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Pancreatic volume associated with endocrine and exocrine function of the pancreas among Japanese alcoholics
Original Paper Pancreatology 2005;5:422–431 DOI: 10.1159/000086543
Received: September 6, 2004 Accepted after revision: January 10, 2005 Published online: June 28, 2005
Pancreatic Volume Associated with Endocrine and Exocrine Function of the Pancreas among Japanese Alcoholics Yuji Nakamuraa, b Susumu Higuchia Katsuya Maruyamaa a b
National Hospital Organization, Kurihama Alcoholism Center, Yokosuka, Kanagawa, and Inagi Municipal Hospital, Inagi, Tokyo, Japan
Key Words Pancreatic volume Helical CT Alcoholism Diabetes Pancreatitis
Abstract Background/Aims: The pancreas is often damaged by excessive alcohol consumption. Because alcohol-related problems and diabetes mellitus (DM) are increasing in Japan, this cross-sectional study was designed to investigate how pancreatic volume (PV, calculated using multi-slice helical computed tomography) represents alcohol consumption and both endocrine and exocrine pancreatic function among alcoholics. Methods: Consenting male and female inpatients undergoing psychiatric therapy for alcoholism from June 2003 to May 2004 were subjected to four-slice MCT to determine PV. Fasting plasma glucose (FPG) and serum lipase levels were examined for endocrine and exocrine pancreatic functions, respectively. Results: The average PVs of 535 male and 117 female patients (57.2 8 21.91 ml and 54.5 8 17.56 ml, respectively) were related to age and height (H) but not to body weight (W). Lipase values had a strong relationship with PV/W. Multiple regression analysis revealed weak associations between PV and both daily ethanol consumption and duration of habitual drinking. The diagnosis of DM in 109 of these alcoholics was more
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strongly associated with the PV/W value than with PV or PV/H. Conclusion: The association of PV with endocrine and exocrine functions suggests new markers, especially PV/W, for the assessment of DM among alcoholic patients. Copyright © 2005 S. Karger AG, Basel and IAP
Introduction
The cellular composition of the pancreas reflects the organ’s diverse endocrine and exocrine functions. Amounting to only 2 percent of the human pancreas, some 100,000 to 1 million islets of Langerhans comprise approximately 1,000 endocrine cells each, of which 70– 80% are producing insulin (-cells) [1]. The morphologic features of the endocrine pancreas are not necessarily considered to be associated with its functional properties, and the concept of a functionally heterogeneous -cell population influences views on the role of pancreatic cells in health and disease [2]. Endocrine function thus seems to be less associated with pancreatic volume than exocrine function, which is represented by the much greater volume of the acinar cell population, comprising 75–90% of the overall mass of the pancreatic gland and its component cells [3].
Yuji Nakamura, MD Inagi Municipal Hospital Ohmaru 1171, Inagi Tokyo 206-0801 (Japan) Tel. +81 42 377 0931, Fax +81 42 379 1310, E-Mail [email protected]
Heavy alcohol consumption is an accepted risk factor for pancreatic diseases, and about half of chronic pancreatitis is associated with alcohol consumption [4]. In 1978, Durbec and Sarles [5] concluded that there was no apparent threshold for alcohol toxicity in the human pancreas. Our colleagues have investigated the associations of chronic pancreatitis and DM among alcoholics [6, 7]. Among several recent studies on alcohol consumption and DM, Nakanishi et al. [8] reported that moderate alcohol consumption (pure ethanol, 23.0–45.9 g/day) by apparently healthy Japanese men is associated with reduced risk for development of impaired fasting glucose or type 2 DM. On the other hand, Kiyohara et al. [9] reported that a high intake of alcohol and a decreased polyunsaturated/saturated fatty acids ratio contribute to the risk for glucose intolerance in contemporary Japanese. DM is a clinically and genetically heterogeneous group of disorders characterized by abnormally high levels of glucose in the blood. The hyperglycemia is due to deficiency of insulin secretion or to resistance of the body’s cells to the action of insulin, or to a combination of the two [10]. Type 2 DM is caused by a combination of genetic and non-genetic factors that result in insulin resistance and insulin deficiency, whereas type 1 DM is caused by -cell destruction, often immune-mediated, that leads to loss of insulin secretion and absolute insulin deficiency. It is estimated that more than 12 million Japanese people are hyperglycemic, and that 95% of these diabetic patients have type 2 DM. These numbers are likely increasing similarly in other nations [11]. Worldwide, type 2 DM accounts for approximately 90–95% of cases in the DM syndrome, while type 1 DM comprises the remaining 5–10. (Despite the ability to detect auto-antibodies, clinical differentiation between types 1 and 2 is not always possible.) Other specific types of DM are thought to be numerically small subclasses, amounting to only 1–2% of all cases in the DM syndrome, e.g. chronic pancreatitis, drug- or chemical-induced endocrinopathy, and infections [10]. Since its introduction in the 1970s, computed tomography (CT) has found wide application within all of the radiological subspecialties [12]. It provides valuable information on the anatomical localization, linear size, surface area, and volume of body structures, including those contained within the body compartment [13]. High-resolution multi-slice helical CT (MCT) can rapidly produce clear, three-dimensional (3-D) images. Whereas a patient’s breathing and digestive movements usually affect imaging of the digestive organs, the high quality of MCT
images makes this technology appropriate for examination of the liver, pancreas, and digestive tract. In addition to speed and high resolution, MCT offers a means of measuring organ volume. Considering that some 93 million CT scans are performed around the world every year, it is important to determine whether 3-D images or organ volume, calculated using CT scans, might serve in an additional role, as indicator of the organ’s functional status. Several studies have reported the benefits of reconstruction based on CT to calculate total liver volume [14, 15]. A few studies have measured PV by CT to investigate the relationship between the size of the pancreas and its endocrine or exocrine function. Using CT to calculate and compare the size of the pancreas in healthy subjects with documented low (n = 5) and high (n = 5) insulin secretion, Nyren et al. [16] found no significant difference in total pancreatic volume (84.8 8 29.4 ml and 79.8 8 8.4 ml for low and high insulin responders, respectively), nor did they find significant differences between the sizes of various parts of the organ (caput, corpus, or cauda). Goda et al. [17] used helical CT to measure PV in 26 patients with type 1 DM, 29 patients with type 2 DM, and 22 healthy individuals. They found a strong correlation between PV and exocrine function for patients with type 1 DM, but the correlation was weak for those with type 2 DM. Whereas small sample sizes in these studies of PV and pancreatic function have limited interpretation of results, studies of larger populations would help to clarify the association between PV and endocrine or exocrine pancreatic function. Moreover, the association between PV and alcohol consumption has not yet been thoroughly investigated. Therefore, we designed this study using MCT to measure PV in alcoholic subjects to evaluate the relationship of pancreatic volume to alcohol-related pancreatic functions – both endocrine and exocrine – as well as the relationship between PV and ethanol consumption.
Pancreatic Volume and Function in Alcoholics
Pancreatology 2005;5:422–431
Patients and Methods Subjects We designed this cross-sectional study to measure PV in patients admitted to our Alcoholism Center from June 2003 to May 2004 for psychiatric treatment of alcoholism. All patients included in the study were diagnosed using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria for alcohol abuse and dependence [18]. Following the institutional ethics committee’s approval for CT examination of the liver and pancreas of all admitted patients, we enrolled 659 alcoholics who had given informed consent to undergo abdominal CT during their hospitalization.
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Of the 659 patients, we excluded 7 whom we suspected of having acute pancreatitis (6 men; 1 woman), who had upper abdominal pain and elevated pancreatic enzymes compatible with standardized criteria for clinical diagnosis of acute pancreatitis [19]. Thus, we enrolled 652 subjects, of whom 535 (82.1%) were male and 117 (17.9%) were female. Habitual Drinking and Smoking History To obtain accurate information, we interviewed each subject three times, once each by a caseworker, a nurse, and a psychiatrist of the Alcoholism Center staff, using oral and written questionnaires about the patient’s history, the age of first habitual drinking, the amount of alcoholic beverage(s) usually consumed, and the reasons for binge-drinking (e.g. work stress, retirement, lost job, marriage, baby, child, death or illness of family or relatives, and sleeplessness). We calculated alcohol consumption per day as pure ethanol, using a standard alcohol content for each alcoholic beverage: beer, 5% (v/v); wine, 12%; sake, 15%; shochu, 25%; gin, 37%; brandy, 40%; and whiskey, 43%. Smoking status was recorded in pack-years. Current smokers included 424 of the men (79.3%) and 59 of the women (50.4%); 20 men (3.7%) and no women (0.0%) had smoked in the past; and 91 men (17.0%) and 58 women (49.6%) had never smoked. Among the 483 current smokers, the men and women smoked an average of 22.9 8 12.00 and 19.0 8 13.12 cigarettes per day, respectively (p = 0.03). Blood Examination Fasting plasma glucose (FPG) was measured three times, once per week for 3 weeks, by the glucose electrode method (Glucose Auto & Stat GA1160, Arkray, Yokohama, Japan). In accordance with Japan Diabetes mellitus Society May 1999 criteria [20], DM was diagnosed when hyperglycemia met the criteria for ‘diabetic type’, defined as FPG of 7.0 mmol/l (126 mg/dl) or higher on two or more occasions when examined on separate days; ‘normal type’, when FPG was below 6.1 mmol/l (110 mg/dl), and ‘borderline type’, when the value fell between the two (FPG 66.1 and !7.0 mmol/l). Patients whose FPG values were ‘borderline type’ (no more than a single diabetic-type value in the three examinations) were diagnosed as having impaired fasting glucose (IFG). Among the 652 patients enrolled, 70 had previously been diagnosed with DM (34 were on no medication, 17 on medication other than insulin, 19 on medication including insulin). None had been diagnosed as having either type 1 DM or autoimmune disease. We enrolled 36 of the 70 diabetic alcoholic patients (32 men; 4 women) in the DM group, who prescribed hypoglycemic medications during this study, although their FPG values did not meet the criteria for DM. We used serum lipase levels rather than measures of pancreatic amylase, trypsin or elastase [21] to indicate exocrine pancreatic function, because the lipase test was the least expensive under Japanese medical insurance. Pancreatic amylase, trypsin, and elastase testing cost nearly 2-fold, 5-fold, and more than 6-fold the cost of testing serum lipase, respectively, in 2003. The non-identified amylase blood test (total amylase) is less than half as costly as the lipase examination (JPY140; USD 1.27), but it is also less specific for the pancreas and is influenced by the salivary gland. We examined serum lipase levels (normal range, 3–55 IU/l) for all patients at admission, using an enzymatic reaction method of assessing 1,2-diglyceride (Automatic Analyzer 7170S, Hitachi, Tokyo, Japan).
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Pancreatic Volume During their hospitalization, all of our alcoholic subjects underwent four-detector abdominal MCT (Asteion/Multi 4 Slice System, Toshiba, Tokyo, Japan) on the morning after overnight fasting. The MCT parameters included slice thickness, 3 mm; reconstruction index, 3 mm; velocity, 10.5 mm/rotation; helical pitch, 3.5; electric power, 120 kV and 195 mAs. The reconstructed spiral CT images were traced for pancreatic outline in each 3 mm image by a gastroenterologist (Y.N.) without knowledge of blood data or patient history, yielding the exact parenchymal outline and excluding the bile duct, dilated pancreatic duct, splenic vein, portal vein, and pancreatic cyst volumes. Stone volume was not excluded, however, owing to the difficulty of visualizing and calculating tiny pancreatic stones. The 2-D areas and then the pancreatic volumes were calculated at a Toshiba workstation. Each PV was revised by patient height (H, m) and body weight (W, kg), and the PV/H and PV/W values as well as PV values were evaluated. Because of the need for further evaluation of non-homogeneous hepatic densities shown by unenhanced CT, we obtained informed consent and performed additional contrast-enhanced CT imaging on 127 of our 652 subjects. Most of these patients did not have hepatic tumors (diagnoses included severe steatohepatitis, chronic hepatitis, and cirrhosis), but 17 had hemangioma and 2 had hepatocellular carcinoma. We compared PVs calculated from images with and without contrast enhancement for each of the 127 subjects. None of the enrolled 652 subjects (all imaged by unenhanced CT and 127 by contrast-enhanced CT as well) showed evidence of pancreatic inflammation (e.g. edema, necrosis). Statistical Analysis All data in this report are expressed as mean 8 SD. Hypothesis testing was two-tailed, and p ! 0.05 was considered to indicate statistical significance. Comparisons involved using the Mann-Whitney U test, Student’s t test, or regression analysis, as appropriate. We used the statistical analysis system for personal computer, Systat 10.2 (Systat Software, Point Richmond, Calif., USA) for all computations. To examine PV by multiple logistic regression analysis, we separated the 652 patients into categories of smaller and larger PV, based on the average PV for each gender: for men, smaller PV, ^57.2 ml (n = 283) and larger PV, 157.2 ml (n = 252); for women, smaller PV, ^54.5 ml (n = 56) and larger PV, 154.5 ml (n = 61). We examined the effects of eight variables, which we coded as follows: (1) age, 0 = less than 60 years and 1 = 60 years or older; (2) height, 0 = average (male 1.66 m, female 1.56 m) or less and 1 = more than average; (3) body weight, 0 = average (male 59.2 kg, female 48.8 kg) or less, and 1 = more than average; (4) pancreatic calcification, 0 = none and 1 = positive; (5) pancreatic cyst, 0 = none and 1 = positive; (6) average daily alcohol consumption: 0 = less than 200 g and 1 = 200 g or more; (7) duration of habitual drinking, 0 = less than 30 years, and 1 = 30 years or more, and (8) smoking, 0 = less than 20 pack-years, and 1 = 20 pack-years or more. In investigating risk for DM by multiple logistic regression analysis, we analyzed the effects of age, sex, PV/W, body mass index (BMI), smoking, duration of habitual drinking, daily ethanol consumption, and pancreatic calcification. We coded the eight risk variables as follows: (1) age, 0 = less than 60 years and 1 = 60 years or more; (2) sex, 0 = female and 1 = male; (3) PV/W, 0 = average (male 0.98 ml/kg, female 1.19 ml/kg) or less, and 1 = more than
Nakamura/Higuchi/Maruyama
Table 1. Multiple logistic regression analysis of pancreatic volume
in 652 alcoholics Risk factors
Odds ratio (95% CI) p value
Age 660 years Height >average (male 1.66 m; female 1.56 m) Weight >average (male 59.2 kg; female 48.8 kg) Pancreatic calcification Pancreatic cyst Smoking 620 pack-years Duration of habitual drinking 630 years Daily ethanol consumption 6200 g/day
0.543 (0.343–0.860) 0.009 1.864 (1.269–2.739) 0.002 1.348 (0.925–1.963) 0.718 (0.434–1.189) 0.546 (0.268–1.114) 1.090 (0.750–1.584)
0.120 0.198 0.096 0.653
0.637 (0.415–0.978) 0.039 0.680 (0.449–1.031) 0.070
average; (4) BMI, 0 = 26 kg/m2 or less and 1 = more than 26 kg/m2; (5) average daily alcohol consumption: 0 = less than 200 g and 1 = 200 g or more; (6) duration of habitual drinking, 0 = less than 30 years, and 1 = 30 years or more; (7) smoking, 0 = less than 20 packyears, and 1 = 20 pack-years or more, and (8) pancreatic calcification, 0 = none and 1 = positive.
Results
The average ages of the 535 male and 117 female patients were 54.2 8 12.44 and 44.6 8 14.21 years, respectively (p ! 0.001); their average respective heights were 1.66 8 0.068 m and 1.56 8 0.054 m (p ! 0.001); their average weights, 59.2 8 11.58 kg and 48.8 8 12.24 kg (p ! 0.001), and their average BMIs, 21.5 8 3.76 kg/m2 and 20.1 8 4.64 kg/m2 (p = 0.002), respectively. The duration of habitual drinking differed significantly between our male and female patients (average, 28.3 8 12.83 vs. 18.2 8 10.57 years; p ! 0.001). The average age of first alcohol drinking also differed (17.9 8 3.77 vs. 20.3 8 5.47 years for men and women, respectively; p ! 0.001), but the average daily ethanol consumption did not differ significantly (163 8 97.6 g/day for men vs. 165 8 90.5 g/day for women). The oral interviews yielded information about the subjects’ binge drinking. The female binge drinkers reported much more stress associated with their interpersonal relationships (e.g. marriage, boyfriends, children), whereas for male binge drinkers the stress was more often associated with work, such as job loss or retirement. These reasons seemed to relate to the subjects’ age differences; in fact, our male alcoholic sub-
Pancreatic Volume and Function in Alcoholics
jects were on average 10 years older than their female counterparts. The average PVs for male and female patients did not differ significantly (57.2 8 21.91 vs. 54.5 8 17.56 ml, respectively). The PV values obtained using the 127 contrast-enhanced images (ml:Y) were close to the PVs calculated from unenhanced images (ml:X) (Y = 0.995X + 4.829; r2 = 0.933, p ! 0.001). Regression analysis showed associations between PV and age for both men and women and between PV and height for males, but there was less evidence of association between PV and body weight (fig. 1). The difference between men’s and women’s average PV/H values (34.5 8 12.74 and 35.0 8 11.27 kg/m, respectively) was not significant, but their average PV/W values (0.98 8 0.371 and 1.19 8 0.510 ml/kg, respectively) differed significantly (p ! 0.001). Among the 652 subjects, 50 (7.7%) had pancreatic cyst(s) and 96 (14.7%) had calcification in the pancreas; 16 (2.5 %) had both pancreatic cyst(s) and calcification. Examination of the relationship of PV value to various potential risk factors by multiple logistic regression analysis (table 1) showed that PV was significantly related to age 660 years (OR 0.543, p = 0.009), greater than average height (OR 1.862, p = 0.002), and duration of habitual drinking 630 years (OR 0.637, p = 0.039). PV was associated with pancreatic cyst (OR 0.546, p = 0.096) and daily ethanol consumption 6200 g (OR 0.680, p = 0.070), but we found no association between PV and body weight, pancreatic calcification, or smoking 620 pack-years. Substitution of lower and higher daily ethanol consumption values for the assigned value of 6200 g in this model showed that this variable has no relationship to PV: For daily ethanol consumption 6100 g, the odds ratio (OR) was 1.182 (95% CI, 0.750–1.848, p = 0.463); for 6150 g, the OR was 0.805 (0.561–1.156, p = 0.240), and for 6250 g, the OR was 0.834 (0.514–1.355, p = 0.464). Likewise, changing the duration of habitual drinking from 630 to 620 years in this model did not reveal an association between habitual drinking and PV (OR = 0.979; 95% CI, 0.648–1.478; p = 0.919). Similarly, increasing the smoking variable from 620 pack-years to 630 packyears in this model did not show a risk for decreasing PV (OR, 0.851; 95% CI, 0.590–1.229; p = 0.390). Among our 652 alcoholic subjects, we diagnosed DM in 109 who had ‘diabetic-type’ FPG results on at least two of three examinations (99 men, 18.5%; 10 women, 8.5%). Another 340 subjects (269 men, 50.3%; 71 women, 60.7%) were diagnosed as normal on the basis of having ‘normaltype’ FPG in all three examinations. The remaining 203 (167 men, 31.2%; 36 women, 30.8%) were diagnosed as
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Fig. 1. Regression analysis for PV (ml) with
age (years), height (m), and weight (kg) among male (o: –––) and female (x: - - - -). a Age (Y) is associated with PV (X), Y = –0.233X + 67.551 (r2 = 0.169) in men; Y = –0.265X + 58.904 (r2 = 0.100) in women. b Height (Y) has a weak association with PV (X), Y = 0.001X + 1.597 (r2 = 0.113) in men; Y = 0.0006X + 1.524 (r2 = 0.087) in women. c Weight (Y) is not associated with PV (X), Y = 0.153X + 50.463 (r2 = 0.083) in men; Y = –0.022X + 50.021 (r2 = 0.001) in women.
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Nakamura/Higuchi/Maruyama
Table 2. Association of pancreatic volume with endocrine and exocrine pancreatic status in 652 alcoholic patients
n
Pancreatic volume, average PV, ml
Endocrine status Normal Men 269 59.9820.22 Women 71 56.4817.03 Impaired fasting glucose Men 167 58.8822.65 Women 36 54.8817.70 DM Men 99 46.9822.38a Women 10 40.0816.61a Exocrine status Low serum lipase Men 358 Women 65 High serum lipase Men 177 Women 52
54.2821.12 51.7814.81
PV/H, ml/m
PV/W, ml/kg
36.1811.51 36.1810.93
1.0480.356 1.2880.560
35.3813.48 35.4811.19
0.9980.362 1.1380.372
28.4813.09b 0.7980.355c 26.0811.63b 0.7880.385c
32.7812.21 33.289.50
0.9380.356 1.0580.369
64.1822.68d 38.5813.15e 1.1280.372f 63.4819.33d 40.7812.57e 1.4180.584f
DM was diagnosed when indicated by at least two of three FPG tests (6126 mg/dl); normal status, when all three tests had normal results (<110 mg/dl); impaired fasting glucose (IFG), when FPG values fell between DM and normal. Low serum lipase was defined as ^24.5 IU/l (average for men) or ^28.3 IU/l (average for women). a PV with DM differed significantly from PV with IFG in men (p < 0.001 [4.3 ! 10–5]) and in women (p = 0.022). b PV/H with DM differed significantly from PV/H with IFG in men (p < 0.001 [6.0 ! 10–5]) and in women (p = 0.024). c PV/W with DM differed significantly from PV/W with IFG in men (p < 0.001 [4.1 ! 10–5]) and in women (p = 0.012). d PV, e PV/H, and f PV/W with high lipase differed significantly from those with low lipase in men and in women (p < 0.001 [men, 8.7 ! 10–7, 6.4 ! 10–7, and 1.7 ! 10–8, respectively; women, 3.2 ! 10–4, 3.6 ! 10–4, and 2.2 ! 10–4, respectively]).
having impaired fasting glucose (IFG). Calculating the average PV, PV/H, and PV/W for the normal, IFG, and DM groups (both male and female), we found much greater differences in these groups’ PV/W values than in either their PV or PV/H values (table 2). Dividing the 652 alcoholics into two groups of men and women by their average serum lipase values (men, 24.5 8 24.06 IU/l; women, 28.3 8 24.33 IU/l) revealed a strong association between lipase levels (both high and low) and PV, PV/H, and PV/W (table 2). Comparing subjects with high and low lipase levels, we found a much greater difference in PV/W values than in either the PV or PV/H values. Multiple regression analysis (table 3) revealed that DM has a strong relationship with PV/W (OR, 0.415; p ! 0.001) and pancreatic calcification (OR, 3.488; p ! 0.001) and DM tends to be associated with smoking status (OR, 1.707; p = 0.053). Among our 96 patients with pancreatic calcification (92 men; 4 women), 36 (34 men; 2 women) were diabetic. We could find no relationship between DM and age, sex, BMI, duration of habitual drinking, or daily ethanol consumption in these alcoholic subjects. Neither reducing the smoking variable from 620 pack-years to 610 pack-years nor increasing it to 630 pack-years showed a significant risk for DM: For 610 pack-years, OR = 0.903 (95% CI, 0.490–1.666, p = 0.745); for 630 pack-years, OR = 1.113 (0.690–1.796, p = 0.662).
Discussion
The results of our investigation for the relationship between 652 alcoholic patients’ pancreatic volumes and their pancreatic function and ethanol consumption indi-
Table 3. Multiple logistic regression analysis of risk for DM in 652 alcoholics
Age 660 years Sex, male PV/W >average (male 0.98 ml/kg; female 1.19 ml/kg) BMI >26 kg/m2 Smoking 620 pack-years Duration of habitual drinking 630 years Daily ethanol consumption 6200 g/day Pancreatic calcification
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Odds ratio (95% CI)
p value
0.853 (0.483–1.507) 1.925 (0.769–4.816) 0.415 (0.255–0.676) 0.896 (0.408–1.966) 1.707 (0.992–2.936) 1.147 (0.660–1.994) 0.969 (0.562–1.670) 3.488 (2.050–5.935)
<0.584 <0.162 <0.001 <0.784 <0.053 <0.627 <0.909 <0.001
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cated that there are associations between PV and both endocrine and exocrine function. PV was related to age and height but not to weight. In fact, the PV/W index had a stronger association with both DM and serum lipase level than did PV itself. We found weak relationships between PV and alcohol consumption and between PV and duration of habitual drinking. When we controlled duration of habitual drinking (630 years) and daily ethanol consumption (6200 g) in multiple logistic regression analysis, we found statistical significance for their relationships with PV, but the level of significance was not attained when we substituted different daily ethanol consumption or duration of habitual drinking values. Prior investigation had revealed no apparent threshold for alcohol toxicity in the human pancreas [5]. It appears that age itself would have more effect on PV than 130 years’ duration of habitual drinking. Although we attempted to obtain accurate information regarding daily ethanol consumption, evaluation based on the subjects’ total ethanol consumption was problematic, because these alcoholics frequently indulged in binge-drinking, which disrupted memory concerning not only their behavior but how much they drank. Moreover, their ethanol consumption changed from day to day, making it difficult to calculate daily, monthly, and yearly alcohol intake. We could not examine normal subjects who did not engage in heavy alcohol consumption, because our study was done in an alcoholism treatment center; thus, we cannot report on the relationships between PV and other variables in non-alcoholic subjects. We suppose, however, that the association between PV and age or height would be a general relationship existing in the normal population and thus would not be specific for alcoholics. Research on many subjects who had never drunk alcohol would be needed to analyze these relationships. Diabetes, especially type 2 DM, is increasing all over the world. The prevalence of type 2 DM in the western world is about 5–10% of the population over 40 years of age. Among all subjects with type 2 DM, 80% are obese, although only 10% of all obese people develop type 2 DM [22]. Type 2 DM in obese subjects is thought to be a multigenetic disease, so the question remains whether obese subjects will ever develop DM. Our results suggest that a simple indicator – PV divided by weight – shows the risk for DM. That PV/W is more strongly associated with DM than BMI suggests an important reason for the development of type 2 DM in some patients. Given the high prevalence of chronic pancreatitis in alcoholics, the question is whether our subjects’ DM is
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type 2 or the other type resulting from alcoholic chronic pancreatitis. Chronic pancreatitis is an irreversible, patchy, and usually progressive fibrosis of the glandular parenchyma, due to duct changes subsequent to necroticinflammatory processes in the pancreas [23]. The gold standard for diagnosing for chronic pancreatitis is histological examination, which is difficult. The Japan Pancreas Society’s diagnostic criteria for chronic pancreatitis specify a definite diagnosis of chronic pancreatitis in the presence of pancreatic stones, as evidenced by intrapancreatic calcifications [24]. These criteria are the same as those in other nations [25], and we used them in diagnosing chronic pancreatitis. Likewise, it was difficult for us to classify alcoholic diabetes as type 2 DM or the other type in patients with alcoholic chronic pancreatitis without pancreatic calcifications. Although there are other diagnostic tools, such as endoscopic retrograde pancreatography (ERP) and the secretin test (duodenal intubation test), it is hard to perform these tests on large numbers of subjects, many of whom refuse to undergo uncomfortable procedures. Multiple logistic regression analysis showed that pancreatic calcification accompanied the risk for DM among alcoholics independently, so we were sure that some patients had developed DM following chronic pancreatitis; however, most of our subjects (543 in 652 subjects, 83.3%) did not have pancreatic calcification. Multiple logistic regression analysis also showed that PV/W accompanied the risk for DM among alcoholics independently, suggesting that the PV/W value would be of benefit in clinical assessment for type 2 DM. It seems too simplistic to be true that decreased PV would indicate diabetes. Diabetes occurs in only about half of patients with chronic pancreatitis, even when almost the entire pancreas has been destroyed, and adenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes [26]. These findings imply a mechanism other than simple reduction in -cell mass. Clarification of the relationship of the islets of Langerhans with chronic pancreatitis, including -cell and -cell contributions [27], for example, would require extensive investigation to obtain much more data from the general population. PV might also depend on race and country, because the average PV in our study was less than that shown by Nyren et al. [16] in Sweden. Investigation of type 1 DM, which we could not include in this study, might have provided more important information concerning PV and endocrine or exocrine pancreatic function. In that regard, Goda et al. [17] reported finding a stronger correlation for type 1 DM than for type 2 DM.
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The association between DM and smoking status was not clarified in our study, because this tendency did not reach statistical significance and we could not find statistical significance when we controlled smoking status to 630 pack-years instead of 620 pack-years. Several studies do show an association between smoking and DM, suggesting that smoking is an independent risk factor for type 2 DM [28]. Because of the large number of smokers and the small number of non-smokers among the Japanese alcoholic population, further study involving larger numbers of non-smokers is needed to elucidate the association PV and smoking among alcoholics. In this study, we used the serum lipase value to indicate exocrine pancreatic function. Tests that can be performed to evaluate exocrine pancreatic function include the secretin test, the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test, and fecal chymotrypsin (FCT), fecal elastase, and serum pancreatic enzyme testing. The secretin test remains the gold standard [29]. Kitagawa et al. [30] reported that in patients with severe or moderate exocrine insufficiency demonstrated by the secretin test, abnormally low levels of exocrine function were observed in 63% by BT-PABA test, in 61% by FCT, and in 44% by pancreatic amylase, while in patients with normal exocrine function demonstrated by the secretin test, abnormally low exocrine function was observed in 28% by BTPABA test, in 28% by FCT, and in 10% by PA. Pezzilli et al. [31] reported that considering only low serum concentrations of the five enzymes studied in diagnosing chronic pancreatitis, trypsinogen showed a sensitivity of 28%, a specificity of 100%, a predictive value of a positive test of 100% and a predictive value of a negative test of 96.4%. After analyzing several factors (accessibility, simplicity, patient acceptability, and cost), we chose the serum lipase test for our alcoholics, although we await reports about the relationship between PV and the secretin test in large numbers of subjects. It is important to analyze patients with regard to steatorrhea, diarrhea, and weight loss in exocrine pancreatic function insufficiency, as well as to analyze pancreatic exocrine enzymes. Alcohol is an important risk factor for diarrhea [32], and alcoholics are frequently malnourished. Nearly all of our alcoholic subjects reported having frequent diarrhea due to heavy alcohol intake when they were drinking, More than 54% of our subjects had BMIs under 21 kg/m2, and during binge-drinking, alcohol may have constituted their sole source of nutrition. Because most of our subjects were diarrheic and hyponutritional, it was difficult to evaluate steatorrhea, diarrhea, and weight loss in relation to their pancreatic function.
Dynamic contrast-enhanced CT is considered the gold-standard imaging modality for the diagnosis and evaluation of patients with pancreatic disease [33]. Our study, which was designed to investigate pancreatic functions using the least invasive method, lacked injection for contrast-enhancement and produced suboptimal images in most patients, resulting in limitation of our ability to detect subtle pancreatic inflammatory and neoplastic lesions. In 127 cases with contrast-enhanced CT, we found that the pancreatic margins were more distinct in contrast-enhanced images than in unenhanced images, and that the PVs calculated from contrast-enhanced images of the same patients were usually slightly larger than those from the unenhanced images. Because we found that the PV detected by contrast-enhanced CT closely approximated PV detected by unenhanced CT, we concluded that it could be worthwhile to evaluate PV by non-contrasted CT methods of measuring PV, which are less invasive and cause less patient discomfort. Although we found that PV was not decreased among subjects with pancreatic calcification, we could not rule out overestimation of PV in cases with pancreatic calcification, because it was difficult to exclude the volume of many tiny calcifications from PV calculated on the basis of tracing by human hands. In the future, further development of computer programs will enable automatic measurement of pancreatic volume that excludes calcification and other extraparenchymal volumes. The Japanese Ministry of Health, Labor, and Welfare recommends limiting radiation exposure to a maximum of 50 mSv per year for whole body and only 13 mSv of abdominal exposure per year for women capable of becoming pregnant. Although the International Commission on Radiological Protection (ICRP) has concerns that a radiation dose increase of 10–30% may occur with use of the multi-slice detector array, it depends upon the choice of several factors: the product of tube current, in milli-amperes (mA), and exposure time, in seconds (s), or mAs; scan volume; helical pitch; and slice width [34–36]. Because our hospital radiologist detected that each subject’s radiation exposure amounted to 30 mSv in this study, we will change our protocol in the future to decrease radiation exposure. MCT technology, which is continually improving, could be used to completely scan every organ more rapidly, providing more accurate 3-D images and volumes, even in patients who are elderly or very ill. The only major problem except the cost of MCT is the risk of high radiation exposure, especially for younger persons, so ways to reduce exposure by multiple cofactors are under
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discussion. The risk versus clinical benefit of diagnostic radiation constitutes an important issue, and the benefits of using diagnostic X-rays need to be weighed against potential risks for cancer [37–39]. Magnetic resonance imaging (MRI) is an alternative method of measuring organ volumes without radiation exposure. In summary, we found that PV detected by MCT is a good way to assess both exocrine and endocrine pancreatic functions, not only to evaluate pancreatic calcification and neoplasms. PV values were associated with subjects’ ages and heights, but not with their weight, and low PV/W had a stronger relationship with diagnosed DM and low serum lipase levels in alcoholic patients. The associations with PV and daily ethanol consumption or duration of habitual drinking were weak. Multiple logistic
regression analysis showed an association between DM and PV/W as well as an association between DM and pancreatic calcification among alcoholics. Smoking status was related to the risk for DM, but ethanol consumption did not carry a significant risk. Information about exact macromorphologic status of the pancreas in health and disease represents a specific new way in which the physician can communicate relevant findings with the diabetologist, investigating genetic and non-genetic issues surrounding insulin sensitivity and -cell function. Additional multicenter, multinational, and multiracial studies are needed to determine the association between organ volume and function. MCT promises to play a key role in measuring the volume of not only the pancreas but other organs as well.
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18 Gelder M, Gath D, Mayou R, Cowen P: Oxford Textbook of Psychiatry, ed 3. Oxford, Oxford University Press, 1996. 19 Sunamura M, Lozonschi L, Takeda K, Kobari M, Matsuno S: Criteria for diagnosis of acute pancreatitis in Japan and clinical implications. Pancreas 1998;16:243–249. 20 Kuzuya T, Nakagawa S, Satoh J, Kanazawa Y, Iwamoto Y, Kobayashi M, et al: Report of the Committee on the Classification and Diagnostic Criteria of Diabetes mellitus. Diabetes Res Clin Pract 2002;55:65–85. 21 Dominguez-Munoz JE, Manes G, Malfertheiner P: Laboratory diagnosis of inflammatory pancreatic disease; in Berger HG, Warshaw AL, Buchler MW, Carr-Locke DL, Neoptolemos JP, Russell C, Sarr MG (eds): The Pancreas. London, Blackwell Science, pp 169–179. 22 Beck-Nielsen H, Hother-Nielsen O: Obesity in type 2 diabetes mellitus; in LeRoith D, Taylor SI, Olefsky JM (eds): Diabetes mellitus: A Fundamental and Clinical Text, ed 3. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 857–868. 23 Kloppel G, Maillet B: Pathology of acute and chronic pancreatitis. Pancreas 1993; 8: 659– 670. 24 Homma T, Harada H, Koizumi M: Diagnostic criteria for chronic pancreatitis by the Japan Pancreas Society. Pancreas 1997;15:14–15. 25 Worning H: Alcoholic chronic pancreatitis; in Berger HG, Warshaw AL, Buchler MW, CarrLocke DL, Neoptolemos JP, Russell C, Sarr MG (eds): The Pancreas. London, Blackwell Science, 1998, pp 672–682. 26 Report of the Expert Committee on the Diagnosis and Classification of Diabetes mellitus: Diabetes Care 1997;20:1183–1197.
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27 Rossi L, Parvin S, Hassan Z, Hildebrand P, Keller U, Ali L, Beglinger C, Azad Khan AK, Whitcomb DC, Gyr N: Diabetes mellitus in tropical chronic pancreatitis is not just a secondary type of diabetes. Pancreatology 2004; 4:461–467. 28 Frier BM: Diabetes mellitus and lifestyle: Driving, employment, prison, insurance, smoking, alcohol, and travel; in Pickup JC, Williams G (eds): Textbook of Diabetes, ed 3. Oxford, Blackwell Science, 2003, pp 68.1– 68.18. 29 Boeck WG, Adler G, Gress TM: Pancreatic function tests: When to choose, what to use. Curr Gastroenterol Rep 2001;3:95–100. 30 Kitagawa M, Naruse S, Ishiguro H, Nakae Y, Kondo T, Hayakawa T: Evaluating exocrine function tests for diagnosing chronic pancreatitis. Pancreas 1997;15:402–408.
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31 Pezzilli R. Talamini G, Gullo L: Behaviour of serum pancreatic enzymes in chronic pancreatitis. Dig Liver Dis 2000;32:233–237. 32 Jokelainen K, Roine RP, Vaananen H, Farkkila M, Salaspuro M: In vitro acetaldehyde formation by human colonic bacteria. Gut 1994; 35:1271–1274. 33 Balthazar EJ: Computed tomography of the pancreas; in Berger HG, Warshaw AL, Buchler MW, Carr-Locke DL, Neoptolemos JP, Russell C, Sarr MG (eds): The Pancreas. London, Blackwell Science, 1998, pp 205–230. 34 Rehani MM, Bongartz G, Golding SJ, Gordon L, Kalender W, Murakami T, et al: Managing patient dose in computed tomography (CT). Downloaded from International Commission on Radiological Protection (ICRP): Information abstracted from ICRP publication 87. www.icrp.org. June 17, 2004. 35 Cohnen M, Poll LJ, Puettmann C, Ewen K, Saleh A, Modder U: Effective doses in standard protocols for multi-slice CT scanning. Eur Radiol 2003;13:1148–1153.
36 Nishizawa K, Matsumoto M, Iwai K, Tonari A, Yoshida T, Takayama M: Dose evaluation and effective dose estimation from multi-detector CT. Igaku Buturi 2002;22:152–158. 37 Berrington de Gonzalez A, Darby S: Risk of cancer from diagnostic X-rays: Estimates for the UK and 14 other countries. Lancet 2004; 363:345–351. 38 Brenner DJ, Elliston CD, Hall EJ, Berdon WE: Estimated risks of radiation-induced fatal cancer from pediatric CT. Am J Roentgenol 2001; 176:289–296. 39 Shrimpton PC, Jones DG, Hillier MC, Wall BF, Le Heron JC, Faulkner K: Survey of CT Practice in the UK. Part 2: Dosimeric Aspects. London, HMSO, Chilton, NRPB-R249, 1991.
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Received: September 6, 2004 Accepted after revision: January 10, 2005 Published online: June 28, 2005
Pancreatic Volume Associated with Endocrine and Exocrine Function of the Pancreas among Japanese Alcoholics Yuji Nakamuraa, b Susumu Higuchia Katsuya Maruyamaa a b
National Hospital Organization, Kurihama Alcoholism Center, Yokosuka, Kanagawa, and Inagi Municipal Hospital, Inagi, Tokyo, Japan
Key Words Pancreatic volume Helical CT Alcoholism Diabetes Pancreatitis
Abstract Background/Aims: The pancreas is often damaged by excessive alcohol consumption. Because alcohol-related problems and diabetes mellitus (DM) are increasing in Japan, this cross-sectional study was designed to investigate how pancreatic volume (PV, calculated using multi-slice helical computed tomography) represents alcohol consumption and both endocrine and exocrine pancreatic function among alcoholics. Methods: Consenting male and female inpatients undergoing psychiatric therapy for alcoholism from June 2003 to May 2004 were subjected to four-slice MCT to determine PV. Fasting plasma glucose (FPG) and serum lipase levels were examined for endocrine and exocrine pancreatic functions, respectively. Results: The average PVs of 535 male and 117 female patients (57.2 8 21.91 ml and 54.5 8 17.56 ml, respectively) were related to age and height (H) but not to body weight (W). Lipase values had a strong relationship with PV/W. Multiple regression analysis revealed weak associations between PV and both daily ethanol consumption and duration of habitual drinking. The diagnosis of DM in 109 of these alcoholics was more
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strongly associated with the PV/W value than with PV or PV/H. Conclusion: The association of PV with endocrine and exocrine functions suggests new markers, especially PV/W, for the assessment of DM among alcoholic patients. Copyright © 2005 S. Karger AG, Basel and IAP
Introduction
The cellular composition of the pancreas reflects the organ’s diverse endocrine and exocrine functions. Amounting to only 2 percent of the human pancreas, some 100,000 to 1 million islets of Langerhans comprise approximately 1,000 endocrine cells each, of which 70– 80% are producing insulin (-cells) [1]. The morphologic features of the endocrine pancreas are not necessarily considered to be associated with its functional properties, and the concept of a functionally heterogeneous -cell population influences views on the role of pancreatic cells in health and disease [2]. Endocrine function thus seems to be less associated with pancreatic volume than exocrine function, which is represented by the much greater volume of the acinar cell population, comprising 75–90% of the overall mass of the pancreatic gland and its component cells [3].
Yuji Nakamura, MD Inagi Municipal Hospital Ohmaru 1171, Inagi Tokyo 206-0801 (Japan) Tel. +81 42 377 0931, Fax +81 42 379 1310, E-Mail [email protected]
Heavy alcohol consumption is an accepted risk factor for pancreatic diseases, and about half of chronic pancreatitis is associated with alcohol consumption [4]. In 1978, Durbec and Sarles [5] concluded that there was no apparent threshold for alcohol toxicity in the human pancreas. Our colleagues have investigated the associations of chronic pancreatitis and DM among alcoholics [6, 7]. Among several recent studies on alcohol consumption and DM, Nakanishi et al. [8] reported that moderate alcohol consumption (pure ethanol, 23.0–45.9 g/day) by apparently healthy Japanese men is associated with reduced risk for development of impaired fasting glucose or type 2 DM. On the other hand, Kiyohara et al. [9] reported that a high intake of alcohol and a decreased polyunsaturated/saturated fatty acids ratio contribute to the risk for glucose intolerance in contemporary Japanese. DM is a clinically and genetically heterogeneous group of disorders characterized by abnormally high levels of glucose in the blood. The hyperglycemia is due to deficiency of insulin secretion or to resistance of the body’s cells to the action of insulin, or to a combination of the two [10]. Type 2 DM is caused by a combination of genetic and non-genetic factors that result in insulin resistance and insulin deficiency, whereas type 1 DM is caused by -cell destruction, often immune-mediated, that leads to loss of insulin secretion and absolute insulin deficiency. It is estimated that more than 12 million Japanese people are hyperglycemic, and that 95% of these diabetic patients have type 2 DM. These numbers are likely increasing similarly in other nations [11]. Worldwide, type 2 DM accounts for approximately 90–95% of cases in the DM syndrome, while type 1 DM comprises the remaining 5–10. (Despite the ability to detect auto-antibodies, clinical differentiation between types 1 and 2 is not always possible.) Other specific types of DM are thought to be numerically small subclasses, amounting to only 1–2% of all cases in the DM syndrome, e.g. chronic pancreatitis, drug- or chemical-induced endocrinopathy, and infections [10]. Since its introduction in the 1970s, computed tomography (CT) has found wide application within all of the radiological subspecialties [12]. It provides valuable information on the anatomical localization, linear size, surface area, and volume of body structures, including those contained within the body compartment [13]. High-resolution multi-slice helical CT (MCT) can rapidly produce clear, three-dimensional (3-D) images. Whereas a patient’s breathing and digestive movements usually affect imaging of the digestive organs, the high quality of MCT
images makes this technology appropriate for examination of the liver, pancreas, and digestive tract. In addition to speed and high resolution, MCT offers a means of measuring organ volume. Considering that some 93 million CT scans are performed around the world every year, it is important to determine whether 3-D images or organ volume, calculated using CT scans, might serve in an additional role, as indicator of the organ’s functional status. Several studies have reported the benefits of reconstruction based on CT to calculate total liver volume [14, 15]. A few studies have measured PV by CT to investigate the relationship between the size of the pancreas and its endocrine or exocrine function. Using CT to calculate and compare the size of the pancreas in healthy subjects with documented low (n = 5) and high (n = 5) insulin secretion, Nyren et al. [16] found no significant difference in total pancreatic volume (84.8 8 29.4 ml and 79.8 8 8.4 ml for low and high insulin responders, respectively), nor did they find significant differences between the sizes of various parts of the organ (caput, corpus, or cauda). Goda et al. [17] used helical CT to measure PV in 26 patients with type 1 DM, 29 patients with type 2 DM, and 22 healthy individuals. They found a strong correlation between PV and exocrine function for patients with type 1 DM, but the correlation was weak for those with type 2 DM. Whereas small sample sizes in these studies of PV and pancreatic function have limited interpretation of results, studies of larger populations would help to clarify the association between PV and endocrine or exocrine pancreatic function. Moreover, the association between PV and alcohol consumption has not yet been thoroughly investigated. Therefore, we designed this study using MCT to measure PV in alcoholic subjects to evaluate the relationship of pancreatic volume to alcohol-related pancreatic functions – both endocrine and exocrine – as well as the relationship between PV and ethanol consumption.
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Patients and Methods Subjects We designed this cross-sectional study to measure PV in patients admitted to our Alcoholism Center from June 2003 to May 2004 for psychiatric treatment of alcoholism. All patients included in the study were diagnosed using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria for alcohol abuse and dependence [18]. Following the institutional ethics committee’s approval for CT examination of the liver and pancreas of all admitted patients, we enrolled 659 alcoholics who had given informed consent to undergo abdominal CT during their hospitalization.
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Of the 659 patients, we excluded 7 whom we suspected of having acute pancreatitis (6 men; 1 woman), who had upper abdominal pain and elevated pancreatic enzymes compatible with standardized criteria for clinical diagnosis of acute pancreatitis [19]. Thus, we enrolled 652 subjects, of whom 535 (82.1%) were male and 117 (17.9%) were female. Habitual Drinking and Smoking History To obtain accurate information, we interviewed each subject three times, once each by a caseworker, a nurse, and a psychiatrist of the Alcoholism Center staff, using oral and written questionnaires about the patient’s history, the age of first habitual drinking, the amount of alcoholic beverage(s) usually consumed, and the reasons for binge-drinking (e.g. work stress, retirement, lost job, marriage, baby, child, death or illness of family or relatives, and sleeplessness). We calculated alcohol consumption per day as pure ethanol, using a standard alcohol content for each alcoholic beverage: beer, 5% (v/v); wine, 12%; sake, 15%; shochu, 25%; gin, 37%; brandy, 40%; and whiskey, 43%. Smoking status was recorded in pack-years. Current smokers included 424 of the men (79.3%) and 59 of the women (50.4%); 20 men (3.7%) and no women (0.0%) had smoked in the past; and 91 men (17.0%) and 58 women (49.6%) had never smoked. Among the 483 current smokers, the men and women smoked an average of 22.9 8 12.00 and 19.0 8 13.12 cigarettes per day, respectively (p = 0.03). Blood Examination Fasting plasma glucose (FPG) was measured three times, once per week for 3 weeks, by the glucose electrode method (Glucose Auto & Stat GA1160, Arkray, Yokohama, Japan). In accordance with Japan Diabetes mellitus Society May 1999 criteria [20], DM was diagnosed when hyperglycemia met the criteria for ‘diabetic type’, defined as FPG of 7.0 mmol/l (126 mg/dl) or higher on two or more occasions when examined on separate days; ‘normal type’, when FPG was below 6.1 mmol/l (110 mg/dl), and ‘borderline type’, when the value fell between the two (FPG 66.1 and !7.0 mmol/l). Patients whose FPG values were ‘borderline type’ (no more than a single diabetic-type value in the three examinations) were diagnosed as having impaired fasting glucose (IFG). Among the 652 patients enrolled, 70 had previously been diagnosed with DM (34 were on no medication, 17 on medication other than insulin, 19 on medication including insulin). None had been diagnosed as having either type 1 DM or autoimmune disease. We enrolled 36 of the 70 diabetic alcoholic patients (32 men; 4 women) in the DM group, who prescribed hypoglycemic medications during this study, although their FPG values did not meet the criteria for DM. We used serum lipase levels rather than measures of pancreatic amylase, trypsin or elastase [21] to indicate exocrine pancreatic function, because the lipase test was the least expensive under Japanese medical insurance. Pancreatic amylase, trypsin, and elastase testing cost nearly 2-fold, 5-fold, and more than 6-fold the cost of testing serum lipase, respectively, in 2003. The non-identified amylase blood test (total amylase) is less than half as costly as the lipase examination (JPY140; USD 1.27), but it is also less specific for the pancreas and is influenced by the salivary gland. We examined serum lipase levels (normal range, 3–55 IU/l) for all patients at admission, using an enzymatic reaction method of assessing 1,2-diglyceride (Automatic Analyzer 7170S, Hitachi, Tokyo, Japan).
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Pancreatic Volume During their hospitalization, all of our alcoholic subjects underwent four-detector abdominal MCT (Asteion/Multi 4 Slice System, Toshiba, Tokyo, Japan) on the morning after overnight fasting. The MCT parameters included slice thickness, 3 mm; reconstruction index, 3 mm; velocity, 10.5 mm/rotation; helical pitch, 3.5; electric power, 120 kV and 195 mAs. The reconstructed spiral CT images were traced for pancreatic outline in each 3 mm image by a gastroenterologist (Y.N.) without knowledge of blood data or patient history, yielding the exact parenchymal outline and excluding the bile duct, dilated pancreatic duct, splenic vein, portal vein, and pancreatic cyst volumes. Stone volume was not excluded, however, owing to the difficulty of visualizing and calculating tiny pancreatic stones. The 2-D areas and then the pancreatic volumes were calculated at a Toshiba workstation. Each PV was revised by patient height (H, m) and body weight (W, kg), and the PV/H and PV/W values as well as PV values were evaluated. Because of the need for further evaluation of non-homogeneous hepatic densities shown by unenhanced CT, we obtained informed consent and performed additional contrast-enhanced CT imaging on 127 of our 652 subjects. Most of these patients did not have hepatic tumors (diagnoses included severe steatohepatitis, chronic hepatitis, and cirrhosis), but 17 had hemangioma and 2 had hepatocellular carcinoma. We compared PVs calculated from images with and without contrast enhancement for each of the 127 subjects. None of the enrolled 652 subjects (all imaged by unenhanced CT and 127 by contrast-enhanced CT as well) showed evidence of pancreatic inflammation (e.g. edema, necrosis). Statistical Analysis All data in this report are expressed as mean 8 SD. Hypothesis testing was two-tailed, and p ! 0.05 was considered to indicate statistical significance. Comparisons involved using the Mann-Whitney U test, Student’s t test, or regression analysis, as appropriate. We used the statistical analysis system for personal computer, Systat 10.2 (Systat Software, Point Richmond, Calif., USA) for all computations. To examine PV by multiple logistic regression analysis, we separated the 652 patients into categories of smaller and larger PV, based on the average PV for each gender: for men, smaller PV, ^57.2 ml (n = 283) and larger PV, 157.2 ml (n = 252); for women, smaller PV, ^54.5 ml (n = 56) and larger PV, 154.5 ml (n = 61). We examined the effects of eight variables, which we coded as follows: (1) age, 0 = less than 60 years and 1 = 60 years or older; (2) height, 0 = average (male 1.66 m, female 1.56 m) or less and 1 = more than average; (3) body weight, 0 = average (male 59.2 kg, female 48.8 kg) or less, and 1 = more than average; (4) pancreatic calcification, 0 = none and 1 = positive; (5) pancreatic cyst, 0 = none and 1 = positive; (6) average daily alcohol consumption: 0 = less than 200 g and 1 = 200 g or more; (7) duration of habitual drinking, 0 = less than 30 years, and 1 = 30 years or more, and (8) smoking, 0 = less than 20 pack-years, and 1 = 20 pack-years or more. In investigating risk for DM by multiple logistic regression analysis, we analyzed the effects of age, sex, PV/W, body mass index (BMI), smoking, duration of habitual drinking, daily ethanol consumption, and pancreatic calcification. We coded the eight risk variables as follows: (1) age, 0 = less than 60 years and 1 = 60 years or more; (2) sex, 0 = female and 1 = male; (3) PV/W, 0 = average (male 0.98 ml/kg, female 1.19 ml/kg) or less, and 1 = more than
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Table 1. Multiple logistic regression analysis of pancreatic volume
in 652 alcoholics Risk factors
Odds ratio (95% CI) p value
Age 660 years Height >average (male 1.66 m; female 1.56 m) Weight >average (male 59.2 kg; female 48.8 kg) Pancreatic calcification Pancreatic cyst Smoking 620 pack-years Duration of habitual drinking 630 years Daily ethanol consumption 6200 g/day
0.543 (0.343–0.860) 0.009 1.864 (1.269–2.739) 0.002 1.348 (0.925–1.963) 0.718 (0.434–1.189) 0.546 (0.268–1.114) 1.090 (0.750–1.584)
0.120 0.198 0.096 0.653
0.637 (0.415–0.978) 0.039 0.680 (0.449–1.031) 0.070
average; (4) BMI, 0 = 26 kg/m2 or less and 1 = more than 26 kg/m2; (5) average daily alcohol consumption: 0 = less than 200 g and 1 = 200 g or more; (6) duration of habitual drinking, 0 = less than 30 years, and 1 = 30 years or more; (7) smoking, 0 = less than 20 packyears, and 1 = 20 pack-years or more, and (8) pancreatic calcification, 0 = none and 1 = positive.
Results
The average ages of the 535 male and 117 female patients were 54.2 8 12.44 and 44.6 8 14.21 years, respectively (p ! 0.001); their average respective heights were 1.66 8 0.068 m and 1.56 8 0.054 m (p ! 0.001); their average weights, 59.2 8 11.58 kg and 48.8 8 12.24 kg (p ! 0.001), and their average BMIs, 21.5 8 3.76 kg/m2 and 20.1 8 4.64 kg/m2 (p = 0.002), respectively. The duration of habitual drinking differed significantly between our male and female patients (average, 28.3 8 12.83 vs. 18.2 8 10.57 years; p ! 0.001). The average age of first alcohol drinking also differed (17.9 8 3.77 vs. 20.3 8 5.47 years for men and women, respectively; p ! 0.001), but the average daily ethanol consumption did not differ significantly (163 8 97.6 g/day for men vs. 165 8 90.5 g/day for women). The oral interviews yielded information about the subjects’ binge drinking. The female binge drinkers reported much more stress associated with their interpersonal relationships (e.g. marriage, boyfriends, children), whereas for male binge drinkers the stress was more often associated with work, such as job loss or retirement. These reasons seemed to relate to the subjects’ age differences; in fact, our male alcoholic sub-
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jects were on average 10 years older than their female counterparts. The average PVs for male and female patients did not differ significantly (57.2 8 21.91 vs. 54.5 8 17.56 ml, respectively). The PV values obtained using the 127 contrast-enhanced images (ml:Y) were close to the PVs calculated from unenhanced images (ml:X) (Y = 0.995X + 4.829; r2 = 0.933, p ! 0.001). Regression analysis showed associations between PV and age for both men and women and between PV and height for males, but there was less evidence of association between PV and body weight (fig. 1). The difference between men’s and women’s average PV/H values (34.5 8 12.74 and 35.0 8 11.27 kg/m, respectively) was not significant, but their average PV/W values (0.98 8 0.371 and 1.19 8 0.510 ml/kg, respectively) differed significantly (p ! 0.001). Among the 652 subjects, 50 (7.7%) had pancreatic cyst(s) and 96 (14.7%) had calcification in the pancreas; 16 (2.5 %) had both pancreatic cyst(s) and calcification. Examination of the relationship of PV value to various potential risk factors by multiple logistic regression analysis (table 1) showed that PV was significantly related to age 660 years (OR 0.543, p = 0.009), greater than average height (OR 1.862, p = 0.002), and duration of habitual drinking 630 years (OR 0.637, p = 0.039). PV was associated with pancreatic cyst (OR 0.546, p = 0.096) and daily ethanol consumption 6200 g (OR 0.680, p = 0.070), but we found no association between PV and body weight, pancreatic calcification, or smoking 620 pack-years. Substitution of lower and higher daily ethanol consumption values for the assigned value of 6200 g in this model showed that this variable has no relationship to PV: For daily ethanol consumption 6100 g, the odds ratio (OR) was 1.182 (95% CI, 0.750–1.848, p = 0.463); for 6150 g, the OR was 0.805 (0.561–1.156, p = 0.240), and for 6250 g, the OR was 0.834 (0.514–1.355, p = 0.464). Likewise, changing the duration of habitual drinking from 630 to 620 years in this model did not reveal an association between habitual drinking and PV (OR = 0.979; 95% CI, 0.648–1.478; p = 0.919). Similarly, increasing the smoking variable from 620 pack-years to 630 packyears in this model did not show a risk for decreasing PV (OR, 0.851; 95% CI, 0.590–1.229; p = 0.390). Among our 652 alcoholic subjects, we diagnosed DM in 109 who had ‘diabetic-type’ FPG results on at least two of three examinations (99 men, 18.5%; 10 women, 8.5%). Another 340 subjects (269 men, 50.3%; 71 women, 60.7%) were diagnosed as normal on the basis of having ‘normaltype’ FPG in all three examinations. The remaining 203 (167 men, 31.2%; 36 women, 30.8%) were diagnosed as
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Fig. 1. Regression analysis for PV (ml) with
age (years), height (m), and weight (kg) among male (o: –––) and female (x: - - - -). a Age (Y) is associated with PV (X), Y = –0.233X + 67.551 (r2 = 0.169) in men; Y = –0.265X + 58.904 (r2 = 0.100) in women. b Height (Y) has a weak association with PV (X), Y = 0.001X + 1.597 (r2 = 0.113) in men; Y = 0.0006X + 1.524 (r2 = 0.087) in women. c Weight (Y) is not associated with PV (X), Y = 0.153X + 50.463 (r2 = 0.083) in men; Y = –0.022X + 50.021 (r2 = 0.001) in women.
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Table 2. Association of pancreatic volume with endocrine and exocrine pancreatic status in 652 alcoholic patients
n
Pancreatic volume, average PV, ml
Endocrine status Normal Men 269 59.9820.22 Women 71 56.4817.03 Impaired fasting glucose Men 167 58.8822.65 Women 36 54.8817.70 DM Men 99 46.9822.38a Women 10 40.0816.61a Exocrine status Low serum lipase Men 358 Women 65 High serum lipase Men 177 Women 52
54.2821.12 51.7814.81
PV/H, ml/m
PV/W, ml/kg
36.1811.51 36.1810.93
1.0480.356 1.2880.560
35.3813.48 35.4811.19
0.9980.362 1.1380.372
28.4813.09b 0.7980.355c 26.0811.63b 0.7880.385c
32.7812.21 33.289.50
0.9380.356 1.0580.369
64.1822.68d 38.5813.15e 1.1280.372f 63.4819.33d 40.7812.57e 1.4180.584f
DM was diagnosed when indicated by at least two of three FPG tests (6126 mg/dl); normal status, when all three tests had normal results (<110 mg/dl); impaired fasting glucose (IFG), when FPG values fell between DM and normal. Low serum lipase was defined as ^24.5 IU/l (average for men) or ^28.3 IU/l (average for women). a PV with DM differed significantly from PV with IFG in men (p < 0.001 [4.3 ! 10–5]) and in women (p = 0.022). b PV/H with DM differed significantly from PV/H with IFG in men (p < 0.001 [6.0 ! 10–5]) and in women (p = 0.024). c PV/W with DM differed significantly from PV/W with IFG in men (p < 0.001 [4.1 ! 10–5]) and in women (p = 0.012). d PV, e PV/H, and f PV/W with high lipase differed significantly from those with low lipase in men and in women (p < 0.001 [men, 8.7 ! 10–7, 6.4 ! 10–7, and 1.7 ! 10–8, respectively; women, 3.2 ! 10–4, 3.6 ! 10–4, and 2.2 ! 10–4, respectively]).
having impaired fasting glucose (IFG). Calculating the average PV, PV/H, and PV/W for the normal, IFG, and DM groups (both male and female), we found much greater differences in these groups’ PV/W values than in either their PV or PV/H values (table 2). Dividing the 652 alcoholics into two groups of men and women by their average serum lipase values (men, 24.5 8 24.06 IU/l; women, 28.3 8 24.33 IU/l) revealed a strong association between lipase levels (both high and low) and PV, PV/H, and PV/W (table 2). Comparing subjects with high and low lipase levels, we found a much greater difference in PV/W values than in either the PV or PV/H values. Multiple regression analysis (table 3) revealed that DM has a strong relationship with PV/W (OR, 0.415; p ! 0.001) and pancreatic calcification (OR, 3.488; p ! 0.001) and DM tends to be associated with smoking status (OR, 1.707; p = 0.053). Among our 96 patients with pancreatic calcification (92 men; 4 women), 36 (34 men; 2 women) were diabetic. We could find no relationship between DM and age, sex, BMI, duration of habitual drinking, or daily ethanol consumption in these alcoholic subjects. Neither reducing the smoking variable from 620 pack-years to 610 pack-years nor increasing it to 630 pack-years showed a significant risk for DM: For 610 pack-years, OR = 0.903 (95% CI, 0.490–1.666, p = 0.745); for 630 pack-years, OR = 1.113 (0.690–1.796, p = 0.662).
Discussion
The results of our investigation for the relationship between 652 alcoholic patients’ pancreatic volumes and their pancreatic function and ethanol consumption indi-
Table 3. Multiple logistic regression analysis of risk for DM in 652 alcoholics
Age 660 years Sex, male PV/W >average (male 0.98 ml/kg; female 1.19 ml/kg) BMI >26 kg/m2 Smoking 620 pack-years Duration of habitual drinking 630 years Daily ethanol consumption 6200 g/day Pancreatic calcification
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Odds ratio (95% CI)
p value
0.853 (0.483–1.507) 1.925 (0.769–4.816) 0.415 (0.255–0.676) 0.896 (0.408–1.966) 1.707 (0.992–2.936) 1.147 (0.660–1.994) 0.969 (0.562–1.670) 3.488 (2.050–5.935)
<0.584 <0.162 <0.001 <0.784 <0.053 <0.627 <0.909 <0.001
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cated that there are associations between PV and both endocrine and exocrine function. PV was related to age and height but not to weight. In fact, the PV/W index had a stronger association with both DM and serum lipase level than did PV itself. We found weak relationships between PV and alcohol consumption and between PV and duration of habitual drinking. When we controlled duration of habitual drinking (630 years) and daily ethanol consumption (6200 g) in multiple logistic regression analysis, we found statistical significance for their relationships with PV, but the level of significance was not attained when we substituted different daily ethanol consumption or duration of habitual drinking values. Prior investigation had revealed no apparent threshold for alcohol toxicity in the human pancreas [5]. It appears that age itself would have more effect on PV than 130 years’ duration of habitual drinking. Although we attempted to obtain accurate information regarding daily ethanol consumption, evaluation based on the subjects’ total ethanol consumption was problematic, because these alcoholics frequently indulged in binge-drinking, which disrupted memory concerning not only their behavior but how much they drank. Moreover, their ethanol consumption changed from day to day, making it difficult to calculate daily, monthly, and yearly alcohol intake. We could not examine normal subjects who did not engage in heavy alcohol consumption, because our study was done in an alcoholism treatment center; thus, we cannot report on the relationships between PV and other variables in non-alcoholic subjects. We suppose, however, that the association between PV and age or height would be a general relationship existing in the normal population and thus would not be specific for alcoholics. Research on many subjects who had never drunk alcohol would be needed to analyze these relationships. Diabetes, especially type 2 DM, is increasing all over the world. The prevalence of type 2 DM in the western world is about 5–10% of the population over 40 years of age. Among all subjects with type 2 DM, 80% are obese, although only 10% of all obese people develop type 2 DM [22]. Type 2 DM in obese subjects is thought to be a multigenetic disease, so the question remains whether obese subjects will ever develop DM. Our results suggest that a simple indicator – PV divided by weight – shows the risk for DM. That PV/W is more strongly associated with DM than BMI suggests an important reason for the development of type 2 DM in some patients. Given the high prevalence of chronic pancreatitis in alcoholics, the question is whether our subjects’ DM is
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type 2 or the other type resulting from alcoholic chronic pancreatitis. Chronic pancreatitis is an irreversible, patchy, and usually progressive fibrosis of the glandular parenchyma, due to duct changes subsequent to necroticinflammatory processes in the pancreas [23]. The gold standard for diagnosing for chronic pancreatitis is histological examination, which is difficult. The Japan Pancreas Society’s diagnostic criteria for chronic pancreatitis specify a definite diagnosis of chronic pancreatitis in the presence of pancreatic stones, as evidenced by intrapancreatic calcifications [24]. These criteria are the same as those in other nations [25], and we used them in diagnosing chronic pancreatitis. Likewise, it was difficult for us to classify alcoholic diabetes as type 2 DM or the other type in patients with alcoholic chronic pancreatitis without pancreatic calcifications. Although there are other diagnostic tools, such as endoscopic retrograde pancreatography (ERP) and the secretin test (duodenal intubation test), it is hard to perform these tests on large numbers of subjects, many of whom refuse to undergo uncomfortable procedures. Multiple logistic regression analysis showed that pancreatic calcification accompanied the risk for DM among alcoholics independently, so we were sure that some patients had developed DM following chronic pancreatitis; however, most of our subjects (543 in 652 subjects, 83.3%) did not have pancreatic calcification. Multiple logistic regression analysis also showed that PV/W accompanied the risk for DM among alcoholics independently, suggesting that the PV/W value would be of benefit in clinical assessment for type 2 DM. It seems too simplistic to be true that decreased PV would indicate diabetes. Diabetes occurs in only about half of patients with chronic pancreatitis, even when almost the entire pancreas has been destroyed, and adenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes [26]. These findings imply a mechanism other than simple reduction in -cell mass. Clarification of the relationship of the islets of Langerhans with chronic pancreatitis, including -cell and -cell contributions [27], for example, would require extensive investigation to obtain much more data from the general population. PV might also depend on race and country, because the average PV in our study was less than that shown by Nyren et al. [16] in Sweden. Investigation of type 1 DM, which we could not include in this study, might have provided more important information concerning PV and endocrine or exocrine pancreatic function. In that regard, Goda et al. [17] reported finding a stronger correlation for type 1 DM than for type 2 DM.
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The association between DM and smoking status was not clarified in our study, because this tendency did not reach statistical significance and we could not find statistical significance when we controlled smoking status to 630 pack-years instead of 620 pack-years. Several studies do show an association between smoking and DM, suggesting that smoking is an independent risk factor for type 2 DM [28]. Because of the large number of smokers and the small number of non-smokers among the Japanese alcoholic population, further study involving larger numbers of non-smokers is needed to elucidate the association PV and smoking among alcoholics. In this study, we used the serum lipase value to indicate exocrine pancreatic function. Tests that can be performed to evaluate exocrine pancreatic function include the secretin test, the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test, and fecal chymotrypsin (FCT), fecal elastase, and serum pancreatic enzyme testing. The secretin test remains the gold standard [29]. Kitagawa et al. [30] reported that in patients with severe or moderate exocrine insufficiency demonstrated by the secretin test, abnormally low levels of exocrine function were observed in 63% by BT-PABA test, in 61% by FCT, and in 44% by pancreatic amylase, while in patients with normal exocrine function demonstrated by the secretin test, abnormally low exocrine function was observed in 28% by BTPABA test, in 28% by FCT, and in 10% by PA. Pezzilli et al. [31] reported that considering only low serum concentrations of the five enzymes studied in diagnosing chronic pancreatitis, trypsinogen showed a sensitivity of 28%, a specificity of 100%, a predictive value of a positive test of 100% and a predictive value of a negative test of 96.4%. After analyzing several factors (accessibility, simplicity, patient acceptability, and cost), we chose the serum lipase test for our alcoholics, although we await reports about the relationship between PV and the secretin test in large numbers of subjects. It is important to analyze patients with regard to steatorrhea, diarrhea, and weight loss in exocrine pancreatic function insufficiency, as well as to analyze pancreatic exocrine enzymes. Alcohol is an important risk factor for diarrhea [32], and alcoholics are frequently malnourished. Nearly all of our alcoholic subjects reported having frequent diarrhea due to heavy alcohol intake when they were drinking, More than 54% of our subjects had BMIs under 21 kg/m2, and during binge-drinking, alcohol may have constituted their sole source of nutrition. Because most of our subjects were diarrheic and hyponutritional, it was difficult to evaluate steatorrhea, diarrhea, and weight loss in relation to their pancreatic function.
Dynamic contrast-enhanced CT is considered the gold-standard imaging modality for the diagnosis and evaluation of patients with pancreatic disease [33]. Our study, which was designed to investigate pancreatic functions using the least invasive method, lacked injection for contrast-enhancement and produced suboptimal images in most patients, resulting in limitation of our ability to detect subtle pancreatic inflammatory and neoplastic lesions. In 127 cases with contrast-enhanced CT, we found that the pancreatic margins were more distinct in contrast-enhanced images than in unenhanced images, and that the PVs calculated from contrast-enhanced images of the same patients were usually slightly larger than those from the unenhanced images. Because we found that the PV detected by contrast-enhanced CT closely approximated PV detected by unenhanced CT, we concluded that it could be worthwhile to evaluate PV by non-contrasted CT methods of measuring PV, which are less invasive and cause less patient discomfort. Although we found that PV was not decreased among subjects with pancreatic calcification, we could not rule out overestimation of PV in cases with pancreatic calcification, because it was difficult to exclude the volume of many tiny calcifications from PV calculated on the basis of tracing by human hands. In the future, further development of computer programs will enable automatic measurement of pancreatic volume that excludes calcification and other extraparenchymal volumes. The Japanese Ministry of Health, Labor, and Welfare recommends limiting radiation exposure to a maximum of 50 mSv per year for whole body and only 13 mSv of abdominal exposure per year for women capable of becoming pregnant. Although the International Commission on Radiological Protection (ICRP) has concerns that a radiation dose increase of 10–30% may occur with use of the multi-slice detector array, it depends upon the choice of several factors: the product of tube current, in milli-amperes (mA), and exposure time, in seconds (s), or mAs; scan volume; helical pitch; and slice width [34–36]. Because our hospital radiologist detected that each subject’s radiation exposure amounted to 30 mSv in this study, we will change our protocol in the future to decrease radiation exposure. MCT technology, which is continually improving, could be used to completely scan every organ more rapidly, providing more accurate 3-D images and volumes, even in patients who are elderly or very ill. The only major problem except the cost of MCT is the risk of high radiation exposure, especially for younger persons, so ways to reduce exposure by multiple cofactors are under
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discussion. The risk versus clinical benefit of diagnostic radiation constitutes an important issue, and the benefits of using diagnostic X-rays need to be weighed against potential risks for cancer [37–39]. Magnetic resonance imaging (MRI) is an alternative method of measuring organ volumes without radiation exposure. In summary, we found that PV detected by MCT is a good way to assess both exocrine and endocrine pancreatic functions, not only to evaluate pancreatic calcification and neoplasms. PV values were associated with subjects’ ages and heights, but not with their weight, and low PV/W had a stronger relationship with diagnosed DM and low serum lipase levels in alcoholic patients. The associations with PV and daily ethanol consumption or duration of habitual drinking were weak. Multiple logistic
regression analysis showed an association between DM and PV/W as well as an association between DM and pancreatic calcification among alcoholics. Smoking status was related to the risk for DM, but ethanol consumption did not carry a significant risk. Information about exact macromorphologic status of the pancreas in health and disease represents a specific new way in which the physician can communicate relevant findings with the diabetologist, investigating genetic and non-genetic issues surrounding insulin sensitivity and -cell function. Additional multicenter, multinational, and multiracial studies are needed to determine the association between organ volume and function. MCT promises to play a key role in measuring the volume of not only the pancreas but other organs as well.
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