J Hepatobiliary Pancreat Sci (2014) 21:562–572 DOI: 10.1002/jhbp.115
ORIGINAL ARTICLE
Paradoxical impact of the remnant pancreatic volume and infectious complications on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy Rie Sato · Masashi Kishiwada · Naohisa Kuriyama · Yoshinori Azumi · Shugo Mizuno · Masanobu Usui · Hiroyuki Sakurai · Masami Tabata · Tomomi Yamada · Shuji Isaji
Published online: 14 May 2014 © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Background The aim of the present study was to evaluate perioperative risk factors for development of nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), paying special attention to remnant pancreatic volume (RPV) and postoperative infection. Methods We reviewed the charts of 110 patients who had been followed more than 6 months after PD. These patients were classified into the two groups according to RPV measured by CT volumetry at one month: large-volume group (LVG) (10 ml or more, n = 75) and small-volume group (SVG) (less than 10 ml, n = 35). Results Nonalcoholic fatty liver disease developed in 44 (40.0%), being significantly higher in SVG than in LVG: 54.2% vs. 33.3% (P = 0.037). SVG was characterized as significantly higher incidence of pancreatic adenocarcinoma, while LVG was characterized as significantly higher incidences of soft pancreas, postoperative infection and pancreatic fistula. In LVG, the incidence of NAFLD was significantly higher in patients with suspicion of infection than in those without it: 45.2% vs. 18.1% (P = 0.014), while not different in SVG. By multivariate analysis, independent risk factor was determined as RPV and suspicion of infection in the whole patients, and in LVG it was suspicion of infection, while in SVG it was not identified. Conclusion After PD, RPV and status of postoperative infection paradoxically influenced the development of NAFLD. R. Sato · M. Kishiwada (*) · N. Kuriyama · Y. Azumi · S. Mizuno · M. Usui · H. Sakurai · M. Tabata · T. Yamada · S. Isaji Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan e-mail: [email protected]
Keywords Gut-derived endotoxin · Multiple parallel hit theory · Nonalcoholic steatohepatitis · Pancreatic exocrine insufficiency · Pancreatic fistula
Introduction Nonalcoholic fatty liver disease (NAFLD) has become widespread in the world and parallels the frequency of obesity, insulin resistance and metabolic syndrome [1]. NAFLD is characterized by two steps of intrahepatic lipid accumulation and inflammatory progression to fibrosis [2]. In recent years, much attention has been paid to NAFLD because NAFLD includes a disease spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis [3]. In contrast to conventional NAFLD, it has been recently known that pancreaticoduodenectomy (PD) is associated with development of NAFLD [4, 5]. In 2010, we reported the incidence of NAFLD after PD as 37.0% and revealed that NAFLD after PD was significantly associated with the following three factors: pancreatic adenocarcinoma, resection line, and postoperative diarrhea, suggesting the contribution of malnutrition due to pancreatic exocrine deficiency [6]. We also encountered two patients with PD who later developed NASH confirmed by liver biopsy, in whom treatment of infectious complications and high-dose pancreatic enzyme supplementation improved liver dysfunction and liver steatosis [7]. The pathogenesis of NAFLD after PD may therefore differ from that of conventional NAFLD. In the pathogenesis of conventional NAFLD/NASH, Day et al. [8] presented more than a decade ago the so-called “two hit” theory, suggesting that after a first hit of hepatic steatosis the second hit, such as inflammation and
J Hepatobiliary Pancreat Sci (2014) 21:562–572
563
gut-derived endotoxin is required to develop NASH. Recently, however, Tilg et al. [9] proposed a new model suggesting that many hits may act in parallel, finally resulting in liver inflammation and that gut-derived and adipose tissue-derived factors may play central roles. They further suggested that inflammation could take place first before hepatic steatosis. We therefore hypothesized that the remnant pancreatic volume (RPV) and/or postoperative infectious complications after PD influenced the development of NAFLD. The aim of the present study was to evaluate the various perioperative risk factors for the development of NAFLD after PD, paying special attention to RPV and the status of postoperative infection.
Definition of NAFLD
Methods
We measured RPV at one month after operation by CT volumetry. Serial transverse enhanced CT scan images were obtained at 2.0 or 2.5 mm intervals. Each slice of the remnant pancreas parenchyma was traced, and the corresponding area was calculated as the sum of pancreatic tissue area (Fig. 1a). Major vessels such as the splenic vein and dilated pancreatic duct (3 mm or more) were excluded. As a normal control, we measured the whole pancreatic volume, and volumes of pancreatic head and body-tail separately (its border: the center of portal vein) in five trauma patients (mean age: 63.3, range: 45–77) who did not have abdominal injury. As a result, the whole pancreatic volume was 70.08 ± 21.24 ml (range: 46.64–99.90), the volume of pancreatic head was 32.72 ± 9.6 ml (range: 22.87–48.50), and the volume of pancreatic body-tail was 37.36 ± 17.41 ml (range: 23.77–66.5).
Patients Among the consecutive 139 patients who underwent PD from April 2007 to March 2012, we retrospectively reviewed the charts of the 110 patients who had been followed more than 6 months postoperatively. The 12 patients who died within 6 months and 17 who were transferred to other hospitals within 6 months after operation were excluded. Among these 110 patients, the mean age was 66.8 years, and males/females were 66/44. The indication of PD was pancreatic adenocarcinoma (n = 58), intraductal papillarymucinous neoplasm (IPMN) (n = 21), bile duct carcinoma (n = 9), ampullary carcinoma (n = 7), other neoplasms (n = 7), metastatic pancreatic tumor (n = 3) and benign diseases (n = 5). Surgical procedure was conventional PD in 16 patients, pylorus-preserving PD (PPPD) in six and subtotal stomach-preserving PD (SSPPD) in 88. Combined resection of other organs was performed in 44 patients for the portal vein/superior mesenteric vein, in four for the hepatic artery, in four for the stomach or colon, and in three for the distal pancreas (middle pancreas preserved). For the patients without pancreatic adenocarcinoma, we did not perform dissection of the nerve plexus around the superior mesenteric artery (SMA). Surgical reconstructions were performed according to a modification of the Child’s method and feeding jejunostomy was placed intraoperatively for early postoperative enteral nutrition. Almost all patients after PD were given pancreatic enzyme, but the time of initiating and dosage of pancreatic enzyme supplementation was determined by each surgeon. The dosage of pancreatic enzyme preparations at 3 months after PD was no administration in eight patients, normal dose (pancreatin 1.5–3.0 g) in nine, and high dose (pancreatin 6 g or more or pancrealipase 1800 mg) in 93.
The median CT attenuation value of the liver parenchyma was measured, using a 5-point scale of certainty on plane CT, preoperatively and at 1, 3, 6 and 12 months after PD. We defined a hepatic CT value of less than 40 HU as NAFLD [6]. Comparison of CT attenuation value between the liver and spleen was not used in this study, because the CT value of the spleen was highly influenced in the patients with resection of the splenic vein and/or artery at the time of PD [10]. Measurement of RPV
Correlation between RPV and development of NAFLD The average RPV in the 110 patients was 16.98 ± 10.79 ml (range: 2.08–42.40 ml). To determine the most reliable value of RPV for discriminating NAFLD and non-NAFLD, we examined the 19 values of RPV from 7 ml to 25 ml by performing stepwise selection of multivariate logistic regression. As a result, RPV could be classified into the two groups: large-volume group (LVG) (RPV of 10 ml or more, mean: 21.92 ± 9.54 ml, n = 75) and small-volume group (SVG) (RPV of less than 10 ml, mean: 6.32 ± 2.12 ml, n = 35) (Fig. 1b). Evaluation of clinical factors We evaluated the variables from pre-, intra- and postoperative factors. Preoperative factors included age, sex, diabetes mellitus (DM), diagnosis, chomoradiotherapy, pancreatic duct dilation. Intraoperative factors included pancreatic consistency (soft or hard) and surgical procedure. Postoperative
564 Fig. 1 (a) CT volumetry of remnant pancreas. The remnant pancreas parenchyma of 2 or 2.5 mm slice CT is traced, and the corresponding area is calculated as the sum of pancreatic tissue area. (b) The distribution of remnant pancreatic volume is classified into the two groups; small-volume group (SVG) is less than 10 ml and large-volume group (LVG) is 10 ml or more
J Hepatobiliary Pancreat Sci (2014) 21:562–572
(a)
(b) (n)
(ml) Small-volume group (SVG) (n=35)
Large-volume group (LVG) (n=75)
the following clinical findings: body temperature, heart rate, respiratory rate and WBC count [13]. Blood culture was usually performed by using aerobic and anaerobic blood culture bottles when body temperature exceed 38°C. As a result, we examined bacterial blood culture in 37 patients, showing culture positive in 11.
factors included postoperative infectious complications and pancreatic functions. Since exact methods for evaluation of pancreatic endocrine and exocrine functions are expensive and labor intensive, there has been an increased need in clinical practice for a simple and widely available screening tool for detection of pancreatic functions. Recently, Lindkvist et al. [11] reported significance of nutritional makers such as albumin, prealbumin, magnesium, HbA1c and cholesterol to predict the probability of pancreatic exocrine insufficiency. Furthermore, Yadav et al. [12] has suggested that decreased levels of serum amylase in type 2 DM is associated with decreased pancreatic function. To predict the remnant pancreatic functions, therefore, we examined serum levels of albumin, cholesterol, amylase and HbA1c as nutritional makers before and 1, 3, 6 and 12 months after pancreatectomy. In the present study, the patients were diagnosed as DM when either one of fasting blood sugar of 126 mg/dl or more and HbA1c of 6.5% or more was found or when DM treatment had been introduced preoperatively.
All statistical analyses were performed using the SPSS 22.0 for Windows (IBM, Armonk, NY, USA). The results of the continuous variables were expressed as mean values with standard deviation (SD), and the statistical significance was determined by the paired t-test or Mann–Whitney U-test. Dichotomous variables were evaluated by χ2 analysis or Fisher’s test, as appropriate. Risk factors associated with development of NAFLD were analyzed by uni- and multivariate analysis (multiregression analysis). Results were considered significant when the P-values were less than 0.05.
Status of postoperative infection
Results
In the present study, the status of postoperative infection was originally classified into the three grades on postoperative 7–28 days: suspicion of infection, clinically overt infections and systemic inflammatory response syndrome (SIRS). Suspicion of infection was defined as white blood cell (WBC) count 12,000/mm3. Clinically overt infections included pancreatic fistula, bile leakage, abdominal abscess, enterocolitis, pneumonia, cholangitis and wound infection. SIRS was defined by two or more of
Incidence of NAFLD
Statistical analysis
Among 110 patients, 44 (40%) developed NAFLD after PD. When the number of patients with NAFLD was examined according to time (month) of diagnosis after PD, 90.9% (40/44) of patients developed NAFLD within 3 months (Fig. 2a). Median CT values (HU) at preoperation, 1, 3, 6 and 12 months after PD were compared between the patients with and without NAFLD: 56.8 vs. 60.0, 44.1 vs. 53.4, 19.1
J Hepatobiliary Pancreat Sci (2014) 21:562–572
(a)
(b)
(n)
with NAFLD
25 Liver CT value (HU)
Fig. 2 (a) Number of the patients with nonalcoholic fatty liver disease (NAFLD) according to time (month) of diagnosis after pancreaticoduodenectomy (PD). (b) Change of liver CT value according to the patients with or without NAFLD. (* P < 0.05 with Bonferroni’s correction)
565
20 15
26 10
14
without NAFLD
*
60
40
20
5
3
0 ~1M
2~3M
vs. 54.6 (P < 0.05 with Bonferroni’s correction), 28.3 vs. 56.0 and 41.6 vs. 57.7 (Fig. 2b). CT values remained almost unchanged in the patients without NAFLD, but significantly decreased at 3 month in those with NAFLD. Comparison of clinical factors between LVG and SVG Significant differences between LVG and SVG were found in the incidences of pancreatic adenocarcinoma (34.6% vs. 91.4%, P < 0.001), preoperative chemoradiotherapy (28.0% vs. 82.8%, P < 0.001), preoperative pancreatic duct dilation (44.0% vs. 71.4%, P = 0.007), soft pancreas (53.3% vs. 14.2%, P = 0.006), suspicion of infection (56.0% vs. 20.0%, P < 0.001), clinically overt infection (52.0% vs. 25.7%, P = 0.010), SIRS on POD7-28 (41.3% vs. 20.0%, P = 0.028) and NAFLD (33.3% vs. 54.2%, P = 0.037). There were no significant differences in the incidences of blood culture examined and blood culture positive between the two groups (Table 1). Additionally, we compared the incidence of NAFLD between soft and hard pancreas, paying attention to RPV. In LVG, RPV was significantly larger in soft pancreas than in hard pancreas: 26.40 ± 9.02 ml vs. 16.81 ± 7.37 ml (P < 0.001); however, the incidence of NAFLD did not differ between soft and hard pancreas: 32.3% vs. 34.3% (P = 0.870). In SVG, RPV did not differ between soft and hard pancreas: 6.46 ± 2.41 ml vs. 6.30 ± 2.10 ml (P = 0.878), and the incidence of NAFLD did not differ either: 53.3% vs. 60.0% (P = 0.782). Change of nutritional markers between LVG and SVG The chronological changes of nutritional markers were compared between LVG and SVG. Serum albumin levels (g/dl) were significantly lower in SVG than in LVG at 3, 6 and 12 months: 3.2 ± 0.4 vs. 3.5 ± 0.7 (P = 0.005), 3.3 ± 0.6
1
4~6M 7~12M
0 preop
1
3 Months
6
12
vs. 3.7 ± 0.6 (P = 0.007) and 3.3 ± 0.6 vs. 3.8 ± 0.6 (P = 0.003) (Fig. 3a). Serum cholesterol levels (mg/dl) were significantly lower in SVG than in LVG at 1 and 12 months: 90 ± 14 vs. 122 ± 51 (P = 0.004) and 105 ± 44 vs. 153 ± 40 (P = 0.001) (Fig. 3b). Although serum amylase levels (IU/L) were significantly lower in SVG than in LVG at 1 month: 27.9 ± 17.1 vs. 46.4 ± 26.1 (P = 0.004), HbA1c levels (%) were significantly higher in SVG than in LVG at 1 month: 7.0 ± 0.9 vs. 5.7 ± 1.0 (P = 0.01) (Fig. 3c,d). Preand postoperative prevalence of DM was not significantly different between SVG and LVG: 28.5% vs. 21.3% (P = 0.234) and 34.6% vs. 28.6% (P = 0.505). Postoperative complications in LVG and SVG The incidence of pancreatic fistula (grades A, B and C) was significantly higher in LVG than in SVG: 22.0% vs. 2.9% (P = 0.018). Although not significantly different, the incidences of pancreatic fistula (grades B and C) and intraabdominal abscess were higher in LVG than in SVG: 9.3% vs. 0% (P = 0.057) and 9.3% vs. 0% (P = 0.057) (Table 2). NAFLD and status of postoperative infection with respect to each LVG and SVG The incidence of NAFLD according to status of postoperative infection was further analyzed with respect to each LVG and SVG. In LVG, its incidence was significantly higher in 42 patients with suspicion of infection than in 33 without it: 45.2% vs. 18.1% (P = 0.014), while in SVG it did not differ between seven patients with suspicion of infection and 28 patients without it: 57.1% vs. 53.6% (P = 0.865) (Fig. 4a). As of clinically overt infection, however, the incidence of NAFLD did not significantly differ between the patients with and without it in LVG and SVG, respectively: 38.5% vs. 27.7% (P = 0.327) and 66.7% vs. 50.0% (P = 0.387)
566
J Hepatobiliary Pancreat Sci (2014) 21:562–572
Table 1 Patient characteristics in large-volume group (LVG) and small-volume group (SVG) Variable Preoperative factors Mean age Gender (male/female) Diabetes mellitus Diagnosis: Pancreatic adenocarcinoma Bile duct carcinoma Ampullary carcinoma IPMN Other neoplasm Metastatic pancreatic tumor Benign disease Preoperative chemoradiotherapy Pancreatic duct dilation* Intraoperative factors Soft pancreas Surgical procedure (PD/SSPPD/PPPD) Postoperative factors High dose pancreatic enzyme replacement Postoperative infectious complication Suspicion of infection** on POD7-28 Clinically overt infection on POD7-28 SIRS on POD7-28 Blood culture examined Blood culture positive NAFLD
LVG (n = 75)
SVG (n = 35)
P-value
66.3 48/27 16 (21.3%) 26 (34.6%) 8 7 18 7 3 5 21 (28.0%) 33 (44.0%)
67.9 18/17 10 (28.5%) 32 (91.4%) 1 0 3 0 0 0 29 (82.8%) 25 (71.4%)
NS NS NS
ORIGINAL ARTICLE
Paradoxical impact of the remnant pancreatic volume and infectious complications on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy Rie Sato · Masashi Kishiwada · Naohisa Kuriyama · Yoshinori Azumi · Shugo Mizuno · Masanobu Usui · Hiroyuki Sakurai · Masami Tabata · Tomomi Yamada · Shuji Isaji
Published online: 14 May 2014 © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Background The aim of the present study was to evaluate perioperative risk factors for development of nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), paying special attention to remnant pancreatic volume (RPV) and postoperative infection. Methods We reviewed the charts of 110 patients who had been followed more than 6 months after PD. These patients were classified into the two groups according to RPV measured by CT volumetry at one month: large-volume group (LVG) (10 ml or more, n = 75) and small-volume group (SVG) (less than 10 ml, n = 35). Results Nonalcoholic fatty liver disease developed in 44 (40.0%), being significantly higher in SVG than in LVG: 54.2% vs. 33.3% (P = 0.037). SVG was characterized as significantly higher incidence of pancreatic adenocarcinoma, while LVG was characterized as significantly higher incidences of soft pancreas, postoperative infection and pancreatic fistula. In LVG, the incidence of NAFLD was significantly higher in patients with suspicion of infection than in those without it: 45.2% vs. 18.1% (P = 0.014), while not different in SVG. By multivariate analysis, independent risk factor was determined as RPV and suspicion of infection in the whole patients, and in LVG it was suspicion of infection, while in SVG it was not identified. Conclusion After PD, RPV and status of postoperative infection paradoxically influenced the development of NAFLD. R. Sato · M. Kishiwada (*) · N. Kuriyama · Y. Azumi · S. Mizuno · M. Usui · H. Sakurai · M. Tabata · T. Yamada · S. Isaji Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan e-mail: [email protected]
Keywords Gut-derived endotoxin · Multiple parallel hit theory · Nonalcoholic steatohepatitis · Pancreatic exocrine insufficiency · Pancreatic fistula
Introduction Nonalcoholic fatty liver disease (NAFLD) has become widespread in the world and parallels the frequency of obesity, insulin resistance and metabolic syndrome [1]. NAFLD is characterized by two steps of intrahepatic lipid accumulation and inflammatory progression to fibrosis [2]. In recent years, much attention has been paid to NAFLD because NAFLD includes a disease spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis [3]. In contrast to conventional NAFLD, it has been recently known that pancreaticoduodenectomy (PD) is associated with development of NAFLD [4, 5]. In 2010, we reported the incidence of NAFLD after PD as 37.0% and revealed that NAFLD after PD was significantly associated with the following three factors: pancreatic adenocarcinoma, resection line, and postoperative diarrhea, suggesting the contribution of malnutrition due to pancreatic exocrine deficiency [6]. We also encountered two patients with PD who later developed NASH confirmed by liver biopsy, in whom treatment of infectious complications and high-dose pancreatic enzyme supplementation improved liver dysfunction and liver steatosis [7]. The pathogenesis of NAFLD after PD may therefore differ from that of conventional NAFLD. In the pathogenesis of conventional NAFLD/NASH, Day et al. [8] presented more than a decade ago the so-called “two hit” theory, suggesting that after a first hit of hepatic steatosis the second hit, such as inflammation and
J Hepatobiliary Pancreat Sci (2014) 21:562–572
563
gut-derived endotoxin is required to develop NASH. Recently, however, Tilg et al. [9] proposed a new model suggesting that many hits may act in parallel, finally resulting in liver inflammation and that gut-derived and adipose tissue-derived factors may play central roles. They further suggested that inflammation could take place first before hepatic steatosis. We therefore hypothesized that the remnant pancreatic volume (RPV) and/or postoperative infectious complications after PD influenced the development of NAFLD. The aim of the present study was to evaluate the various perioperative risk factors for the development of NAFLD after PD, paying special attention to RPV and the status of postoperative infection.
Definition of NAFLD
Methods
We measured RPV at one month after operation by CT volumetry. Serial transverse enhanced CT scan images were obtained at 2.0 or 2.5 mm intervals. Each slice of the remnant pancreas parenchyma was traced, and the corresponding area was calculated as the sum of pancreatic tissue area (Fig. 1a). Major vessels such as the splenic vein and dilated pancreatic duct (3 mm or more) were excluded. As a normal control, we measured the whole pancreatic volume, and volumes of pancreatic head and body-tail separately (its border: the center of portal vein) in five trauma patients (mean age: 63.3, range: 45–77) who did not have abdominal injury. As a result, the whole pancreatic volume was 70.08 ± 21.24 ml (range: 46.64–99.90), the volume of pancreatic head was 32.72 ± 9.6 ml (range: 22.87–48.50), and the volume of pancreatic body-tail was 37.36 ± 17.41 ml (range: 23.77–66.5).
Patients Among the consecutive 139 patients who underwent PD from April 2007 to March 2012, we retrospectively reviewed the charts of the 110 patients who had been followed more than 6 months postoperatively. The 12 patients who died within 6 months and 17 who were transferred to other hospitals within 6 months after operation were excluded. Among these 110 patients, the mean age was 66.8 years, and males/females were 66/44. The indication of PD was pancreatic adenocarcinoma (n = 58), intraductal papillarymucinous neoplasm (IPMN) (n = 21), bile duct carcinoma (n = 9), ampullary carcinoma (n = 7), other neoplasms (n = 7), metastatic pancreatic tumor (n = 3) and benign diseases (n = 5). Surgical procedure was conventional PD in 16 patients, pylorus-preserving PD (PPPD) in six and subtotal stomach-preserving PD (SSPPD) in 88. Combined resection of other organs was performed in 44 patients for the portal vein/superior mesenteric vein, in four for the hepatic artery, in four for the stomach or colon, and in three for the distal pancreas (middle pancreas preserved). For the patients without pancreatic adenocarcinoma, we did not perform dissection of the nerve plexus around the superior mesenteric artery (SMA). Surgical reconstructions were performed according to a modification of the Child’s method and feeding jejunostomy was placed intraoperatively for early postoperative enteral nutrition. Almost all patients after PD were given pancreatic enzyme, but the time of initiating and dosage of pancreatic enzyme supplementation was determined by each surgeon. The dosage of pancreatic enzyme preparations at 3 months after PD was no administration in eight patients, normal dose (pancreatin 1.5–3.0 g) in nine, and high dose (pancreatin 6 g or more or pancrealipase 1800 mg) in 93.
The median CT attenuation value of the liver parenchyma was measured, using a 5-point scale of certainty on plane CT, preoperatively and at 1, 3, 6 and 12 months after PD. We defined a hepatic CT value of less than 40 HU as NAFLD [6]. Comparison of CT attenuation value between the liver and spleen was not used in this study, because the CT value of the spleen was highly influenced in the patients with resection of the splenic vein and/or artery at the time of PD [10]. Measurement of RPV
Correlation between RPV and development of NAFLD The average RPV in the 110 patients was 16.98 ± 10.79 ml (range: 2.08–42.40 ml). To determine the most reliable value of RPV for discriminating NAFLD and non-NAFLD, we examined the 19 values of RPV from 7 ml to 25 ml by performing stepwise selection of multivariate logistic regression. As a result, RPV could be classified into the two groups: large-volume group (LVG) (RPV of 10 ml or more, mean: 21.92 ± 9.54 ml, n = 75) and small-volume group (SVG) (RPV of less than 10 ml, mean: 6.32 ± 2.12 ml, n = 35) (Fig. 1b). Evaluation of clinical factors We evaluated the variables from pre-, intra- and postoperative factors. Preoperative factors included age, sex, diabetes mellitus (DM), diagnosis, chomoradiotherapy, pancreatic duct dilation. Intraoperative factors included pancreatic consistency (soft or hard) and surgical procedure. Postoperative
564 Fig. 1 (a) CT volumetry of remnant pancreas. The remnant pancreas parenchyma of 2 or 2.5 mm slice CT is traced, and the corresponding area is calculated as the sum of pancreatic tissue area. (b) The distribution of remnant pancreatic volume is classified into the two groups; small-volume group (SVG) is less than 10 ml and large-volume group (LVG) is 10 ml or more
J Hepatobiliary Pancreat Sci (2014) 21:562–572
(a)
(b) (n)
(ml) Small-volume group (SVG) (n=35)
Large-volume group (LVG) (n=75)
the following clinical findings: body temperature, heart rate, respiratory rate and WBC count [13]. Blood culture was usually performed by using aerobic and anaerobic blood culture bottles when body temperature exceed 38°C. As a result, we examined bacterial blood culture in 37 patients, showing culture positive in 11.
factors included postoperative infectious complications and pancreatic functions. Since exact methods for evaluation of pancreatic endocrine and exocrine functions are expensive and labor intensive, there has been an increased need in clinical practice for a simple and widely available screening tool for detection of pancreatic functions. Recently, Lindkvist et al. [11] reported significance of nutritional makers such as albumin, prealbumin, magnesium, HbA1c and cholesterol to predict the probability of pancreatic exocrine insufficiency. Furthermore, Yadav et al. [12] has suggested that decreased levels of serum amylase in type 2 DM is associated with decreased pancreatic function. To predict the remnant pancreatic functions, therefore, we examined serum levels of albumin, cholesterol, amylase and HbA1c as nutritional makers before and 1, 3, 6 and 12 months after pancreatectomy. In the present study, the patients were diagnosed as DM when either one of fasting blood sugar of 126 mg/dl or more and HbA1c of 6.5% or more was found or when DM treatment had been introduced preoperatively.
All statistical analyses were performed using the SPSS 22.0 for Windows (IBM, Armonk, NY, USA). The results of the continuous variables were expressed as mean values with standard deviation (SD), and the statistical significance was determined by the paired t-test or Mann–Whitney U-test. Dichotomous variables were evaluated by χ2 analysis or Fisher’s test, as appropriate. Risk factors associated with development of NAFLD were analyzed by uni- and multivariate analysis (multiregression analysis). Results were considered significant when the P-values were less than 0.05.
Status of postoperative infection
Results
In the present study, the status of postoperative infection was originally classified into the three grades on postoperative 7–28 days: suspicion of infection, clinically overt infections and systemic inflammatory response syndrome (SIRS). Suspicion of infection was defined as white blood cell (WBC) count 12,000/mm3. Clinically overt infections included pancreatic fistula, bile leakage, abdominal abscess, enterocolitis, pneumonia, cholangitis and wound infection. SIRS was defined by two or more of
Incidence of NAFLD
Statistical analysis
Among 110 patients, 44 (40%) developed NAFLD after PD. When the number of patients with NAFLD was examined according to time (month) of diagnosis after PD, 90.9% (40/44) of patients developed NAFLD within 3 months (Fig. 2a). Median CT values (HU) at preoperation, 1, 3, 6 and 12 months after PD were compared between the patients with and without NAFLD: 56.8 vs. 60.0, 44.1 vs. 53.4, 19.1
J Hepatobiliary Pancreat Sci (2014) 21:562–572
(a)
(b)
(n)
with NAFLD
25 Liver CT value (HU)
Fig. 2 (a) Number of the patients with nonalcoholic fatty liver disease (NAFLD) according to time (month) of diagnosis after pancreaticoduodenectomy (PD). (b) Change of liver CT value according to the patients with or without NAFLD. (* P < 0.05 with Bonferroni’s correction)
565
20 15
26 10
14
without NAFLD
*
60
40
20
5
3
0 ~1M
2~3M
vs. 54.6 (P < 0.05 with Bonferroni’s correction), 28.3 vs. 56.0 and 41.6 vs. 57.7 (Fig. 2b). CT values remained almost unchanged in the patients without NAFLD, but significantly decreased at 3 month in those with NAFLD. Comparison of clinical factors between LVG and SVG Significant differences between LVG and SVG were found in the incidences of pancreatic adenocarcinoma (34.6% vs. 91.4%, P < 0.001), preoperative chemoradiotherapy (28.0% vs. 82.8%, P < 0.001), preoperative pancreatic duct dilation (44.0% vs. 71.4%, P = 0.007), soft pancreas (53.3% vs. 14.2%, P = 0.006), suspicion of infection (56.0% vs. 20.0%, P < 0.001), clinically overt infection (52.0% vs. 25.7%, P = 0.010), SIRS on POD7-28 (41.3% vs. 20.0%, P = 0.028) and NAFLD (33.3% vs. 54.2%, P = 0.037). There were no significant differences in the incidences of blood culture examined and blood culture positive between the two groups (Table 1). Additionally, we compared the incidence of NAFLD between soft and hard pancreas, paying attention to RPV. In LVG, RPV was significantly larger in soft pancreas than in hard pancreas: 26.40 ± 9.02 ml vs. 16.81 ± 7.37 ml (P < 0.001); however, the incidence of NAFLD did not differ between soft and hard pancreas: 32.3% vs. 34.3% (P = 0.870). In SVG, RPV did not differ between soft and hard pancreas: 6.46 ± 2.41 ml vs. 6.30 ± 2.10 ml (P = 0.878), and the incidence of NAFLD did not differ either: 53.3% vs. 60.0% (P = 0.782). Change of nutritional markers between LVG and SVG The chronological changes of nutritional markers were compared between LVG and SVG. Serum albumin levels (g/dl) were significantly lower in SVG than in LVG at 3, 6 and 12 months: 3.2 ± 0.4 vs. 3.5 ± 0.7 (P = 0.005), 3.3 ± 0.6
1
4~6M 7~12M
0 preop
1
3 Months
6
12
vs. 3.7 ± 0.6 (P = 0.007) and 3.3 ± 0.6 vs. 3.8 ± 0.6 (P = 0.003) (Fig. 3a). Serum cholesterol levels (mg/dl) were significantly lower in SVG than in LVG at 1 and 12 months: 90 ± 14 vs. 122 ± 51 (P = 0.004) and 105 ± 44 vs. 153 ± 40 (P = 0.001) (Fig. 3b). Although serum amylase levels (IU/L) were significantly lower in SVG than in LVG at 1 month: 27.9 ± 17.1 vs. 46.4 ± 26.1 (P = 0.004), HbA1c levels (%) were significantly higher in SVG than in LVG at 1 month: 7.0 ± 0.9 vs. 5.7 ± 1.0 (P = 0.01) (Fig. 3c,d). Preand postoperative prevalence of DM was not significantly different between SVG and LVG: 28.5% vs. 21.3% (P = 0.234) and 34.6% vs. 28.6% (P = 0.505). Postoperative complications in LVG and SVG The incidence of pancreatic fistula (grades A, B and C) was significantly higher in LVG than in SVG: 22.0% vs. 2.9% (P = 0.018). Although not significantly different, the incidences of pancreatic fistula (grades B and C) and intraabdominal abscess were higher in LVG than in SVG: 9.3% vs. 0% (P = 0.057) and 9.3% vs. 0% (P = 0.057) (Table 2). NAFLD and status of postoperative infection with respect to each LVG and SVG The incidence of NAFLD according to status of postoperative infection was further analyzed with respect to each LVG and SVG. In LVG, its incidence was significantly higher in 42 patients with suspicion of infection than in 33 without it: 45.2% vs. 18.1% (P = 0.014), while in SVG it did not differ between seven patients with suspicion of infection and 28 patients without it: 57.1% vs. 53.6% (P = 0.865) (Fig. 4a). As of clinically overt infection, however, the incidence of NAFLD did not significantly differ between the patients with and without it in LVG and SVG, respectively: 38.5% vs. 27.7% (P = 0.327) and 66.7% vs. 50.0% (P = 0.387)
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J Hepatobiliary Pancreat Sci (2014) 21:562–572
Table 1 Patient characteristics in large-volume group (LVG) and small-volume group (SVG) Variable Preoperative factors Mean age Gender (male/female) Diabetes mellitus Diagnosis: Pancreatic adenocarcinoma Bile duct carcinoma Ampullary carcinoma IPMN Other neoplasm Metastatic pancreatic tumor Benign disease Preoperative chemoradiotherapy Pancreatic duct dilation* Intraoperative factors Soft pancreas Surgical procedure (PD/SSPPD/PPPD) Postoperative factors High dose pancreatic enzyme replacement Postoperative infectious complication Suspicion of infection** on POD7-28 Clinically overt infection on POD7-28 SIRS on POD7-28 Blood culture examined Blood culture positive NAFLD
LVG (n = 75)
SVG (n = 35)
P-value
66.3 48/27 16 (21.3%) 26 (34.6%) 8 7 18 7 3 5 21 (28.0%) 33 (44.0%)
67.9 18/17 10 (28.5%) 32 (91.4%) 1 0 3 0 0 0 29 (82.8%) 25 (71.4%)
NS NS NS
