Associations between Bright Pancreas and Features of Metabolic Syndrome

Transcription

1 Japan Society of Nigen Dock ORIGINAL ARTICLE Ningen Dock 2012 ; 26 : Associations between Bright Pancreas and Features of Metabolic Syndrome Akihiro Obora 1,2), Takao Kojima 1,2), Takahiro Kato 1), Mio Endo 1), Kiichiro Miyawaki 1), Nobuhiro Fukuta 1), Naomi Ban 1), Masahide Hamaguchi 3) Background We previously reported on an association between increased echogenicity of the pancreas not accompanied by fatty liver and lifestyle-related diseases. In the present study, we examined an association between metabolic syndrome and increased echogenicity of the pancreas not accompanied by fatty liver. Methods We evaluated 1993 subjects who underwent abdominal ultrasonography as examinees of the Medical Health Check-up Center of Murakami Memorial Hospital in 2001 and then underwent abdominal ultrasonography again during the period. Positive hepato-pancreatic contrast on abdominal ultrasonography was defined as bright pancreas. Results During the 2001 ultrasonography examinations, bright pancreas was detected in 776 subjects. This group of subjects had a higher BMI, BW, BP, smoking status and alcohol consumption, significantly higher levels of ALT, γ-gtp, LDL - cholesterol, HDL - cholesterol, TG, fasting blood sugar and hemoglobin A1c, and lower serum amylase. During the 2009 and 2010 examinations, a larger number of subjects (866) were found to have bright pancreas. Conclusion Bright pancreas not accompanied by fatty liver was strongly associated with metabolic syndrome, a lifestyle-related disease. Therefore, it seems necessary to consider bright pancreas to be abnormal and to follow up patients with this condition while providing guidance on lifestyle improvement and/or other interventions. Key Words : bright pancreas, metabolic syndrome, ultrasonography, fatty pancreas Abdominal ultrasonography can detect increased echogenicity of the pancreas in the health check-ups of disease-free individuals. We previously defined this finding as ʻbright pancreasʼ and reported on its clinical importance 1. Marks et al. 2 reported that increased pancreatic echogenicity on abdominal ultrasonography might From the 1) Department of Gastroenterology, Murakami Memorial Hospital, Asahi University, 2) Medical Health Check-up Center of Murakami Memorial Hospital, Asahi University, and 3) Immunology Frontier Research Center at Osaka University. Address for Reprints : Akihiro Obora, Department of Gastroenterology, Murakami Memorial Hospital, Asahi University Hashimoto-cho, Gifu , Japan. Tel Fax a-obora@murakami.asahi-u.ac.jp Received July 11, 2011 ; Accepted November 2, 2011 represent a fatty change of the pancreas and suggested that the increased echogenicity, or ʻbright pancreas,ʼ represents fatty pancreas. Bright pancreas is usually accompanied by fatty liver 1,3. Also, it is widely recognized that many patients with fatty liver have type 2 diabetes mellitus, dyslipidemia, obesity, and/or hypertension 1. Diagnostic criteria 4 for metabolic syndrome were established by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) in 2001, and a close association has been shown between nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome 5-7. However, bright pancreas has not yet been recognized as an abnormal feature of the pancreas, and even when we detect bright pancreas in examinees, no medication is recommended. To assess the etiology of bright pancreas and evaluate its clinical importance, we performed 27 (935)

2 a long-term follow-up study, investigating its appearance and disappearance, as well as associations between bright pancreas and metabolic disorders including metabolic syndrome. Methods Study Design and Population We previously performed a cross sectional study to examine an association between bright pancreas and metabolic syndrome. In our previous study, there were 3,563 subjects (2,228 men and 1,335 women), who gave informed consent. Briefly, those enrolled were persons who received health check-ups at the Medical Health Check-up Center of Murakami Memorial Hospital in The following criteria were applied: 1) free of fatty liver, 2) no history of treatment for hepatic malignancy, 3) free of known liver diseases including viral hepatitis, alcoholic liver injury, autoimmune hepatitis and primary biliary cirrhosis, and 4) no medical history of treatment for pancreatic tumors, 5) free of known pancreatic diseases including acute pancreatitis, chronic pancreatitis and autoimmune pancreatitis. These 3,563 subjects were prospectively followedup. Among them, 1,993 underwent abdominal ultrasonography at our hospital during the period. The basic characteristics of this population were: 1252 men, average age at first visit, 46.5 ± 8.0 years; 741 women, average age at first visit 45.0 ± 7.2 years; mean follow-up period 8.7 ± 0.7 years; follow-up rate, 55.9%. All 1,993 subjects were included in the analysis. The initial examination was performed in 2001 and the second during the period. Drinking habit, smoking status, sex, age, body mass index (BMI), and metabolic syndrome were defined as the causative factors of bright pancreas for comparison. Data Collection Health check-ups used for the collection of data in this study included the following tests: blood-cell counts, blood chemistry, and abdominal ultrasonography. The medical history and lifestyle factors of all subjects, including physical activity and smoking and alcohol consumption habits, were surveyed employing a standardized self-administered questionnaire. When the participants had difficulty completing the questionnaire, trained nurses provided assistance. We conducted blood and urine examinations using a MODULAR ANALYTICS system (Hitachi High-Technologies Corp., Ltd., Tokyo, Japan). Standardized Questionnaire for Lifestyle Factors A standardized questionnaire was administered to all subjects by the same trained team of interviewers. Regarding smoking status, they were divided into 3 groups: never smoked, ex-smoker and current smoker, and the Brinkman index was calculated for each group using data obtained by interview. Alcohol consumption habits were evaluated by asking subjects about the amounts and types of alcoholic beverages consumed each week during the past month, and then estimating the mean ethanol intake per week. The validity of information related to alcohol consumption had been previously confirmed. The total amount of alcohol consumed per week was calculated in grams, and then assigned to 1 of 4 grades: no or minimal alcohol consumption, <40 g/week; light alcohol consumption, g/ week; moderate alcohol consumption, g/ week; and excessive alcohol consumption, >280 g/ week. Definition of Bright Pancreas The diagnosis of bright pancreas was based on the results of abdominal ultrasonography performed by trained technicians with an Aloka SSD-650CL system (Aloka Co., Ltd., Tokyo, Japan). Ultrasonography was performed during a health check-up by a technician in a standardized manner 8 and the images were stored in an image server. Then, each image was evaluated by a doctor accredited by the Japanese Society of Gastroenterology. Both the first and follow-up evaluations were made by the same doctor using the same criteria. The ultrasonography system mentioned above was used for both evaluations. All subjects underwent examination in a fasted state. When the pancreas was poorly visualized, further examination was carried out, changing the patientʼs position. As a result, there were no poorly visualized pancreases in either the first or follow-up evaluations. The average percentage of subjects with a poorly visualized pancreas on abdominal ultrasonography performed at our medical health check-up center between 2001 and 2010 was 0.87%. The same definitions of bright pancreas were used for the first and follow-up examinations, i.e. increased echogenicity of the pancreas compared to the liver for subjects without fatty liver and equal or increased echogenicity of the pancreas compared to 28 (936)

3 Obora, et al. : Relevance of bright pancreas in metabolic syndrome Fig. 1. Definition of bright pancreas Bright pancreas is defined as positive hepato-pancreatic echo contrast not accompanied by fatty liver, based on increased echogenicity of the pancreas. When fatty liver is present, bright pancreas is defined as equal echogenicity or increased echogenicity of the pancreas. the liver for patients with fatty liver. Subjects with fatty liver at the first evaluation were excluded from the follow-up evaluation so the follow-up evaluation was performed only on subjects without fatty liver at the first evaluation. For patients who developed fatty liver during the follow-up period, bright pancreas was defined as equal or increased echogenicity of the pancreas compared to the liver (Fig. 1). In the case of presence of fatty liver, equal echogenicity or increased echogenicity of the pancreas was defined as bright pancreas. Metabolic syndrome The ATP III proposed the following 5 abnormalities to define metabolic syndrome: 1) abdominal obesity (abdominal circumference 102 cm for men and 88 cm for women); 2) elevated serum triglycerides ( 1.70 mmol/l [ 150 mg/dl]); 3) decreased high density lipoprotein (HDL) cholesterol (<1.04 mmol/l [<40 mg/dl] for men and <1.30 mmol/l [<50 mg/dl] for women); 4) elevated blood pressure (systolic/diastolic blood pressure 130/85 mm Hg); and 5) elevated fasting glucose ( 6.11 mmol/l [ 110 mg/ dl]]) 9. Since waist measurements were not available for our entire study sample, we substituted a BMI of 25 kg/m 2 or greater for all participants as an index of obesity. A BMI of 25 kg/m 2 or greater has been proposed as the cut-off for diagnosing obesity in Asians 7. Individuals with 3 or more of these 5 abnormalities were considered to have metabolic syndrome. Statistical methods The R version (available from was used for statistical analyses. Data were expressed as means (SD). Two groups of subjects were compared using the unpaired t-test and the chi-square test. The associations among 3 groups based on smoking status or 4 groups based on alcohol consumption were compared using the Kruskal- Wallis test. We assessed the odds ratio for appearance or disappearance of bright pancreas using a multivariate logistic model while controlling for potential covariates. In using this model, we selected age, alcohol consumption, serum amylase level, presence of metabolic syndrome, sex, and body weight (BW) change as the potential covariates. The adjusted odds ratio and 95% confidence interval (CI) were calculated. Results Among the 3,563 participants in our previous study 1, 1,993 were followed up in 2009 or We now present the results of the first evaluation for the 1,993 subjects. At the baseline examination, bright pancreas was detected in 776 subjects (38.6% of all subjects) consisting of 571 men (45.6% of all men) and 205 women (27.7% of all women). Bright pancreas was significantly more frequent in men than in women. Comparison of the prevalence of bright pancreas among different age groups revealed that prevalence increased with age in both men and 29 (937)

4 Fig. 2. Percentages of subjects with bright pancreas by sex and age Bright pancreas was more frequent in men. The percentage of bright pancreas increased with age in both men and women. Fig. 3. Associations between bright pancreas and smoking status, amount of alcohol consumed and the frequency of fatty liver (a) The percentage of smokers was significantly higher in the bright pancreas group. (b) The amount of alcohol consumed was significantly higher in the bright pancreas group. (c) The percentage of subjects with fatty liver was significantly higher in the bright pancreas group. women and that this tendency was stronger in women (Fig. 2). Smoking status and alcohol consumption differed between a normal pancreas and a bright pancreas group. (Figs. 3a and 3b). In the bright pancreas group, age, BMI, and BW were higher than those in the normal pancreas group. The prevalences of hypertension, type 2 diabetes mellitus, dyslipidemia, and the metabolic syndrome were higher in the bright pancreas than in the normal pancreas group (Fig. 4). Liver enzymes such as ALT, AST and γ-gtp were higher and serum amylase was lower in the bright pancreas than in the normal pancreas group (Table 1). The follow-up examination was performed a mean of 3,170 days (8.7 years) after the baseline examination. We found that bright pancreas had disappeared in 30.6% of men and 28.8% of women with baseline bright pancreas, while appearing in 28.9% of men and 23.7% of women with an initially normal pancreas. Overall, 866 subjects (43.5%) were found to have bright pancreas, a clear increase in prevalence, at the follow-up examination (Fig. 5). 30 (938)

5 Obora, et al. : Relevance of bright pancreas in metabolic syndrome Fig. 4. Associations with metabolic syndrome features MS: metabolic syndrome, HDL-C: HDL-cholesterol Comparison of various parameters between the normal pancreas and bright pancreas groups revealed strong associations between bright pancreas and individual metabolic syndrome features. Table 1. Comparison between normal pancreas and bright pancreas groups normal bright pancreas p n Age 44.8 ± ± 7.7 <0.001 ALT (IU/L) 19 ± ± 9.9 <0.001 AST (IU/L) 15.4 ± ± Body mass index (kg/m2) 21.2 ± ± 2.5 <0.001 Body weight (kg) 57.5 ± ± 10 <0.001 CRP (mg/dl) 0.1 ± ± γgtp (IU/L) 18.5 ± ± 32.3 <0.001 HDL-cholesterol (mg/dl) 55.8 ± ± 13.6 <0.001 LDL-cholesterol (mg/dl) ± ± 31.7 <0.001 Total cholesterol (mg/dl) ± ± 34.5 <0.001 Triglyceride (mg/dl) 87 ± ± 61 <0.001 Alcohol (g/day) 12.7 ± ± 19.8 <0.001 Hemoglobin A1c (JDS) 4.9 ± ± 0.6 <0.001 Amylase (IU/L) ± ± 49.4 <0.001 Fasting blood sugar (mg/dl) 95.2 ± ± 16.9 <0.001 Systolic blood pressure (mmhg) ± ± 16.4 <0.001 Diastolic blood pressure (mmhg) 71.8 ± ± 10.5 <0.001 Brinkman index ± ± <0.001 Observation period (day) ± ± Values are expressed as means ± SD. P values < 0.05 were considered statistically significant. 31 (939)

6 Fig. 5. Long-term courses of bright pancreas in men and women In 324 of 1,217 subjects (26.6%) in the normal pancreas group, bright pancreas was newly detected. In 234 of 776 subjects (30.2%) in the bright pancreas group, normalization of the pancreas was observed. No difference was noted between men and women. Table 2a. Comparison between group with newly detected bright pancreas and group whose pancreases remained normal Group in which bright pancreas appeared normal developed p n BW 0.7 ± ± 3.9 <0.001 BMI 0.3 ± ± 1.4 <0.001 ALT 0.2 ± ± AST 7.2 ± ± CRP 0 ± ± γgtp 5.3 ± ± HDL-cholesterol 2.3 ± ± LDL-cholesterol -5.7 ± ± Total cholesterol 1 ± ± Triglyceride -8.2 ± ± Amylase -8.4 ± ± Alcohol -0.7 ± ± Hemoglobin A1c (JDS) 0.5 ± ± Brinkman index 14.3 ± ± Fasting blood sugar -0.2 ± ± 10.8 <0.001 Systolic blood pressure 3.7 ± ± Diastolic blood pressure 3.1 ± ± Differences between the findings of the first and second evaluations are shown. The group with a newly detected bright pancreas had significantly increased BW, BMI,total cholesterol and fasting blood sugar, as well as hypertension. These findings indicate an association between bright pancreas and the development of metabolic syndrome. Table 2b. Comparison between group whose pancreases remained bright and group with improvement of bright pancreas Group in which bright pancreas disappeared persistent cured p n BW -0.2 ± ± BMI -0.1 ± ± ALT -0.9 ± ± AST 6.9 ± ± CRP 0 ± ± γgtp 4.4 ± ± HDL-cholesterol 3.9 ± ± LDL-cholesterol -9.9 ± ± Total cholesterol -3.1 ± ± Triglyceride ± ± Amylase -6.7 ± 26-9 ± Alcohol -1.9 ± ± Hemoglobin A1c (JDS) 0.4 ± ± Brinkman index 27.3 ± ± Fasting blood sugar 1.1 ± ± Systolic blood pressure 4.1 ± ± Diastolic blood pressure 3.1 ± ± Differences between the findings of the first and second evaluations are shown. The group with improvement of bright pancreas had a significantly reduced total cholesterol level. These findings suggest improvement of bright pancreas is associated with amelioration of dyslipidemia. 32 (940)

7 Obora, et al. : Relevance of bright pancreas in metabolic syndrome Table 3a. Adjusted odds ratios for appearance of bright pancreas appearance of bright pancreas odds ratio(95% CI) P values age 1.05 ( ) <0.001 alcohol 1.01 (1-1.01) amylase 0.99 ( ) <0.001 Metabolic syndrome(ms) 2.51 ( ) male 1.04 ( ) 0.81 body weight change 1.1 ( ) <0.001 We assessed the odds ratios for appearance of bright pancreas using the multivariate logistic model while controlling for potential covariates. We selected age, alcohol consumption, serum amylase, presence of metabolic syndrome, sex, and body weight change as potential covariates. Table 3b. Adjusted odds ratios for disappearance of bright pancreas disappearance of bright pancreas odds ratio (95% CI) P values age 0.97 ( ) alcohol 1.01 ( ) <0.001 amylase 1 (1-1) 0.88 MS 0.4 ( ) male 1.11 ( ) 0.59 body weight change 0.95 ( ) We assessed the odds ratios for disappearance of bright pancreas using the multivariate logistic model while controlling for potential covariates. We selected age, alcohol consumption, serum amylase level, presence of metabolic syndrome, sex, and body weight change as potential covariates. A newly detected bright pancreas group had significantly increased BW, BMI, systolic blood pressure, fasting blood sugar, and hemoglobin A1c as compared to the normal pancreas group. Assessment of fatty liver frequency revealed that 32 subjects in the normal pancreas group and 46 in the bright pancreas group had a newly detected fatty liver. The frequency of fatty liver was significantly higher in the bright pancreas than in the normal pancreas group (Fig. 3c). In a bright pancreas improvement group, there were significant reductions in total cholesterol and HDL cholesterol levels (Table 2a, 2b). Multivariate analysis was performed to identify factors involved in the appearance or disappearance of bright pancreas. Decreased serum amylase, aging, metabolic syndrome, and weight gain were identified as risk factors for the appearance of bright pancreas. Factors associated with the disappearance of bright pancreas were reduced alcohol consumption, improved metabolic syndrome, and weight loss (Table 3a, 3b). Serum amylase levels were not associated with persistence of bright pancreas. Discussion Metabolic syndrome has been shown to be a risk factor for the development of type 2 diabetes mellitus and coronary artery disease and is associated with an increased risk of cerebrovascular disease and all-cause mortality 9. Also, many previous studies have found an association between metabolic syndrome and NAFLD 5-7. Therefore, screening and early intervention for NAFLD, which represents visceral fat deposition, may be important in treating metabolic syndrome. The findings of a previous study have indicated the clinical importance of bright pancreas 10, which is usually detected by abdominal ultrasonography. However, when detected, bright pancreas it is still often ignored and patients are provided with neither lifestyle education nor treatment. Although fatty liver can be universally diagnosed to some extent by assessing the hepatorenal contrast during abdominal ultrasonography, no consensus has been reached on the diagnosis of bright pancreas Fatty change of the pancreas cannot be sufficiently visualized by computed tomography 10 and diagnosis reportedly requires detection of increased echogenicity of the pancreas and hepato-pancreatic contrast during abdominal ultrasonography 13,14. Though diagnosis may be difficult when the reference liver is fatty 15,16, apart from such cases, a fatty pancreas can easily be diagnosed by abdominal ultrasonography. Our study has several limitations. First, the diagnosis of bright pancreas was made by comparing the echogenicity of the pancreas with that of the liver, which poses a limitation in the accuracy of evaluation. A doctor accredited by the Japanese Society of Gastroenterology conducted all evaluations. At the follow-up evaluation, the doctor was blinded to the results of the first examination. When the first and follow-up examinations were compared, the correspondence rate for bright pancreas diagnosis was 95.7% (1,907 of 1,993 subjects). Though diagnostic disagreement is a limitation in studies using ultrasonography, the intra-observer reliability in the present study was comparable to that of Hamaguchi et alʼs study 8 in which the diagnostic performance of ultrasonography was assessed. Second, biopsy was not performed in this epidemiological study for ethical reasons. Third, abdominal circumference was not measured because there were no established 33 (941)

8 diagnostic criteria for metabolic syndrome in Japan when the present study was started in Therefore, we could not use the NCEP ATP III criteria for identification of metabolic syndrome. Therefore, instead of abdominal circumference, BMI was used for identification of metabolic syndrome 7. Increased echogenicity of the pancreas on abdominal ultrasonography is reportedly associated with various factors, such as fatty infiltration and fibrosis of the pancreas due to fatty degeneration or chronic pancreatitis following atrophy of the pancreatic parenchyma 14,17. Increased echogenicity of the pancreas is also reported to occur with aging 18. Our study found that the frequency of bright pancreas increased with aging, and multivariate analysis suggested that advanced age was a significant independent risk factor for bright pancreas. Among the causative factors of bright pancreas, excepting pancreatic diseases and aging, visceral fat deposition is considered to be the most strongly associated factor 10,19. In line with this, we found BW, BMI and frequency of fatty liver to be higher in the bright pancreas group. Bright pancreas also appeared to be associated with lifestyle factors, i.e. alcohol consumption, smoking and metabolic syndrome. In the bright pancreas group, impaired glucose tolerance (reflecting reduced endocrine pancreatic function) and decreased serum amylase (reflecting reduced exocrine pancreatic function) were common, and the prevalences of hypertension and dyslipidemia were higher. Mathur et al. raised the possibility that pancreatic damage connected with metabolic syndrome may be caused by a second hit similar to that in the two-hit theory of the pathogenesis of nonalcoholic steatohepatitis 20. They stated that bright pancreas should be able to be visualized by abdominal ultrasonography based on this mechanism. While it is difficult to draw a conclusion as to the mechanism underlying the development of bright pancreas from the present study, an association between bright pancreas development and visceral fat deposition was strongly suggested. Abdominal ultrasonography is easy to perform. In this study, the ultrasonographic findings of bright pancreas, even in the absence of fatty liver, were strongly associated with metabolic syndrome or its causative factors and correlated with its exacerbation or amelioration. This suggests that the detection of bright pancreas could be an important indicator in diagnosing, treating and following-up metabolic syndrome. We therefore advocate that bright pancreas, as indicated by increased echogenicity of the pancreas on abdominal ultrasonography, should be considered an abnormality. No conflict of interest in this manuscript. Conclusions Increased echogenicity of the pancreas (bright pancreas) on abdominal ultrasonography may represent fatty change or fibrosis of the pancreas, which is associated with metabolic syndrome. Even in persons without fatty liver, bright pancreas should be considered abnormal and they should be instructed in lifestyle improvement and/or provided with treatment. References 1. Hamaguchi M, Kojima T, Nakagawa T, et al. : Relationship between bright pancreas without fatty liver and lifestyle-associated disease at health check-up. Health Evaluation and Promotion 2004 ; 31 : (in Japanese) 2. Marks WM, Filly RA, Callen PW : Ultrasonic evaluation of normal pancreatic echogenecity and its relationship to fat deposition. Radiology 1980 ; 137 : van Geenen EJ, Smits MM, Schreuder TC, et al. : Nonalcoholic fatty liver disease is related to nonalcoholic fatty pancreas disease. Pancreas 2010 ; 39 : Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults : Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001 ; 285: Dixon JB, Bhathal PS, Obrien PE : Nonalcoholic fatty liver disease : predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001 ; 121 : Marchesini G, Bugianesi F, Forlani G, et al. : Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003 ; 37 : Hamaguchi M, Kojima T, Takeda N, et al. : The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005 ; 143 : Hamaguchi M, Kojima T, Itoh Y, et al. : The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007 ; 102 : Eckel RH, Grundy SM, Zimmer PZ : The metabolic syndrome. Lancet 2005 ; 365 : Lee JS, Kim SH, Jun DW, et al. : Clinical implication of fatty pancreas : Correlations between fatty pancreas and metabolic syndrome. World J Gastroenterol 2009 ; 15 : 34 (942)

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