . Pharmacological strategies for NAFLD include the prescription of statin, thiazolidinediones, metformin , and subcutaneous injection of glucagon-like peptide 1 receptor agonist dulaglutide  should be considered.
The readers are warned not to overinterpret the study results because our study has five limitations:
- The findings may only be generalized to similar populations, such as stable long-term hospitalized patients with schizophrenia.
- A lack of comparison is found between other populations with different clinical features. Further observational studies may explore the comparisons of NAFLD among long-term hospitalized patients and other populations, such as patients without long stay in hospitals, patients in the community, patients with early-onset psychosis, and the general population.
- The current study is a cross-sectional design, which included variables of cumulative dosage of antipsychotics and type of antipsychotics only during one year before the commencement of the study. We did not explore the causal effect of different types, doses, and the length of use of SGAs on the occurrence of NAFLD. If our study had adopted a design similar to one cohort study , which observed the effect of SGAs on the occurrence of NAFLD for three years, the causal relationship between drug characteristics, such as type of antipsychotics as well as the dose of antipsychotics and occurrence of NFALD, may have been more robust.
- A smaller size of this current study may have a lower statistical power, which may be unable to detect other risk factors related to NAFLD. Enlarging sample size is needed for further studies.
- Other risk factors, such as metabolic syndrome , and psychopathology (i.e., negative symptoms)  were not included in this study. It is worth exploring similar factors in further studies.
The findings of our study revealed a high prevalence of NAFLD among long-term hospitalized patients with schizophrenia. Hypertriglyceridemia and obesity were found to be significant risk factors of NAFLD. To prevent severe complications caused by NAFLD, timely, we suggest that comprehensive and prompt assessment of the presence of NAFLD as well as intervention is mandatory for maintaining well-being and quality of life in the long-term care for patients with schizophrenia.
| Acknowledgements|| |
The members of the study group are Mei-Li Huang and Wen-Shiu Wang. We thank dozens of mental health professionals who participated in the preparation and conducting of the survey.
| Financial Support and Sponsorship|| |
This work was supported by the Yuli Hospital, the Ministry of Health and Welfare, Taiwan (grant number YLH-IRP-10204).
| Conflicts of Interest|| |
All authors declare that they do not have any conflicts of interest in reporting this study.
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[Table 1], [Table 2]