|Ahead of print
Pancreatic exocrine insufficiency occurs in most patients following pancreaticoduodenectomy
Thogari K Kumar1, Mallika Tewari1, SK Shukla2, SP Mishra3
1 Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
3 Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Submission||24-Nov-2018|
|Date of Decision||21-Apr-2019|
|Date of Acceptance||28-Apr-2019|
|Date of Web Publication||19-Sep-2021|
Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Pancreatic exocrine insufficiency (PEI) is a well-defined complication of malignant diseases and pancreatic resection; however, study results of PEI are less consistent. Assessment of PEI by estimation of fecal elastase (FE)-1 in stool by enzyme-linked immunosorbent essay (ELISA) is a relatively inexpensive, noninvasive, and simple test. This study assessed exocrine function of pancreas following pancreaticoduodenectomy (PD) by estimating FE-1.
Methods: This prospective hospital-based study involved 30 patients who had undergone PD for malignancy. All 30 patients had an uneventful postoperative period under the unit's enhanced recovery after surgery (ERAS) protocol with no Grade B, C postoperative pancreatic fistula/postpancreatectomy hemorrhage as per the International Study Group of Pancreatic Surgery (ISGPS) definitions. Stool samples were collected postoperatively 3 months after surgery from all patients irrespective of clinical symptoms. The analysis was based on a solid phase ELISA used for the quantitative determination of human elastase 1 in feces. Fecal elastase was considered normal if >200 μg/gm stool, moderately reduced if 100–200 μg/gm stool, and severely reduced if <100 μg/gm stool.
Results: Among 30 patients included, fecal elastase levels were moderately reduced in 10 (33.33%) and severely reduced in 20 (66.67%) patients (P <0.0001). Mean (± standard deviation) of fecal elastase was 87.12 ± 38.76 with median of 74.6 μg/gm stool. There was no significant difference in the fecal elastase levels between men and women (P = 0.057), age (P = 0.48), pancreatic duct diameter (P = 0.609), pancreatic texture (P = 0.286), and presence or absence of clinical symptoms (P = 0.181).
Conclusions: PD was frequently associated with PEI. Unfortunately PEI is an under recognized and under treated long-term sequel of PD. Fecal elastase 1 should be performed routinely in both symptomatic and asymptomatic patients. Pancreatic enzyme replacement therapy should be considered in every patient after PD.
Keywords: Pancreatic cancer, pancreatic exocrine insufficiency, pancreaticoduodenectomy, periampullary cancer, stool elastase
Key Message: Pancreatic Exocrine Insufficiency (PEI) often occurs after pancreaticoduodenectomy. Fecal elastase-1 test helps in its detection and pancreatic enzyme replacement therapy should be considered to improve the quality of life of such patients.
| » Introduction|| |
Pancreatic exocrine insufficiency (PEI) is defined as inadequate pancreatic enzyme activity for digestion caused by insufficient pancreatic enzyme production, insufficient activation, or disturbed enzyme deactivation. PEI is a known complication of malignant diseases, pancreatic resection, and postsurgical alteration of the anatomy of the foregut.
The available data indicate that PEI occurs in 46–100% of patients with resectable pancreatic and ampullary cancers. The pancreatic secretion is a clear fluid liquid, 97% of water and electrolytes, and 3% of proteins. These 3% of proteins are mainly represented by proteases (80%), amylase (7%), lipase (4%), and nucleases (1%). Normal absorption of nutrients involves a complex mixture of digestive enzymes and bile salts, and an intact intestinal mucosa to enable the uptake of these hydrophobic complexes. Under normal conditions, pancreatic enzyme release occurs in response to nutritional intake. The initial stimulus is seeing, smelling, and tasting of food that is vagal mediated and termed cephalic phase. Next gastric distension increases pancreatic enzyme secretion via the gastropancreatic reflex (gastric phase). The passage of chyme through the duodenum provides the most robust stimulation of exocrine pancreatic secretion, particularly the passage of hydrolyzed triglycerides. This is termed as intestinal phase mostly mediated by cholecystokinin.,,
In patients following pancreaticoduodenectomy (PD), a duodenal resection, which is the strongest pancreatic exocrine stimulator, contributes to decreased postprandial enzyme secretion. This decreased pancreatic exocrine secretion shifts the site of maximal nutrient absorption from the proximal to distal small intestine. Mechanisms of PEI include reduction of glandular tissue following pancreatic resection, impending postoperative pancreatic duct occlusion, extensive denervation following lymph node dissection, and surgically altered anatomy.,
Typical symptoms of PEI are abdominal discomfort, weight loss, steatorrhea, malnutrition, and vitamin deficiency.
There are direct and indirect methods for estimation of PEI. Direct measurements require duodenal intubation and aspiration of pancreatic secretion after administration of secretagogues. The direct methods though very sensitive and specific are invasive, time-consuming, and expensive. The indirect tests on the contrary are relatively simple to perform and measure either the pancreatic enzyme or the by-products of enzyme activity. Estimation of fecal elastase (FE)-1 in stool by enzyme-linked immunosorbent assay (ELISA) is a relatively inexpensive, noninvasive, and simple test. Testing for elastase 1 in the stool has several advantages over testing for fecal fat, trypsin, or chymotrypsin. This test does not require a timed stool collection or special diet and has a 99% negative predictive value for PEI.
The present study was done with an aim to prospectively assess exocrine function of pancreas, following PD by fecal elastase test.
| » Patients and Methods|| |
This is a prospective, hospital-based study conducted in a tertiary care hospital. A total of 30 patients who were admitted in indoor surgical oncology unit and underwent pylorus-resecting PD with Blumgart's duct-to-mucosa pancreaticojejunostomy were included in the study. All patients received adjuvant therapy but none of them received neoadjuvant therapy. Stool samples were collected 3 months after surgery from these patients and stored at -70°C. All stool samples were analyzed at one time later. An informed consent was obtained from each patient and the study was approved by the institutional ethics committee.
Fecal elastase test
The analysis was based on a solid phase ELISA used for the quantitative determination of human elastase-1 in feces. The polyclonal antibodies used in this assay are specifically directed against defined sequences of the human pancreatic elastase-1 molecule. The assay is species-specific and does not cross-react with porcine elastase found in pancreatic exocrine supplements. Human elastase-1 is remarkably stable, remains undegraded during intestinal transit, and is found in the stool in about a sixfold concentration as compared with pancreatic juice, thereby fecal elastase reflects the secretory capacity of the pancreas. Fecal elastase was expressed as μg/gram of stool and was considered ''normal'' if greater than 200 μg/gm stool, ''moderately reduced'' if 100–200 μg/gm, or ''severely reduced'' if less than 100 μg/gm.
Categorical variables were presented in absolute numbers and percentage (%) and continuous variables were presented as mean ± standard deviation and median. Normality of data was tested by Kolmogorov–Smirnov test. If the normality was rejected then nonparametric test was used.
Statistical tests were applied as follows-
- Quantitative variables were compared using independent t-test (as the data sets were normally distributed) between the two groups and analysis of variance test between three groups
- Qualitative variables were correlated using Chi-square test/Fisher's exact test
- Pearson correlation coefficient was used to assess the association of age and elastase value.
A P value of <0.05 was considered statistically significant.
The data were entered in MS EXCEL spreadsheet and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0.
| » Results|| |
The baseline characteristics of 30 patients who underwent PD for malignancy are provided in [Table 1]. Ampulla was the most common location of tumor in this study comprising 22 (73.33%) cases. Other sites of periampullary region, such as pancreatic head, duodenum, and distal bile duct constituted five (16.67%) cases, two (6.67%) cases, and one (3.33%) case, respectively. All 30 patients had an uneventful postoperative period under the unit's enhanced recovery after surgery (ERAS) protocol with no Grade B, C postoperative pancreatic fistula of postpancreatectomy hemorrhage as per the International Study Group of Pancreatic Surgery (ISGPS) definitions.
Among 30 patients, fecal elastase-1 levels were moderately reduced in 10 (33.33%) and severely reduced in 20 (66.67%) patients. FE-1 levels were significantly reduced (P < 0.0001) in all 30 patients when compared with normal level of fecal elastase level (200 μg/gm). The mean value of fecal elastase level was 87.12 with a median of 74.6 μg/gm of stool. Fecal elastase levels ranged between 20 and 159.67 μg/gm of stool.
Association of preoperative pancreatic duct diameter and fecal elastase values was not significant (P = 0.609) as assessed by Pearson correlation coefficient; the correlation of coefficient was -0.097 [Figure 1]. There was no significant difference (P = 0.057) when the mean and median of fecal elastase levels were compared between men and women [Table 2]. Association of age and fecal elastase values was also not significant (P = 0.48) as assessed by Pearson correlation coefficient; the correlation of coefficient was 0.134 [Figure 2]. The effect of different age groups on fecal elastase level was further examined [Table 3]. Again, fecal elastase levels in different age groups showed no significant difference (P = 0.565) in different age groups. Similarly, fecal elastase levels showed no significant association between symptomatic and asymptomatic patients (P = 0.181) and with pancreatic texture (P = 0.286) [Table 4].
|Figure 1: Correlation between elastase value and pancreatic duct diameter|
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| » Discussion|| |
The development of PEI after pancreatic surgery/PD is an understudied topic even though it has been reported as a common clinical manifestation after surgery. PEI is also common in those patients who are about to undergo PD, particularly those with adenocarcinoma. Quality of life (QOL) decreases if there is an impairment of the pancreatic exocrine function after PD.
The current standard of publicly reported postoperative outcomes as set forth by the Center of Medicare and Medicaid is often a 30-day measure. However, the 30-day measure may not adequately capture the incidence of a variable to accurately portray its true impact. Damhuis et al. reported increased postoperative mortality rates at 90 days as compared to 30 days for eight different cancer types. Other complications of gastrointestinal surgery, such as anastomotic leak, were also found to demonstrate a similar trend. Similarly, in an analysis done by Lim et al., 30-day outcome reporting of endocrine insufficiency and exocrine insufficiency significantly underestimated the true incidence: 30-day reporting did not capture 78% of cases of endocrine and exocrine insufficiency that ultimately developed in the postoperative period. Endocrine and exocrine insufficiencies are functional outcomes. They found that 48% of subjects develop exocrine insufficiency even after 90 days; it is possible that with a larger follow-up study that allows for analysis of longer-term follow-up, one might better determine if 90 days, or a longer time point, should serve as the gold standard for postpancreatectomy functional assessment. They concluded that the reporting of postoperative pancreatic insufficiency should not be limited to the 30-day reporting measure as it underestimates its true incidence of these complications.
In our study, we assessed the exocrine function of pancreas in 30 patients who underwent PD by measuring fecal elastase-1 levels 3 months after PD.
Among 30 patients, fecal elastase levels were moderately reduced in ten (33.33%) patients and severely reduced in 20 (66.67%) patients. Armstrong et al. in 2002 evaluated pancreatic exocrine function in ten patients prospectively following PD for malignant periampullary tumors by using fecal elastase-1 and they found that all patients had severe PEI. In a study by Halloran et al., among 37 patients who underwent PD, 31 (84%) had fecal elastase levels <200 μg/gm stool. Similar findings were reported by Tran et al. in 87.8% of their 55 patients and Sikkens et al. in 92% of their 29 patients. Fecal elastase levels were significantly reduced (P < 0.0001) in all (100%) of our 30 patients when compared with normal level of fecal elastase level (200 μg/gm) of it.
The mean value of fecal elastase levels in our study was 87.12 μg/gm stool with a median of 74.6 μg/gm stool. Minimum value of fecal elastase was 20 μg/gm stool with a maximum of 159.67 μg/gm stool. The findings are similar to that reported by Halloran et al. wherein after 3 months of PD the mean fecal elastase level in their study was 88 μg/gm stool. A summary of a few other studies examining fecal elastase after PD is summarized in [Table 5].,,,,,,
|Table 5: A summary of reports measuring fecal elastase after pancreaticoduodenectomy|
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Lim et al. conducted a study from 2002 to 2012 in 227 patients and concluded that neoadjuvant chemotherapy, adjuvant chemotherapy, and adjuvant radiation therapy were associated with the development of postoperative PEI. Neoadjuvant radiation therapy was not associated with the development of postoperative PEI. Study conducted by Bock et al. in 2012 after a follow-up of 1 year concluded that those undergoing PD in younger age are more likely to develop diabetes mellitus and steatorrhea than those who undergo surgery at an older age. Halloran et al. studied 40 patients who underwent pancreatic resection for malignancy. They kept primary endpoint as coefficient of fat absorption (CFA) <93% as PEI. CFA <93% was present in 67% of patients at 6 weeks and in 55% at 12 months. PEI using FE-1 was present in 77 and 83% of patients, respectively. They concluded that PEI is more common following pancreatic resection without significant symptoms. These patients have tendency toward poorer QOL.
Sato et al. compared the exocrine function and morphology of 24 patients who underwent pylorus preserving pancreaticoduodenectomy (PPPD) with 12 patients who underwent distal pancreatectomy (DP). They concluded that postoperative exocrine pancreatic function after PPPD and DP was significantly influenced by the morphology of the pancreas at the presumed transection line. The preoperative morphology of the presumably remaining pancreas, especially duct-parenchymal ratio will predict the exocrine pancreatic function short term after pancreatectomy. Fujino et al. conducted a study on 56 patients who underwent PD from 1998 to 2003 regarding changes in the remnant pancreatic duct size, pancreatic exocrine and endocrine functions, and nutritional status in their follow-up period. They concluded that there was no significant difference in the impaired exocrine function rate between the nondilated and dilated groups.
QOL is an important outcome measure after pancreatic resection for malignancy because various surgical approaches aimed at prolonged survival can have a great impact on patient's performance. Although many studies have addressed the QOL issue, it is difficult to compare results because of difference in methods, study designs, and patient characteristics in these studies. Most studies revealed a large decrease in most QOL scales immediately after surgery followed by a slow recovery to preoperative level by 12–24 months after surgery. Study conducted by Huang et al. about QOL in patients who underwent PD from 1981 to 1997 showed that survivors of PD had near normal QOL scores. Result showed that more than 92% of patients who underwent PD for adenocarcinoma are able to do their normal activity. The surgical techniques of resection and reconstruction do not seem to affect QOL.
Unfortunately, PEI is frequently overlooked in daily clinical practice, and physicians are often not well informed about the need to supplement PEI. This was confirmed in a survey conducted on members of the Dutch and German patient associations for pancreatic disorders that clearly showed that most patients suffering from PEI after surgery are undertreated even in countries with well-organized healthcare systems.
Fecal elastase-1 should be performed routinely, even in asymptomatic patients, since clinical signs of steatorrhea may be absent in patients that tend to limit fat intake to reduce their symptoms. Pancreatic enzyme replacement therapy (PERT) should be considered in every patient with proven PEI, irrespective of the underlying disease or prognosis. Even in the case of asymptomatic PEI, treatment is indicated because studies have shown that malnutrition may develop in these patients. To reduce morbidity and mortality, it is very important to treat patients with a sufficient dose of pancreatic enzymes. The resulting symptoms have a substantial impact on the patient's QOL. Though QOL was not measured in this study, we plan to do so in a subsequent analysis.
Two double-blind randomized controlled trials evaluated PERT for PEI after surgery for cancer., In these studies, when compared with a placebo, PERT (in the form of pancreatin formulated as enteric-coated minimicrospheres) was associated with a significant improvement in fat and protein digestion after pancreatic resection for pancreatic cancer. In addition, PERT was associated with significant weight gain and reduced stool frequency.
| » Conclusions|| |
PEI is a known complication of PD. Now that the postoperative mortality after PD has substantially decreased, more attention needs to be focused on the diagnosis and treatment of the functional consequences after PD. Estimation of fecal elastase 1 in stool by ELISA is a relatively inexpensive, noninvasive, and simple test. A significant decrease in fecal elastase levels was found in 100% of our patients after PD emphasizing that PERT should be considered more routinely and stool for elastase should be periodically monitored to guide this therapy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]