Background & Aims: Malnutrition persists in most patients with chronic pancreatitis despite an adequate clinical response to oral pancreatic enzyme substitution therapy. Our aims were to analyze the accuracy of the 13C-mixed triglyceride breath test as a tool for evaluating the effect of enzyme therapy on fat digestion in chronic pancreatitis, and to analyze the impact of modifying the therapy according to the breath test on patients’ nutritional status. Methods: The accuracy of the breath test for monitoring the effect of therapy was evaluated prospectively in 29 patients with maldigestion secondary to chronic pancreatitis by using the coefficient of fat absorption as the gold standard. Therapy was modified to obtain a normal breath test result in a further 20 chronic pancreatitis patients with malnutrition despite an adequate clinical response to the enzyme therapy; the impact of this therapeutic modification on patients’ nutritional status was evaluated. Results: The coefficient of fat absorption and breath test results were similar when assessing fat absorption before and during treatment. Modification of the enzyme therapy to normalize fat absorption as assessed by the breath test in the second group of 20 patients was associated with a significant increase of body weight (P < .001), and serum concentrations of retinol binding protein (P < .001) and prealbumin (P < .001). Conclusions: The 13C-mixed triglyceride breath test is an accurate method to evaluate the effect of enzyme therapy on fat digestion. This method is simpler than the standard fecal fat test to assess therapy in patients with pancreatic exocrine insufficiency. Normalizing fat absorption improves nutrition in these patients.
Section snippets
Methods
Two consecutive prospective studies were performed to evaluate the accuracy and the clinical usefulness and impact of the 13C-MTG breath test as a tool for assessing and optimizing oral enzyme substitution therapy in patients with chronic pancreatitis.
Accuracy of the 13C-Mixed Triglyceride Breath Test for Evaluating the Effect of Enzyme Therapy on Fat Digestion
CFA increased significantly from 80.8% ± 11.0% before enzyme substitution therapy to 93.5% ± 3.4% during therapy (P < .001) (Figure 1). Similarly, 13CO2-CRR in the context of the 13C-MTG breath test increased from 23.3% ± 15.9% before therapy to 61.5% ± 16.7% during therapy (P < .001) (Figure 1). The absolute improvement of fat digestion obtained by enzyme substitution therapy was 11.0% (1.1%–39.4%) and 32.9% (8.4%–79.1%), as measured by fecal fat quantification and 13C-MTG, respectively. All
Discussion
In this study we corroborate previous findings that fat malabsorption of exocrine pancreatic insufficiency can be corrected3, 12, 13, 14, 15, 16, 17 and that a breath test can be used to assess the response to enzyme therapy.12, 17, 18, 19, 20, 21, 22 Important findings of our study are that the 13C-MTG breath test is a simple, accurate, alternative method to the quantitative fecal fat test to assess correction of fat malabsorption during therapy, and that 1 year after correction of fat
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Both acute and chronic pancreatitis are frequent diseases of the pancreas, which, despite being of benign nature, are related to a significant risk of malnutrition and may require nutritional support. Acute necrotizing pancreatitis is encountered in 20 % of patients with acute pancreatitis, is associated with increased morbidity and mortality, and may require artificial nutrition by enteral or parenteral route, as well as additional endoscopic, radiological or surgical interventions. Chronic pancreatitis represents a chronic inflammation of the pancreatic gland with development of fibrosis. Abdominal pain leading to decreased oral intake, as well as exocrine and endocrine failure are frequent complications of the disease. All of the above represent risk factors related to malnutrition. Therefore, patients with chronic pancreatitis should be considered at risk, screened and supplemented accordingly. Moreover, osteoporosis and increased facture risk should be acknowledged in patients with chronic pancreatitis, and preventive measures should be considered.
Exocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine, leading to the maldigestion of nutrients and macronutrients, resulting in their variable deficiencies. EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately. There is an urgent need to increase awareness of and treatment for this condition. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review was to provide Best Practice Advice on the epidemiology, evaluation, and management of EPI.
This Expert Review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations.
Best Practice Advice Statements
EPI should be suspected in patients with high-risk clinical conditions, such as chronic pancreatitis, relapsing acute pancreatitis, pancreatic ductal adenocarcinoma, cystic fibrosis, and previous pancreatic surgery.
EPI should be considered in patients with moderate-risk clinical conditions, such as duodenal diseases, including celiac and Crohn's disease; previous intestinal surgery; longstanding diabetes mellitus; and hypersecretory states (eg, Zollinger–Ellison syndrome).
Clinical features of EPI include steatorrhea with or without diarrhea, weight loss, bloating, excessive flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition.
Fecal elastase test is the most appropriate initial test and must be performed on a semi-solid or solid stool specimen. A fecal elastase level <100 μg/g of stool provides good evidence of EPI, and levels of 100–200 μg/g are indeterminate for EPI.
Fecal elastase testing can be performed while on pancreatic enzyme replacement therapy.
Fecal fat testing is rarely needed and must be performed when on a high-fat diet. Quantitative testing is generally not practical for routine clinical use.
Response to a therapeutic trial of pancreatic enzymes is unreliable for EPI diagnosis.
Cross-sectional imaging methods (computed tomography scan, magnetic resonance imaging, and endoscopic ultrasound) cannot identify EPI, although they play an important role in the diagnosis of benign and malignant pancreatic disease.
Breath tests and direct pancreatic function tests hold promise, but are not widely available in the United States.
Once EPI is diagnosed, treatment with pancreatic enzyme replacement therapy (PERT) is required. If EPI is left untreated, it will result in complications related to fat malabsorption and malnutrition, having a negative impact on quality of life.
PERT formulations are all derived from porcine sources and are equally effective at equivalent doses. There is a need for H2 or proton pump inhibitor therapy with non–enteric-coated preparations.
PERT should be taken during the meal, with the initial treatment of at least 40,000 USP units of lipase during each meal in adults and one-half of that with snacks. The subsequent dosage can be adjusted based on the meal size and fat content.
Routine supplementation and monitoring of fat-soluble vitamin levels are appropriate. Dietary modifications include a low-moderate fat diet with frequent smaller meals and avoiding very-low-fat diets.
Measures of successful treatment with PERT include reduction in steatorrhea and associated gastrointestinal symptoms; a gain of weight, muscle mass, and muscle function; and improvement in fat-soluble vitamin levels.
EPI should be monitored and baseline measurements of nutritional status should be obtained (body mass index, quality-of-life measure, and fat-soluble vitamin levels). A baseline dual-energy x-ray absorptiometry scan should be obtained and repeated every 1–2 years.
The diagnosis of pancreatic exocrine insufficiency (PEI) is challenging. The 13C mixed triglyceride breath test (13C MTGT) has emerged as a promising diagnostic method. However, there is need to assimilate high quality evidence to understand its accuracy and address variation in the conduct of the test. This systematic review aims to appraise the existing literature on the methodology and accuracy of the 13C MTGT.
A systematic literature search of PUBMED, MEDLINE, and EMBASE databases identified articles describing the use of the 13C MTGT in the analysis of pancreatic function in adults. Data extraction addressed each methodological step in detail. These were combined in a narrative synthesis. For quantitative analysis, those studies within this search that assessed the accuracy of the 13C MTGT were selected.
37 studies were included for qualitative review, 6 assessed sensitivity and specificity of the 13C MTGT against another measure of PEI and were included in quantitative synthesis. Areas with a majority consensus were pre-test overnight fasting, a test meal with a lipid load of at least 10 g, within-test control of exercise and dietary intake, breath sampling every 30 min and the preference of isotope ratio mass spectrometry (IRMS) for analysis. Good evidence suggests there is no benefit to extend the total timeframe of breath sampling beyond 6 h. Areas of uncertainty are a) Duration of PERT cessation b) the addition of metoclopramide, c) the ideal test meal and d) if the time frame can be shortened. Quantitative analysis among 6 studies demonstrated a pooled sensitivity and specificity of the 13C MTGT for diagnosing PEI of 0.84 (95% CI: 0.73–0.91) and 0.87 (95% CI: 0.79–0.93) respectively.
There is yet to emerge a clear standard of breath test methodology that is validated for all causes of PEI and suitable for routine use. The accuracy of the 13C MTGT for diagnosing PEI is encouraging when compared to other measures. We present a suggested set protocol based on the current literature and identify areas that need further, high quality evidence. With refinement, the 13C MTGT could become a valuable, non-invasive PEI diagnostic tool that could be used outside of specialist centres.
Pancreatic exocrine insufficiency (PEI) is a common complication following pancreatoduodenectomy (PD) leading to malnutrition. The course of PEI and related symptoms and vitamin deficiencies is unknown. This study aimed to assess the (long-term) incidence of PEI and vitamin deficiencies after PD.
A bi-centre prospective observational cohort study was performed, including patients who underwent PD for mainly pancreatic and periampullary (pre)malignancies (2014–2018). Two cohorts were formed to evaluate short and long-term results. Patients were followed for 18 months and clinical symptoms were evaluated by questionnaire. PEI was based on faecal elastase-1 (FE-1) levels and/or clinical symptoms.
In total, 95 patients were included. After three months, all but three patients had developed PEI and 27/29 (93%) patients of whom stool samples were available showed abnormal FE-1 levels, which did not improve during follow-up. After six months, all patients had developed PEI. During follow-up, symptoms resolved in 35%–70% of patients. Vitamin D and K deficiencies were observed in 48%–79% of patients, depending on the moment of follow-up; 0%–50% of the patients with deficiencies received vitamin supplementation.
This prospective study found a high incidence of PEI after PD with persisting symptoms in one-to two thirds of all patients. Limited attention was paid to vitamin deficiencies. Improved screening and treatment strategies for PEI and vitamins need to be designed.
Malnutrition in chronic pancreatitis is complex and multifactorial, with malabsorption, pain, toxic dependencies and co-morbidities, such as diabetes, each playing a role. The aims of this systematic review were to assess the impact of nutritional intervention on markers of nutritional status in this complex patient group.
A systematic review of EMBASE and PubMed was carried out in February 2020, identifying 2620 articles. After screening to exclude those reporting short term changes (less than 3 months), with only one data point, or in the wrong population, eight papers were selected for analysis.
Seven studies documented the impact of a nutritional intervention, one was an observational study only. Overall, studies were limited by predominantly retrospective designs, heterogenous populations and poor control of potentially confounding variables. Data could not be combined due to variability in reporting methods. All studies exploring nutritional intervention, whether that consisted of advice by a specialist dietitian, dose escalation of pancreatic enzymes, oral nutritional supplements or enteral feeding, demonstrated improved body weight and pain control, whereas patients who did not receive an intervention deteriorated nutritionally.
Patients with chronic pancreatitis benefit from nutritional intervention. Further work is required to explore the impact of nutritional intervention on body composition and functional outcomes.
Digestive capacity of the gastrointestinal tract, largely but not wholly, depends on exocrine pancreatic function to achieve near complete digestion and absorption of ingested food. Coefficient of fat absorption (CFA), the proportion of ingested fat absorbed (normal >93%), reflects digestive capacity. Exocrine pancreatic insufficiency (EPI) is the state of insufficient digestive capacity (CFA <93%) caused by severe loss of pancreatic exocrine function despite variable compensation by upregulation of extra-pancreatic lipolysis. Fecal elastase 1 (FE1) level is the most widely used, though imperfect, non-invasive test of pancreatic enzyme output. Decline in pancreas enzyme output, or pancreatic exocrine dysfunction (EPD), has a variable correlation with measurable decline in CFA. EPI results in steatorrhea, weight loss and nutrient deficiency, which are mitigated by pancreatic enzyme replacement therapy (PERT). We propose a staging system for EPD, based on measurement of fecal elastase (FE1) and, if necessary, CFA and serum fat-soluble vitamin levels. In Stage I (Mild) EPD, FE1 is 100–200 mcg/gm; if steatorrhea is present, non-pancreatic causes are likely. In Stage II (Moderate) EPD), FE1 is < 100 mcg/gm without clinical and/or laboratory evidence of steatorrhea. In Stage III, there are marked reductions in FE1 and CFA, but vitamin levels remain normal (Severe EPD or EPI without nutritional deficiency). In Stage IV all parameters are abnormal (Severe EPD or EPI with nutritional deficiency). EPD stages I and II are pancreas sufficient and PERT may not be the best or first approach in management of early-stage disease; it needs further study to determine clinical utility. The term EPI refers strictly to EPD Stages III and IV which should be treated with PERT, with Stage IV requiring micronutrient supplementation as well.
Supported by a grant from the Health Institute Carlos III, Spanish Ministry of Health (G03/156), and the Foundation for Research in Digestive Diseases.
