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Psychosomatic Medicine 68:563-569 (2006)
© 2006 American Psychosomatic Society

ORIGINAL ARTICLES

Depression, Anxiety, and Nonalcoholic Steatohepatitis

Jill E. Elwing, MD, Patrick J. Lustman, PhD, Hanlin L. Wang, MD, PhD and Ray E. Clouse, MD

From the Division of Gastroenterology (J.E.E., R.E.C.), Department of Psychiatry (P.J.L., R.E.C.), and Division of Anatomic Pathology (H.L.W.), Washington University School of Medicine, St. Louis, Missouri.

Address correspondence and reprint requests to Ray E. Clouse, MD, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8124, St. Louis, MO 63110. E-mail: rclouse{at}im.wustl.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Nonalcoholic steatohepatitis (NASH) is a morbid liver disease with limited treatment. Depression and anxiety have been associated recently with insulin resistance and inflammatory states, factors that are relevant to the development of NASH. We hypothesized that depression and anxiety would be more prevalent in NASH patients and predict more severe histological findings on liver biopsy.

Methods: Histories of major depressive disorder (MDD) and generalized anxiety disorder (GAD) were determined using a structured interview and DSM-IV criteria in 36 NASH subjects and 36 matched controls without liver disease who had undergone cholecystectomy. Histological changes on liver biopsy in NASH subjects were age-adjusted and compared in subjects with and without psychiatric disorders. A multivariate model incorporating other potential risk factors for NASH (female sex, body mass index, waist-to-hip ratio, and presence of diabetes) was used to determine independent effects of MDD and GAD on severity of histological findings.

Results: NASH subjects had significantly increased lifetime rates of MDD (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.4–10.2; p = .018) and GAD (OR 5.0, 95% CI, 1.7–14.9; p = .005). The onset of psychiatric illness preceded diagnosis of liver disease by 18 to 20 years. Each psychiatric disorder was associated with more severe histological features (p < .05 for each), the effect of GAD on fibrosis stage persisting in the multivariate model.

Conclusions: MDD and GAD are overrepresented in NASH subjects and are associated with more advanced liver histological abnormalities. Additional investigation will be required to determine if depression and anxiety affect the development or progression of NASH and serve as modifiable risk factors.

Key Words: nonalcoholic steatohepatitis • insulin resistance • major depressive disorder • generalized anxiety disorder

Abbreviations: BMI = body mass index; DIS = Diagnostic Interview Schedule; DSM-IV = Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition; GAD = generalized anxiety disorder; MDD = major depressive disorder; NASH = nonalcoholic steatohepatitis; PHQ = Patient Health Questionnaire; WHR = waist-to-hip ratio; OR = odds ratio; CI = confidence interval.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Nonalcoholic steatohepatitis (NASH) is present in as much as 2% to 4% of the US population, the prevalence in at-risk populations with diabetes and obesity reaching 20% (1). NASH now is recognized as the most common cause of cryptogenic cirrhosis and carries a prognosis resembling that of hepatitis C (2). With obesity being predicted to afflict 40% of the US population by 2025 (3), NASH has become a significant public health concern. A growing body of literature has established insulin resistance as one causative factor and positioned NASH as the hepatic manifestation of the metabolic syndrome (4). It is unlikely that insulin resistance alone is sufficient to cause all the histological characteristics of NASH, candidate cofactors including inflammatory states and oxidative stress (3). Treatment options remain limited, highlighting the importance of identifying modifiable risk factors for disease development or progression.

Depression and anxiety predict subsequent development of type 2 diabetes, poor glycemic control in diabetic patients, increased diabetes complications, and acceleration of coronary heart disease in diabetic and nondiabetic subjects independently of traditional risk factors (5–9). The mechanism of this effect is uncertain, but poor adherence to treatment regimens is not conspicuously at fault (10). Patients with depression exhibit glucose intolerance and elevated insulin levels after oral glucose loading, suggestive of insulin resistance, an alternative explanation (11). Treatment of depression and anxiety can improve hyperglycemia in diabetes, at least in the short term, independently of change in weight or adherence to diabetes management (12–14). Thus, anxiety- and depression-associated insulin resistance is suspected and could provoke development of NASH or accelerate its course in genetically or environmentally susceptible individuals. Depression and anxiety also resemble inflammatory states (15–17), thereby potentially providing the additional requisite stimulus for histological progression.

Depression and anxiety are treatable conditions that may represent modifiable risk factors for NASH, but their prevalence and relevance in this liver disease have not been explored. We aimed to compare the rates of criteria-defined major depressive disorder (MDD) and generalized anxiety disorder (GAD) in NASH subjects to those in a comparison group and determine the relationship of antecedent psychiatric illness to liver biopsy findings. We hypothesized that these psychiatric disorders would be more prevalent in the NASH subjects and predict advanced histological features.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Subjects
Presence of psychiatric illness was assessed in 36 subjects with NASH treated at Washington University from 2000 to 2001. All adult patients with histologic evidence of NASH on liver biopsy that could be identified through billing records of the Department of Internal Medicine and Division of Anatomic Pathology covering this time frame were recruited through written correspondence, with subsequent telephone contact. Potential subjects were excluded if interview or record review indicated any of the following: liver biopsy unavailable for review, diagnosis of other or additional liver disease, history of consuming >40 g/week of alcohol, history of any substance abuse, morbid obesity with body mass index (BMI) >40 kg/m2, history of gastric bypass surgery, use of specific medications (amiodarone, perhexiline, tamoxifen, high-dose glucocorticoids, methotrexate, nifedipine, or diltiazem), or history of total parenteral nutrition for >3 months. Of the 88 patients identified, 35 were unreachable, 7 were excluded from participation (3 with previous gastric bypass, 3 without biopsy, 1 with alcohol use above threshold), 4 were deceased, and 6 refused, leaving 36 subjects for study.

Potential control subjects were identified from a list provided by the Department of Surgery of adult patients who had undergone cholecystectomy over the same time period as liver biopsy in the NASH subjects. Postcholecystectomy patients were chosen as the comparison group because they were likely to have had abdominal imaging, were symptomatic and seeking medical care (allowing for nonspecific effects of illness on psychiatric symptoms and psychiatric illness on health-care seeking behavior), and have many demographic and anthropometric features similar to patients with NASH. For this initial case-control comparison, matching these clinical features between groups seemed of greater importance than choosing a control group with alternative liver diseases. Consecutive patients who had been imaged with CT or ultrasound of the abdomen within 12 months of cholecystectomy and had no imaging features of liver steatosis were considered eligible, acknowledging the noninvasive nature of these screening tests but also their limited sensitivity for steatosis involving less than 33% of hepatocytes (18). They were recruited through written correspondence with subsequent telephone contact if participation was required for matching. As with the NASH subjects, control subjects were excluded if interview or record review detected any of the exclusion criteria listed above, with the exception of liver biopsy.

From a pool of 147 potential control subjects, a match was selected for each NASH subject using the following features and thresholds: age at time of liver biopsy or cholecystectomy (±5 years), BMI at time of liver biopsy or cholecystectomy (±3.0), waist-to-hip ratio at time of interview (WHR; ±0.15), and gender. Contact with control subjects continued until each NASH subject was matched. Informed consent for participation was obtained from all subjects at the time of first telephone contact. This study was reviewed and approved by the Human Studies Committee of Washington University.

Assessment Protocol
An initial 30-minute telephone interview was performed by a research team member who was aware of subject diagnosis (NASH or control). The semistructured interview was conducted to obtain medical history; detailed alcohol, tobacco, and chronic disease history, including presence or absence of other liver diseases, diabetes, hypertension, and hypercholesterolemia; and medication history. Height, current weight, and waist and hip circumference measurements were collected. An instructional sheet and measuring tape had been mailed before the interview, demonstrating the method for determining waist and hip circumference. Current BMI was calculated from self-reported height and weight for comparison to BMI at the time of liver biopsy or cholecystectomy but was not used in statistical analyses. Medical charts of participants were reviewed to determine height and weight at time of NASH diagnosis or cholecystectomy (measured at the outpatient faculty offices without abundant clothing), presence of comorbid illness, and any evidence of other liver disease. In order to avoid confounding from alcoholic liver disease, a conservative level of alcohol consumption of <40 g/week was chosen as the inclusion threshold. After confirmation that each participation criterion was met, the subject was referred for a second telephone interview to collect psychiatric information. For both NASH and control subject groups, 100% of the requested clinical data was obtained. Data collection occurred between February 1, 2004, and September 1, 2004.

Psychiatric Assessments
Psychiatric assessments were performed by a trained interviewer blinded to the subject’s medical diagnosis and to study hypotheses. The interviewer was instructed to avoid questions regarding prior medical diagnoses, and the subject was instructed not to reveal diagnosis of liver disease or history of cholecystectomy. MDD and GAD were determined with appropriate sections of the National Institute of Mental Health Diagnostic Interview Schedule (DIS), Version III, a standardized interview that establishes diagnoses in accordance with the criteria specified in the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) (19). This highly structured interview, with demonstrated reliability, validity, and suitability for telephone use (20,21), is sensitive to psychiatric diagnoses in patients with systemic illness, such as diabetes, wherein some apparent symptoms of psychiatric disorder may result from metabolic derangements (22). The DIS allows characterization of MDD and GAD over the course of the subject’s lifetime, enables dating of disorder onset, and permits some assessment of illness severity by extracting data on relapses, episode duration, and treatment. Subjects who reported sufficient criteria-defining symptoms at any time in their lives were considered to have lifetime histories of MDD or GAD; the subset of these who fulfilled diagnostic criteria at the time of the present interview (not necessarily at the time of liver biopsy or surgery) were diagnosed also as having current illness. Subjects with onset of psychiatric illness after the date of liver biopsy or cholecystectomy were not considered psychiatrically ill for this study.

Depression questions from the Patient Health Questionnaire (PHQ), a diagnostic instrument validated for use in nonpsychiatric settings, also were administered (23). The PHQ provides categorical algorithms for diagnosing psychiatric disorders using modified criteria from the DSM-IV and includes a continuous scale for measuring depression severity from the 9 MDD criterion symptoms (PHQ-9). Each symptom is rated from "0" (not at all) to "3" (nearly every day) over the 2-week period before the interview. The PHQ-9 was used to corroborate findings from the DIS by providing a severity rating of current symptoms.

Histological Methods
Liver biopsy specimens from the NASH subjects were reviewed by an investigator who was blinded to the presence or absence of psychiatric disorder and to the study hypotheses. Each biopsy was rated using criteria recently published by Brunt (24): severity of steatosis using a score of 0 (0% of hepatocytes involved), 1 (>0% to 33%), 2 (>33% to 66%), or 3 (>66% to 100%); grade of necroinflammatory change (hepatocyte ballooning, lobular inflammation, portal inflammation) using a score of 0 (none), 1 (mild), 2 (moderate), or 3 (severe); and stage of fibrosis using a score of 0 (none), 1 (zone 3 perivenular perisinusoidal/pericellular fibrosis, focal or extensive), 2 (same as 1 but with focal or extensive periportal fibrosis), 3 (bridging fibrosis, focal or extensive), or 4 (cirrhosis) (24). Given the established effect of age on histological severity, especially fibrosis (25,26), individual scores were divided by subject age in years to examine the effects of independent variables on acceleration of histological change.

Statistical Methods
Grouped data are reported as mean ± SE throughout. Comparisons between groups were performed with two-tailed Student’s t test or Fisher’s exact test, as appropriate, and corresponding odds ratios (OR) and 95% confidence intervals (CI) are reported. Logistic regression was used to determine the effect of subject group on presence of psychiatric illness after controlling for univariate differences in clinical characteristics. Multiple linear regression was used to determine independent effects of clinical characteristics on age-adjusted histologic scores with all potentially relevant predictors entered into the model and no elimination. For each analysis, {alpha} of 0.05 was used for statistical significance and 0.1 for a statistical trend.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Clinical characteristics of the groups with and without NASH are shown in Table 1. Only the differences in diabetes rate and WHR in men were significant, both being greater in the NASH subjects. A trend toward higher WHR in women with NASH also was evident.


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  		TABLE 1. Clinical Characteristics of the Subject Groups

 

NASH subjects had significantly increased rates of both lifetime MDD (OR, 3.8; 95% CI, 1.4–10.2; p = .018) and lifetime GAD (OR, 5.0; 95% CI, 1.7–14.9, p = .005) (Figure 1). The two psychiatric diagnoses were present concurrently in some subjects, and the proportion of subjects with either MDD or GAD (or both) was significantly greater in the NASH group (63.8% versus 33.3%; OR, 3.53; 95% CI, 1.34–9.34; p = .018) (Figure 1). ORs were not reduced for the ability of NASH to predict MDD and GAD when the analyses were controlled for differences in diabetes rate and WHR (MDD: OR, 6.2; 95% CI, 1.9–20.7; p = .008; GAD: OR, 6.3; 95% CI, 1.9–21.5; p = .003). In these statistical models, WHR also was associated independently with MDD (p = .02). MDD was diagnosed in one control subject with its first presentation after the time of cholecystectomy; in accordance with the Methods, this diagnosis was not considered in the analyses.


Figure 18
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  		Figure 1. Rates of lifetime psychiatric diagnoses in NASH and control subjects. Rates for each studied diagnosis were greater in the NASH subjects. *p < .05; **p < .01.

 

Psychiatric illness characteristics did not differ between NASH and control subjects (Table 2). Age at onset of MDD and GAD was similar between groups, as was duration of psychiatric illness before diagnosis of liver disease or cholecystectomy (MDD: 19.8 ± 2.9 years versus 25.0 ± 2.0 years, p = .12; GAD: 18.1 ± 2.9 years versus 14.8 ± 1.9 years, p = .99). A majority of both NASH and control subjects meeting criteria for psychiatric illness had received psychopharmacologic treatment at some point in their lifetimes, but more NASH subjects overall tended toward having received these medications (52.8% versus 30.6%, p = .09). Although the proportion of subjects with psychiatric illness having currently active symptoms was similar between groups, the actual rate of current MDD trended toward being higher in NASH subjects compared with controls (p = .09) and the rate of current GAD was higher in the NASH group (p = .003). These increased rates of current psychiatric illness were corroborated by findings on the PHQ-9 (Figure 2).


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  		TABLE 2. Features of Major Depressive Disorder and Generalized Anxiety Disorder in Afflicted Individuals From Each Subject Group

 

Figure 28
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  		Figure 2. Findings from the nine depression symptoms on the Patient Health Questionnaire (PHQ-9). NASH subjects endorsed more symptoms and had higher cumulative scores than the control subjects. *p < .05; **p < .01. Error bars represent SE.

 

Liver biopsy scores in NASH subjects showed moderate degrees of steatosis (2.5 ± 0.1) and fibrosis (1.7 ± 0.2), with milder necroinflammatory change (1.2 ± 0.1). Only 3 subjects had cirrhosis. Age-adjusted histological features were influenced by the presence of psychiatric illness (Figure 3). Subjects with MDD demonstrated more steatosis than those without psychiatric diagnoses (p = .049), and those with GAD had higher grade of inflammation (p = .034) and stage of fibrosis (p = .042) than those without psychiatric diagnoses. To see if these effects were independent of other relevant clinical variables, multivariate models for each histological feature were tested that included sex, BMI (at time of liver biopsy or cholecystectomy), WHR, and presence of diabetes, as well as the psychiatric disorders, although there were no significant univariate differences in the additional variables between NASH subjects with a psychiatric diagnosis or without. The regression analyses revealed an independent contribution of GAD toward predicting fibrosis stage (p = .038) and a trend for MDD as a predictor of steatosis (p = .056). Female sex (p = .008) and presence of diabetes (p = .024) also independently predicted fibrosis stage.


Figure 38
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  		Figure 3. Severity of liver histology in NASH subjects in relation to presence or absence of psychiatric illness. Histological scores in each category were adjusted for subject age as described in the Methods. MDD = major depressive disorder; GAD = generalized anxiety disorder. *p < .05 compared with subjects having no psychiatric diagnosis. Error bars represent SE.

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
In this study we found increased lifetime rates of MDD and GAD in NASH subjects compared with an obese comparison group after controlling for differences in diabetes rate and WHR between groups. These findings were corroborated by higher rates of current psychiatric diagnoses and elevated PHQ-9 scores in the NASH group. Both psychiatric diagnoses were associated with greater histologic change on liver biopsy, and the effect of GAD on fibrosis was independent of other explanations, including sex, BMI, WHR, and presence of diabetes. A similar independent effect of MDD on steatosis trended toward significance (p = .056). Considering the prolonged time between the first manifestations of psychiatric illness and the diagnosis of liver disease (18–20 years on average), our findings suggest that anxiety and depression may influence the development or progression of NASH. This remains speculative, however, as causality rarely is determined from a retrospective, case-controlled study design.

NASH is thought to be a product of insulin resistance and inflammatory or oxidative stress. The causative role of insulin resistance has been well established, even in lean, nondiabetic patients (27–29), and insulin-sensitizing medications can improve both liver enzymes and histology (29). Although less established, depression and anxiety also appear associated with insulin resistance. Meta-analyses demonstrate significant associations between depression or anxiety and hyperglycemia in both type 1 and 2 diabetic patients, associations that are insufficiently explained by poor adherence to diabetes treatment regimens or weight (5,6,10). The associations also are reflected by the increased rates of diabetes complications, with small to moderate effect sizes of depression on most recognized complications (retinopathy, nephropathy, neuropathy, sexual dysfunction, and macrovascular complications) (30). Depression accelerates the appearance and progression of coronary heart disease in diabetic and nondiabetic subjects (9,31), a finding at least partially independent of hyperglycemia in diabetic subjects (32) and potentially related to depression-associated insulin resistance (33). Abnormally elevated blood glucose levels and insulin responses to glucose tolerance testing also have been demonstrated in depressed subjects with and without diabetes (11,34).

Treatment trials provide further support for a relationship between depression and insulin resistance. Modest short-term improvement in glycemic control with antidepressant treatment or psychotherapy has been documented in diabetic patients, the effect being independent of change in weight or adherence to diabetes management (12–14). Additionally, treatment of depression with a tricyclic antidepressant increased insulin sensitivity in nondiabetic patients, an effect observed without change in BMI, fasting blood glucose, or basal insulin (35). Although the co-occurrence of depression and the metabolic syndrome may be partially heritable, modulation of depressive symptoms in one of a genetically identical twin pair correlated with individual measurements reflecting the syndrome (blood pressure, BMI, WHR, triglycerides, and glucose levels) (36). Increases in counterregulatory hormones (cortisol, epinephrine, growth hormone) in depression and anxiety may be partially responsible for impaired glucose regulation and insulin resistance seen with these disorders, but this has not been established (37).

Progression from steatosis to NASH likely requires additional insults such as inflammation and oxidative stress. Treatment with the antioxidants betaine and vitamin E in small studies has produced improvement in transaminases and liver histology (38,39). Data also suggest that cytokines (e.g., IL-6, IL-8, TNF{alpha}) play a role in NASH (40), and decreased cytokine levels with weight loss or with the TNF{alpha} inhibitor pentoxifylline correlate with improvement in liver enzymes and insulin resistance (39,41). The fact that depression and psychological stress are associated with markers of inflammation (15,16,42) provides additional biological plausibility to the theory that MDD and GAD increase the risk for progression of NASH. Multiple reports have demonstrated increased IL-6 levels in average-age and elderly depressed subjects (15–17). Penninx et al. (15) found increased IL-6 and TNF{alpha} levels in 145 depressed subjects compared with a large comparison group after controlling for health and demographic features. Maes et al. (17) showed that stress states (e.g., posttraumatic stress disorder) were associated with increased IL-6 levels; levels of IL-6 receptor were further elevated when acute stress was combined with depression. Acute psychological stress associated with examination-taking or physical injury also elevates cytokine levels (42,43). Ozcan et al. also demonstrated decreased antioxidant enzyme activity and increased markers of oxidative stress in subjects with depression when compared with a control group (44).

The strength of our conclusions is limited by possible medication effects, small sample size, and the potential for ascertainment bias. Because many of the subjects had received psychopharmacologic agents intermittently before liver biopsy, it is possible that treatment affected the histology either positively (improving psychiatric illness, thereby blunting adverse effects) or negatively through a direct drug effect. A wide variety of medications was used, duration of treatment was variable, and NASH is not a recognized outcome of common antidepressant or antianxiety medications. Nevertheless, a drug effect cannot be excluded. Power to detect independent effects of psychiatric illness on histology was limited by small sample size, and multivariate analyses are inherently unstable when sample sizes and numbers of outcome events are small. Thus, the effect of psychiatric illness on histology and its relationship to potential mediators or modulators would be better established in prospective studies with larger study populations. Additionally, age adjustment of histologic features assumes some degree of linearity to NASH progression over time, yet this component of the natural history of the disease remains unknown.

Relative diagnosis rates between groups may have been affected by methods used for identification of study subjects or definition of the control group. Subjects were acquired as consecutive candidates who satisfied a priori participation criteria, none of which related to psychiatric symptoms or history. It is unlikely that psychiatric illness was overrepresented in NASH subjects because of enhanced symptom reporting and resultant increased health care seeking compared with the cholecystectomy patients. NASH is determined objectively by laboratory testing and imaging, whereas decisions regarding operative intervention often are determined by subjective complaints in patients with presumed gallstone disease, facts that might have promoted greater psychiatric diagnosis rates in the comparison group. Nevertheless, NASH is a chronic illness with the potential for longstanding effects on mood. We excluded psychiatric diagnoses that first presented after liver biopsy or cholecystectomy, and psychiatric illness predated NASH or cholecystectomy by an average of 15 to 25 years, but an effect of occult liver disease on psychiatric functioning cannot be excluded. Within the NASH group, psychiatric information precisely at the time of biopsy possibly could have provided superior correlative information.

The method of excluding liver disease in the control subjects also was imperfect, although ultrasound and CT scanning have sensitivities exceeding 90% for steatosis of 33% or greater, a threshold surpassed by all of our NASH subjects (18). However, failure to exclude NASH in some of the control subjects potentially would have minimized rather than augmented our finding. Similarly, the methods used to determine WHR were suboptimal, and this important anthropometric measurement was taken at the time of interview rather than the time of liver biopsy or cholecystectomy. Self-measured WHR was required because many subjects no longer lived in the St. Louis area. This method is sufficiently accurate for epidemiologic studies, but subjects tend to underestimate circumferences (45,46). Despite our attempts to match controls with NASH subjects by WHR, a systematic bias left male controls with lower WHR than their liver-disease counterparts. Statistically controlling for differences did not reduce the impact of NASH on presence of either psychiatric illness, but WHR was independently associated with MDD in our subjects and may remain at least a partial mediator of the discovered relationships in this study. Observations linking stress to enhanced visceral fat deposition in human and animal studies may be relevant in this regard (47–49). All the potential biases and artifacts inherent to case-controlled studies may have influenced our findings, but the importance of psychiatric illness was supported by the histologic differences within the NASH group, analyses that were not influenced by these factors.

Current management recommendations for NASH focus on reducing factors associated with insulin resistance. Nonrandomized studies support gradual weight loss (50). Insulin-sensitizing agents, antioxidants, and TNF{alpha} inhibitors were beneficial in studies with small sample sizes, but their efficacy and safety in long-term management require better demonstration before widespread use can be recommended. Identification of depression and anxiety as potentially modifiable risk factors for NASH provides novel treatment targets, and additional research to investigate effects of psychiatric intervention on inflammatory markers, insulin resistance, and liver histology is recommended. Depression treatment, particularly with pharmacologic agents, does not reliably produce dramatic or sustained glycemic improvement in diabetes, raising questions regarding optimal duration or type of intervention that may reverse insulin resistance associated with psychiatric illness (12).

Alternatively, it remains possible that an unrecognized factor is responsible for both psychiatric disorder and insulin resistance or that anxiety and depression are further manifestations of the metabolic syndrome, conclusions that may limit benefits of psychiatric intervention on insulin resistance and its consequences (51). Recent longitudinal studies in young adolescents suggest that obesity is a predictor of the subsequent development of depression (52), and resistance to insulin effects on central neurons has been hypothesized to play a role in depression (53,54). Some information also supports a favorable mood effect from insulin-sensitizing agents or nonpharmacologic interventions with insulin-sensitizing effects (54–57). Thus, even if our findings from this retrospective, case-controlled study are supported by additional investigations associating psychiatric disorder with NASH, the nature of the relationship may not be easily established. Likewise, the status of MDD and GAD as modifiable risk factors for occurrence or histological progression of the liver disease remains far from determined. However, in other insulin-resistance settings (viz., type 2 diabetes), depression screening and management are entering into medical care standards both for prevention of overt disease and development of complications (58,59).

Further studies are required both to confirm an association of NASH with psychiatric disorder and to determine the nature of any relationship discovered. The comparison group chosen for our study was meant, in part, to control for the nonspecific and potentially specific effects of obesity on psychiatric findings. Further comparison now is required to subjects with other biopsy-proven liver diseases. Similarly, the relationship of depression and anxiety to the histologic features found in our NASH subjects should be examined across the spectrum of liver disease. Epidemiologic studies could be used to evaluate the risk of subsequent NASH diagnosis in subjects with depression or anxiety and verify or refute our interview findings. The effects of depression interventions on liver chemistries or histology, particularly those with sustained mood effects, also would be of interest, as would the effects of conventional NASH treatments on mood. A host of investigations may be required to fully clarify these findings.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

Supported by NIDDK Grants R01DK063202 and R01DK53060.

DOI:10.1097/01.psy.0000221276.17823.df


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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