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What are the longterm effects of pancreatitis?

What are the longterm effects of pancreatitis?


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As the title asks, what are the longterm effects of pancreatitis? Having one event, is the person more susceptible to have a recurrence, or are they at higher risk of other conditions such as diabetes?


Pancreatitis may cause a condition called"systemic inflammatory response syndrome", a immune system reaction affecting the whole body.

Also, more frequently, pancreatitis is linked with steatorrhea, which means oily fat, and it may cause malnutrition and weight loss, due to restriction of secretions containing digestive enzymes. Longer term inflammations of pancreas may cause fibrosis (scar tissue) in the organ, therefore restricting the endocrine functions including insulin secretion, so acquired diabetes is another risk.

Obstruction of the bile duct and jaundice, leading to possible liver damage is another complication of pancreatitis.


Is it long-term continuous drinking or the post-drinking withdrawal period that triggers the first acute alcoholic pancreatitis?

Objective: Unlike patients with alcoholic hepatitis, patients with acute alcoholic pancreatitis seldom come into the hospital in an intoxicated state. Long-term history of heavy drinking induces increases in the serum pancreatic enzymes and pancreatitis-associated protein profiles during the withdrawal period. The aim of this study was to investigate the role of withdrawal in triggering acute alcoholic pancreatitis by studying the time-course of development of the first symptoms of the first acute alcoholic pancreatitis.

Material and methods: One hundred patients (85 M, 15 F, mean age 46, range 18-73 years) with the first acute alcoholic pancreatitis were asked three different questions in an attempt to clarify the same issue: Had you already stopped continuous drinking before the start of the acute abdominal pain that later led to hospitalization? Had you already stopped continuous drinking before you started to experience nausea or vomiting? How many hours after taking the last drop of alcohol did you start to feel pain (0 h, 1<6 h, 7-12 h, 13-24 h, 25-48 h, >48 h)? The amount of alcohol consumed was evaluated 1) during the past week and 2) during the past 2 months. The severity of the pancreatitis was assessed by serum C-reactive protein concentration, presence of necrosis, the development of pancreatic complications and the length of stay in hospital and in the intensive care unit.

Results: Eighty-five patients were able to respond to the questions. Of these, 69% had developed pain and 91% nausea/vomiting only after they had already stopped continuous drinking. Whereas 29% of the patients developed some symptoms before stopping drinking, the majority of the patients developed symptoms during the first day after cessation (43%) or later (28%), mainly during the second day of cessation of drinking. In both the univariate analysis and the multivariate analysis the timing of the symptoms was dependent on the amount of alcohol consumed during the previous 2 months and in the past week.

Conclusions: In the majority of patients with first acute alcoholic pancreatitis, the symptoms begin during the early withdrawal period. The withdrawal period might be more important than previously emphasized in the development of acute alcoholic pancreatitis.


References

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Effect of Jejunal Long-Term Feeding in Chronic Pancreatitis

ABSTRACT. Background: In the late course of chronic pancreatitis (CP), weight loss is often seen because of reduced caloric intake and a reduction of pancreatic enzyme secretion, resulting in maldigestion. Most of these patients can be managed by dietary recommendations and pancreatic enzyme supplementation. However, approximately 5% of these patients are reported to be candidates for enteral nutrition support during their course of CP. Although small bowel access for enteral feeding can be easily obtained by percutaneous endoscopic gastrojejunostomy (PEG/J) or direct percutaneous endoscopic jejunostomy (DPEJ), to date there are no data regarding clinical outcome and safety of long-term jejunal feeding in CP. Methods: From January 1999 to October 2002, 57 patients receiving enteral nutrition by PEG/J or DPEJ were retrospectively analyzed during a follow-up period of 6 months. There were 38 females and 19 males, with an average age of 46.6 years. Results: Small-bowel access was obtained by PEG/J in 53 patients and by DPEJ in 4. Duration of enteral feeding was 113 days. Average body weight significantly increased from 64.8 kg at day 1 to 69.1 kg at day 180 (p

Chronic pancreatitis (CP) causes many digestive and metabolic disturbances and a progressive degradation of a patient’s nutritional state. The relationship between nutrition and CP is bilateral: nutrition is one of the factors involved in the onset of CP, whereas poor food intake is one of its consequences and is one of the major predictors of poor outcome. The onset of malnutrition in CP is late in the disease course. Only after 80% to 90% loss of exocrine function will signs of malabsorption occur.1 The principal mechanisms of malnutrition in CP are a reduction in nutrient intake, a reduction in nutrient absorption, and an increased metabolic activity.

Pain of varying severity and duration is a leading clinical symptom in up to 90% of patients with CP.^sup 2^ Because of food intake-related abdominal pain, patients often eat too little.3

Gastroparesis, reported in up to 44% of patients with small-duct CP, may lead to nausea and vomiting and therefore further contribute to poor oral food intake and clinical decline.4 Patients with CP often display an elevated basal metabolic rate of approximately 110% of baseline (35 kcal/kg/24 hours) as a result of the chronic inflammation.5 This, in combination with poor oral food intake, accounts for the initial 10% to 20% loss of body weight.6

The onset of diabetes mellitus is reported in 60% to 70% of CP patients, and the probability of endocrine insufficiency progressively increases within 10 years after the diagnosis of CP.7 Steatorrhea is observed in about 30% of all cases, resulting in further weight loss.8-10 In this stage, the nutritional status of the patient can be greatly disturbed.

Before the initiation of nutrition support, nutritional risk should be assessed. Many nutrition screening tools exist. Kondrup et al11 developed a screening tool that includes measurements of undernutrition and disease severity in order to evaluate if a patient is at risk for malnutrition. In addition, patients may be evaluated using the subjective global assessment of Detsky et al.12 This approach classifies patients subjectively according to data obtained from their history and physical examination.

Nutrition support in CP patients is an ongoing challenge for clinicians. Although most of these patients can be managed by dietary recommendations and pancreatic enzyme supplementation, approximately 5% had severe and ongoing malnutrition and maldigestion. In these patients, enteral nutrition should be recommended. Enteral feeding beyond the ligament of Treitz is preferred over parenteral nutrition because enteral nutrition is less costly and has the advantages of reduced infectious and metabolic complications.13 In addition, enteral feeding maintains gut integrity and is fundamental in supporting the gut immune system, important for the at-risk patient.14 Further, enteral feeding beyond the ligament of Treitz allows the pancreatic gland to rest and minimizes pancreatic secretion, which may result in a reduction of abdominal pain.15 Additionally, jejunal feeding during acute flares of CP can reduce the incidence of nosocomial infections and the duration of systemic inflammatory response and severity.16,17

Endoscopie small-bowel access may be obtained by 2 methods. The first method, percutaneous endoscopic gastrojejunostomy (PEG/J), has been reported with a 100% success rate and no major complications.18 In this method, a PEG tube is used as a conduit to place a jejunal feeding tube with an over-the-guidewire method. The second method, direct percutaneous endoscopie jejunostomy (DPEJ), directly places a jejunal tube into the small bowel by using an enteroscope or pediatric colonoscope to reach the puncture site beyond the ligament of Treitz. Good results with only minor complications have been reported by Shike et al.19

Patients with a severe course of CP who have recurrent flares with abdominal pain, poor oral food intake, and whose illness cannot be controlled by oral dietary recommendations may benefit from long- term nutrition support by jejunal feeding. Unfortunately, there are no controlled data available from patients with CP using enterai feeding protocols. Current outcome data are based solely on case reports.

The aim of this current study was to analyze the safety and clinical outcome in patients receiving longterm nutrition support by PEG/J or DPEJ feeding during their course of CP.

From January 1999 to October 2002, 57 patients with CP referred to the nutrition service of the Medical University of South Carolina were retrospectively evaluated. All patients were hospitalized at the time of tube placement because of an acute flare-up of CP. Nutritional status in all patients was assessed by using the Subjective Global Assessment (SGA) score. Nutrition support was delivered either by PEG/J or DPEJ.

Endoscopic placement of a percutaneous tube system (DPEJ or PEG/ J) was usually performed under the use of conscious sedation and local anesthesia at the skin puncture site. Procedures were performed either in the intensive care units, at the bedside, or in the endoscopy suite. All patients were given cefazolin 1 g IV as single dose prophylaxis against infection before the endoscopie procedure.

A Wilson-Cook 24 Fr tulip-tip PEG or Boston Scientific (Natrick, MA) 24 Fr PEG was inserted with the standard push or pull technique. The endoscope was then reinserted and the internal bumper of the PEG tube located. A grasping forceps was placed through the endoscope and the PEG tube was cannulated by pushing the grasping forceps through the PEG to the outside of the patient. A flexible, 0.035 guidewire is grasped by the forceps and pulled back through the PEG into the stomach and advanced under direct endoscopie visualization into the fourth portion of the duodenum. The grasping forceps and guidewire were then advanced another 8-10 cm beyond the tip of the endoscope under direct visualization. A 12 Fr J-tube was then threaded over the guidewire and advanced to the proximal jejunum. The guidewire and forceps are removed and the endoscope was then withdrawn by gently rotation. If a large loop of J-tube was visualized within the stomach, the J-tube placement was repeated.18

Direct Percutaneous Endoscopic Jejunostomy

A standard, commercially available, pull-type 20 Fr PEG kit (Microinvasive Endoscopy Boston Scientific Corp) was used for the DPEJ procedure. After insertion of the endoscope to the jejunum, a skin puncture site was determined by using abdominal wall transillumination and abdominal wall finger palpation with endoscopie gastric mucosal visualization. A 19-gauge needle was passed into the bowel through the abdominal wall. To fix the small bowel wall against the abdominal wall, the 19-gauge needle was grasped with a snare passed through the endoscope. An incision of 1 cm at the skin puncture site of the needle was made. An introducer cannula with a plastic outer sheath was then passed through the abdominal wall into the jejunum just adjacent to the 19-gauge needle. The snare was released from the 19-gauge needle and placed around the cannula to stabilize it within the small bowel. The guidewire was passed through the plastic sheath, grasped with the snare and pulled with the endoscope out through the patient’s mouth. A standard PEG tube was attached to the guidewire and then pulled through the skin incision site in the abdominal wall. The final position of the DPEJ was confirmed endoscopically.20

All patients were able to begin tube feeding within 12 hours after enterai access was obtained. A standard polypeptide diet (SD) was administrated by initially using a continuous 24-hour feeding regimen. The volume and rate of jejunal feeding were adjusted, depending on individual tolerance of the feeding formula. The feeding rate was increased with the goal of reaching the full caloric requirement on day 3. The total daily caloric requirement was calculated using the HarrisBenedict formula, individually adjusted to the patient’s clinical course and physical activity. An elemental diet (ED) was only administrated in patients with suspected intolerance to the SD. In addition, patients were allowed to consume clear liquids orally if tolerated. Patients took their medications orally. Patients were converted routinely to an overnight cyclic feeding regimen. The characteristics of the enteral feeding formulas are summarized in Table I.

Type and composition of tube feeding

Data Collection and Statistical Analysis

Institutional review board approval for the research project was obtained before the data collection. Data were collected retrospectively from the patient’s hospital and clinic medical records. Abdominal pain and gastrointestinal symptoms (nausea, vomiting, diarrhea) were evaluated by questioning patients during their hospitalization for enterai tube placement (day 0) and again during their regular follow-up consultations at days 90 and 180. All hospitalizations and not routinely planned physician visits related to CP were further recorded. The type and amount of narcotic drug intake were also analyzed. Follow-up data that were not documented in the medical records are indicated as not reported. Statistical analysis was performed using Intercooled STATA 8.0 for Windows (2003, STATA Corporation, College Station, TX). Because some continuous variables within the dataset were not normally distributed, we performed a nonparametric test for matched pairs of observations, using the Wilcoxon matched-pairs signed-ranks test. The null hypothesis (H0) is that both observation groups come from the same distribution the alternative (H1) is that 2 groups do not come from the same distribution. Test results with p values of &le0.05 were considered significant.

The etiologies for CP in our patient group were secondary to alcohol consumption (n = 16 28%), papillary stenosis (n = 10 17%), pancreas divisum (n = 9 16%), papillary dysfunction (n = 5 9%), gallstones (n = 5 9%), metabolic disorders (n = 2 4%), and idiopathic pancreatitis (n = 10 17%). The majority of patients had ongoing weight loss with moderate to severe malnutrition. All patients had previously received dietary recommendations, attempts at oral nutritional supplementation, analgesia, enzyme supplementation, and insulin if required. Eight patients (17%) with moderate to severe malnutrition (SGA category: 4 patients B and 4 patients C) who were candidates for elective pancreatic surgery and who failed to thrive with an adequate dietary regimen also received long-term enteral feeding before surgery. The characteristics of the 57 patients are shown in Table II.

Small bowel access was obtained by PEG/J in 53 patients (93%) and by DPEJ in the remaining 4 patients (7%). Twenty-three patients (40%) had an average weight loss of 13.5 kg (range, 4-35) during the previous 6 months before small bowel feeding was initiated. The average enteral feeding time was 113 days (range, 3-180). In 1 patient, tube removal at day 3 was related to a colon mesentery injury after DPEJ-tube placement, necessitating emergency laparotomy. Elective pancreatic surgery was undertaken in 8 patients: there were 6 distal pancreatectomies, 1 lateral pancreaticojejunostomy (Partington-Rochelle) and 1 pancreaticoduodenectomy (Whipple). Before patients underwent elective surgery, enterai feeding was provided for an average of 76.8 days (range, 46-111). All patients who underwent either emergency or elective surgery were excluded from further data collection and analysis.

The patient’s average weight before initiation of enterai feeding was 64.8 kg (range, 36-108.5). After 90 days of follow-up, the overall mean body weight significantly increased to 67.7 kg (range, 39.5-113.5 p

Patient characteristics (n = 57)

FIG. 1. Patient’s average body weight over 6 months (kg).

SGA is a tool to determine nutritional status, thus predicting the degree of malnutrition. The SGA data before and after treatment initiation are shown in Table III.

Pain, Pain Medication, and Gastrointestinal Symptoms

Initially, 55 patients (96%) presented with abdominal pain. Pain medication consisted of regular intake of nonsteroidal antiinflammatory drugs (NSAID) in 3 patients (5.3%), opiate derivatives in 23 patients (44%), and a combination of opiate derivatives with NSAID or antidepressants in 26 (45.6%) cases. Further, 51 patients (90%) had gastrointestinal symptoms such as vomiting or nausea (n = 38 74.5%), diarrhea and vomiting (n = 10 19.6%), and diarrhea (n = 3 5.9%). After 90 days, only 27 patients (48% p

Subjective Global Assessment (SGA)

Laboratory Analysis, Physician Visits, and Rehospitalizations

Albumin levels increased from 2.9 g/dL at initiation to 3.2 g/dL (p .05), although a continuous decline was observed (Figs. 3-5).

On average, patients required 3.6 physician visits (range, 1-12) and underwent 1.8 rehospitalizations (range, 0-5) over the next 6 months (Table VI).

In all patients, tube feeding with a SD was introduced within 12 hours after tube placement. The full nutritional goal was reached after 5 days in 84% of patients. One patient underwent emergency laparotomy because of a colon mesentery injury at day 3, and intolerance to enterai feeding was observed in another 8 patients (14%). A switch to an ED in these 8 patients was beneficial in 4 of them (7%), allowing their full caloric needs to be delivered by enterai feeding. The 4 remaining patients had intolerance to jejunal feeding, with no clinical progress and ongoing abdominal pain, abdominal cramps, and diarrhea. In these patients, the feeding devices were removed after an average feeding period of 81 days (range, 30-148).

Ten patients had complications related to the tube or tube feeding. These complications include tube dislodgement (6 patients), tube obstruction (2 patients), and wound infection (1 patient). Whereas the wound infection was treated conservatively, tube dislodgement and obstruction required ambulatory endoscopic reintervention. One patient (1.7%) had a major complication: 3 days after DPEJ-tube placement, emergency laparotomy was required because of a colon mesentery injury (Table VII).

Abdominal Pain, GI-Symptoms and Narcotic Use

FIG. 2. Abdominal pain, GI symptoms, and narcotic use over 6 months (% of patients).

Abdominal pain, GI symptoms, and narcotic use

Type of GI symptoms, type of narcotics

Approximately 75% of patients with a chronic underlying gastroenterological disease are reported to have protein-energy malnutrition.21 This number may be higher in patients with CP. In CP, approximately 80% of patients can be managed through dietary recommendations, but approximately 5% to 10% are reported to need parenteral nutrition (PN) or enterai tube feeding during their course of CP.22 In the past, nutrition support in CP was synonymous with PN. However, increased cost, the high rate of septic complications, and other associated morbidities with this route of therapy have led to questions about the overall appropriateness of parenteral nutrition support in CP.23

A favorable impact on patient outcomes with enterai tube feeding compared with PN has been shown in several prospective, randomized controlled trials in a variety of disease processes ranging from trauma and head injury to acute pancreatitis.2 Unfortunately, there are little captured data available regarding the utility of enterai feeding into the jejunum in patients with CP. Currently, the literature is established solely according to case reports.

In our series, small-bowel feeding delivered by PEG/J or DPEJ over an average feeding ime of 113 days (range, 3-180) resulted in a statistically significant (p

FIG. 3. Average patient albumin level over 6 months (G/DL).

It is evident from these data that long-term jejunal feeding in CP significantly increases a patient’s weight and improves their nutritional status. Therefore, this therapy may help to minimize malnutrition-related morbidity and mortality.31 In addition, analysis of plasma albumin levels after 6 months also showed significant improvement from 2.6 g/dL to 3.4 g/dL (p

FIG. 4. Average patient serum amylase over 6 months (IU/L).

Pain in CP is by far the most common and recalcitrant indication for medical treatment. However, pain is difficult to quantify. The assessment of its significance may be clouded by a patient’s addiction to alcohol and narcotic analgesics. The mechanism of pain in CP is incompletely understood and perhaps multifactorial. The view that chronic pain will subside as the disease progresses to the point of organ failure (burnout) has been widely accepted.34 However, that process may take an unpredictable number of years or may never occur. Some studies suggest that the likelihood of spontaneous pain relief is low.35 In addition, our data also suggest that jejunal feeding provides a clinical benefit in terms of reducing abdominal pain and gastrointestinal side effects. Although 96% of patients initially had abdominal pain and 90% had gastrointestinal side effects such as nausea, vomiting, and diarrhea, only 23% reported ongoing abdominal pain after 6 months. Also, the percentage of patients regularly using narcotic drugs dropped to 27%, and the percentage of patients with gastrointestinal side effects declined continuously to 14.6%.

FIG. 5. Average patient serum lipase over 6 months (IU/L).

There are several theories about the etiology of pain in CP. The one likely etiology may be elevated cholecystokinin levels secondary to pancreatic protease deficiency.36,37 Feeding low in the gastrointestinal tract invokes a degree of pancreatic gland stimulation that differs little from parenteral nutrients.38 Decreasing pancreatic stimulation to subclinical levels of secretion is thought to relieve abdominal pain and might explain the reduction in abdominal pain observed during longterm jejunal feeding in our study.39 The benefit of jejunal feeding on gastrointestinal side effects might be further explained by the fact that gastroparesis in small duct pancreatitis is seen in up to 44% of patients, with associated symptoms such as nausea, vomiting, and abdominal pain.4

Patients with CP frequently undergo diagnostic or therapeutic endoscopy of the upper gastrointestinal tract. Small-bowel access for feeding can be easily obtained in almost all cases during such interventions without requiring additional endoscopic interventions. CP often presents with intermittent inflammatory flares, often requiring hospitalization for pain management and rehydration. PEG/ J and DPEJ tubes can also be used as small-bowel decompression devices to reduce abdominal distention, nausea, and vomiting during such acute episodes. NPO periods can therefore be shortened, and oral feeding can often be reinstated earlier, without the need for temporary or long-term TPN.

Physician visits, rehospitalizations

The answer to the question of whether efficacy of jejunal feeding in CP is affected by the cause of the CP remains speculative. However, in our series all patients (n = 4 8%) with ongoing weight loss (3.7 kg range, 2-5.5) had nonalcoholic pancreatitis. The failure of treatment in this group of patients is further underlined by the fact that they also needed a higher number of physician visits (7 range, 1-12) because of abdominal pain and gastrointestinal side effects. The switch to an ED did not influence their poor clinical course.

All patients were initially fed with a SD, which was well tolerated in 86%. Only 4 patients (7%) of 8 (14%) receiving an ED tolerated the ED better than the SD. Therefore, we conclude that small-bowel feeding in CP with a SD is safe, cost efficient, and, in most cases, well tolerated.

According to the literature, between 58% and 67% of patients need surgery during their course of CP.40 In our series with a follow-up period of 180 days, elective surgery was undertaken in 8 patients (14%) with moderate to severe malnutrition (SGA category: 4 patients B and 4 patients C) resistant to dietary recommendations. Before undergoing elective surgery, they received jejunal feeding for an average of 76.8 days (range, 46-111), resulting in an average weight gain of 3.1 kg (range, 2-10). According to our findings, moderately or severely malnourished patients scheduled for major pancreatic surgery may be candidates for longterm jejunal feeding delivered before their operative procedure to reduce malnutrition-associated perioperative risks.41

During the follow-up, the mean number of CP-related emergency physician visits (3.6) and rehospitalizations (1.8) was low compared with our clinical experience with this difficult patient group. The patients treated in this study represent a subgroup of patients with severe CP who had ongoing weight loss or severe malnutrition in spite of the best standard of supportive medical care.

In our series, complications related to jejunal feeding were managed by upper gastrointestinal endoscopy (n = 8), conservatively by local wound infection (n = 1), or by emergency laparotomy in a case of abdominal pain with colon mesentery injury (n = 1).

We feel that jejunal access and jejunal feeding in CP can be considered safe, with a major complication rate of approximately around 1.8% and zero mortality in experienced hands.

After reviewing the findings in this retrospective study, we are convinced that the use of jejunal feeding in patients with chronic, recurrent pancreatitis is an important interventional approach, with evidence for decreasing stimulation and inflammation of the pancreas. There was clear evidence in our study of a decrease in associated clinical symptoms, including weight loss, abdominal pain, nausea, and vomiting. Indirectly, those results are confirmed by the reduction in our patients’ use of narcotics and by the favorable nutrition therapy outcomes, including weight gain, malnutrition rate, and increases in serum albumin levels. In addition, jejunal feeding significantly improves nutritional outcomes in malnourished CP patients.

There are limitations to this study. The major limitations are the retrospective nature of the study and the lack of a control group. A further limitation is the fact that there was no follow-up of the gastrointestinal symptoms, abdominal pain, or anthropomtrie parameters after the feeding tubes were removed. In addition, we have only assessed the abdominal pain as subjective specification and not according to a standardized questionnaire or a systematic objective method such as the visual analog scale.

We are planning to conduct a prospective study that is designed to address these limitations and to define the extent to which long- term enterai tube feeding enhances nutritional status, reduces abdominal pain, gastrointestinal symptoms, and other health care resource use in patients with chronic, recurrent pancreatitis.

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21. Papini-Berto SJ, Dichi JB, Dichi I, Victoria CR, Burini RC. Protein-energy malnutrition as a consequence of the hospitalization of gastroenterologic patients. Arq Gastroenterol. 199734: 13-21.

22. Meier R. Nutrition in chronic pancreatitis. In: Buechler M, Friess H, Uhl W, Malfertheiner P, eds. Chronic Pancreatitis. Berlin: Blackwell Science 2002:421-427.

23. Koretz RL. Nutritional supplementation in the ICU: how critical is nutrition for the critically ill? Am J Respir Crit Care Med. 1995151:570-573.

24. Charash WE, Kearney PA, Annus KA, et al. Early enteral feeding is associated with attenuation of the acute phase/cytokine response and improved outcome following multiple trauma. J Trauma. 199437:1015-1018.

25. Moore FA, Moore EE, Jones TN, McCroskey BL, Peterson VM. TEN versus TPN following major abdominal trauma: reduced septic morbidity. J Trauma. 198929:916-923.

26. Moore EE, Jones TN. Benefits of immediate jejunostomy feeding after major abdominal trauma: a prospective, randomized study. J Trauma. 198626:874-881.

27. Suchner U, Senftleben U, Eckart T, et al. Enteral versus parenteral nutrition: effects on gastrointestinal function and metabolism. Nutrition. 199612:13-22.

28. Young B, Ott L, Twyman D, et al. The effect of nutritional support on outcome from severe head injury. J Neurosurg. 1987 67:668-676.

29. Windsor AC, Kenwar S, Li AG, et al. Compared with parenteral nutrition, enterai feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut. 1998 42:431- 435.

30. Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos CA. Enterai nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial. Br J Surg. 199784:1665-1696.

31. Klein S, Kinney J, Jeejeebhoy KJ, et al. Nutrition support in clinical practice: review of published data and recommendations for future research directions: National Institutes of Health, American Society for Parenteral and Enteral Nutrition, and American Society for Clinical Nutrition. JPEN J Parenter Enteral Nutr. 199721:133- 156.

32. Grant JR. Nutritional assessment in clinical practice. Nutr Clin Pract. 19861:3-11.

33. Fleck A. Acute phase response: implications for nutrition and recovery. Nutrition. 19884:109-117.

34. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Gastroenterology. 198486: 820- 888.

35. Lankisch PG, Seidensticker F, Lohr-Happe A, Otto J, Creutzfeldt W. The course of pain is the same in alcohol- and non alcohol-induced chronic pancreatitis. Pancreas. 199510: 338-341.

36. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology. 1998115:765-776.

37. Toskes PP. Update on diagnosis and management of chronic pancreatitis. Curr Gastroenterol Rep. 19991:145-153.

38. Corcoy R, Martin-Sanchez J, Domingo P, et al. Nutrition in the patient with severe acute pancreatitis. Nutrition. 1988 4:269- 275.

39. Helton WS. Intravenous nutrition in patients with acute pancreatitis. In: Rombeau JL, ed. Clinical Nutrition: Parenteral Nutrition. Philadelphia, PA: WB Saunders 1990:442-461.

40. Levy P, Milan C, Pignon JP, Baetz A, Bernades P. Mortality factors associated with chronic pancreatitis: unidimensional and multidimensional analysis of a medical-surgical series of 240 patients. Gastroenterology. 198996:1165-1172.

41. McClave SA, Schnider HL, Spain DA. Preoperative issues in clinical nutrition. Chest. 1999115(Suppl):64S-70S.

Zeno Stanga, MD*[double dagger] Urs Giger, MD*[dagger] Arthur Marx, MD and Mark H. DeLegge, MD, FACG, CNSP*

From the * Section of Nutrition, Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina [dagger] Department of General Surgery, Kantonsspital Fribourg, Fribourg, Switzerland [double dagger] Division of Endocrinology and Diabetes, University Hospital Bern, Bern, Switzerland and the Department of Internal Medicine and Social and Preventive Medicine, University of Bern, Bern, Switzerland

Received for publication February 18, 2004.

Accepted for publication October 1, 2004.

Correspondence: Mark H. DeLegge, MD, FACG, CNSP, Section of Nutrition, Digestive Disease Center, Medical University of South Carolina (MUSC), 96 Jonathan Lucas St, Ste 210, Charleston, SC 29425. Electronic mail may be sent to [email protected]

Copyright American Society for Parenteral and Enteral Nutrition Jan/ Feb 2005

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What's to know about chronic pancreatitis?

Chronic pancreatitis is a long-term progressive inflammatory disease of the pancreas that leads to permanent breakdown of the structure and function of the pancreas.

The pancreas is a gland organ that is located in the abdomen, behind the stomach and below the ribcage. It specializes in producing important enzymes and hormones that help break down and digest foods. It also makes insulin to moderate the levels of sugar in the blood.

The most common cause is long-term alcohol abuse – it is thought to account for between 70 and 80 percent of all cases.

Chronic pancreatitis results in over 122,000 visits to a doctor and 56,000 hospitalizations annually in the United States.

Significantly more men than women are affected.

Share on Pinterest The pancreas produces important enzymes and hormones that help break down foods.

The following treatments are commonly recommended for chronic pancreatitis.

Lifestyle changes

People with chronic pancreatitis will need to undergo some lifestyle changes. These will include:

  • Stopping alcohol consumption: Giving up drinking will help prevent further damage to the pancreas. It will also contribute significantly towards relieving the pain. Some people may need professional help to quit alcohol.
  • Stopping tobacco use: Smoking is not a cause of pancreatitis, but it can accelerate the progression of the disease.

Pain management

Treatment should not only focus on helping ease the pain symptoms, but also depression which is a common consequence of long-term pain.

Doctors will usually use a step-by-step approach, in which mild painkillers are prescribed, gradually becoming stronger until pain becomes manageable.

The pancreas may stop producing insulin if the damage is extensive. The individual is likely to have developed diabetes type 1.

Regular insulin treatment will become part of the treatment for the rest of the person’s life. Diabetes type 1 caused by chronic pancreatitis involves injections, not tablets, because most likely the digestive system will not be able to break them down.

Surgery

Severe chronic pain sometimes does not respond to painkilling medications. The ducts in the pancreas may have become blocked, causing an accumulation of digestive juices which puts pressure on them, causing intense pain. Another cause of chronic and intense pain could be inflammation of the head of the pancreas.

Several forms of surgery may be recommended to treat more severe cases.

Endoscopic surgery

A narrow, hollow, flexible tube called an endoscope is inserted into the digestive system, guided by ultrasound. A device with a tiny, deflated balloon at the end is threaded through the endoscope. When it reaches the duct, the balloon is inflated, thus widening the duct. A stent is placed to stop the duct from narrowing back.

Pancreas resection

The head of the pancreas is surgically removed. This not only relieves the pain caused by inflammation irritating the nerve endings, but it also reduces pressure on the ducts. Three main techniques are used for pancreas resection:

  • The Beger procedure: This involves resection of the inflamed pancreatic head with careful sparing of the duodenum, the rest of the pancreas is reconnected to the intestines.
  • The Frey procedure: This is used when the doctor believes pain is being caused by both inflammation of the head of the pancreas as well as the blocked ducts. The Frey procedure adds a longitudinal duct decompression to the pancreatic head resection – the head of the pancreas is surgically removed, and the ducts are decompressed by connecting them directly to the intestines.
  • Pylorus-sparing pancreaticoduodenectomy (PPPD): The gallbladder, ducts, and the head of the pancreas are all surgically removed. This is only done in very severe cases of intense chronic pain where the head of the pancreas is inflamed, and the ducts are also blocked. This is the most effective procedure for reducing pain and conserving pancreas function. However, it has the highest risk of infection and internal bleeding.

Total pancreatectomy

This involves the surgical removal of the whole pancreas. It is very effective in dealing with the pain. However, a person who has had a total pancreatectomy will be dependent on treatment for some of the vital functions of the pancreas, such as the release of insulin.

Autologous pancreatic islet cell transplantation (APICT)

During the total pancreatectomy procedure, a suspension of isolated islet cells is created from the surgically removed pancreas and injected into the portal vein of the liver. The islets cells will function as a free graft in the liver and will produce insulin.

Taking dietary measures to reduce the effects of pancreatitis are vital.

The pancreas is involved in digestion, but pancreatitis can impair this function. This means that people with the disease will have difficulty digesting many foods.

Rather than three large meals a day, people with pancreatitis will be advised instead to consume six small meals. It is also better to follow a low-fat diet.

Managing the diet during pancreatitis aims to achieve four outcomes:

  • reducing the risk of malnutrition and shortages of certain nutrients
  • avoiding high or low blood sugar
  • managing or preventing diabetes, kidney disease, and other complications
  • decreasing the likelihood of an acute flare-up of pancreatitis

A diet plan will either be drawn up by the doctor, or the patient may be referred to a qualified dietitian. The plan is based on the current levels of nutrients in the blood shown in diagnostic testing.

Meal plans will generally involve food sources that are high in protein and have dense nutritional content. These are likely to include whole grains, vegetables, fruits, low-fat dairy products, and lean protein sources, such as boneless chicken and fish.

Fatty, oily, or greasy foods should be avoided, as these can trigger the pancreas to release more enzymes than usual. As a primary cause of chronic pancreatitis, alcohol is also best avoided while on a pancreatitis-friendly diet.

Depending on the extent of the damage, patients may also have to take artificial versions of some enzymes to aid digestion. These will ease bloating, make their feces less greasy and foul-smelling, and help any abdominal cramps.


Prognosis and Long Term Outcomes of Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is characterized by pancreatic swelling and irregular narrowing of the main pancreatic duct, which often mimic pancreatic cancer (1, 17, 18, 20). AIP was recently classified into two types based on the pathological differences: type 1 for lymphoplasmacytic sclerosing pancreatitis (LPSP) and type 2 for idiopathic duct centric chronic pancreatitis (IDCP) or AIP with granulocytic epithelial lesion (GEL) (39). Type 1 AIP is closely associated with increased IgG4 antibodies in the serum and affected tissues (6, 7, 39, 47). Although the long-term prognosis and outcomes are relatively well described in type 1 AIP, these outcomes are less understood in type 2 AIP. Accordingly the following discussion primarily refers to type 1 AIP, while what is understood regarding type 2, which is almost exclusively found in Western countries, is discussed at the end (8, 28).

Long-term prognosis and outcome of type 1 AIP

Most patients with type 1 AIP (referred to as “AIP” in this section) respond favorably to corticosteroid therapy, which results in the amelioration of symptomatic, radiographic, serologic, and pathologic findings. It is possible for patients to have a spontaneous recovery. However, during long-term follow-up, some patients with AIP are noted to progress to the advanced stage of pancreatic stone formation after recurrence, which may be similar to the findings of chronic pancreatitis (Figure 1) (29, 30, 40). In addition, the possibility of an association with malignant conditions, such as pancreatic cancer or other malignancies has been reported (4, 5, 10, 32, 37, 44).

Progression to chronic pancreatitis

AIP is characterized by high serum IgG4 concentration,IgG4-positive staining plasma cell infiltration in affected pancreatic tissue, and a favorable response to corticosteroid therapy. Imaging analyses by ultrasonography (US), computed tomography (CT), and endoscopic retrograde cholangiopancreatography (ERCP) show sonolucent (i.e., hypoechoic) swelling and irregular narrowing of the main pancreatic duct, both of which are due to lymphoplasmacytic inflammation at the acute stage. In 1995, Yoshida et al. first proposed the concept of AIP, which was considered to be free from calcification and to rarely progress to ordinary chronic pancreatitis (46). Although most patients have a favorable response to corticosteroid therapy, some develop pancreatic atrophy and stone formation with irregular dilatation of the main pancreatic duct (MPD) (30, 40). These imaging findings mimic those of chronic pancreatitis, suggesting that in some cases AIP may progress into chronic pancreatitis.

If this is the case, ordinary chronic pancreatitis could also include the advanced stage of AIP. This is supported by the observation that serum IgG4 remains elevated in over 60% of patients after clinical improvement (19). To clarify whether ordinary chronic pancreatitis includes the advanced stage of AIP, we measured serum levels of IgG4 in 175 patients with chronic pancreatitis who had been diagnosed before 1995, when the concept of AIP was first proposed. High serum IgG4 concentrations were found in 7.4% of patients with ordinary chronic pancreatitis, suggesting that the advanced stage of AIP may result in the development of ordinary chronic pancreatitis (21). Similarly, serum IgG4 was elevated in 11.9% of sera from Korean patients with ordinary chronic pancreatitis (2). A French study showed that more than one third of AIP patients developed pancreatic imaging abnormalities of atrophy, calcification, and/or duct irregularities and functional insufficiency within 3 years of diagnosis (28). Finally, one autopsy case of AIP showed similar pathological findings to chronic pancreatitis instead of the typical AIP findings of abundant lymphoplasmacytic infiltration, IgG4-bearing plasma cell infiltration, and obstructive phlebitis (25).

Pancreatic stone formation

Features of chronic pancreatitis include clinical findings of exocrine or endocrine dysfunction, imaging findings of pancreatic calcifications in the parenchyma or duct, and irregular MPD dilatation, and pathological findings of acinar or ductal cell loss, fibrosis, and stone formation. Of all these findings, pancreatic stone formation is a representative imaging finding that particularly correlates well with functional and pathological abnormalities.

The reported prevalence of pancreatic stone formation in AIP has been variable. Increased or de novo stone formation, including small calculi, was seen in 28 of 69 (41%) patients followed for at least 3 years at our institution (Shinshu University Hospital). Multivariate analysis identified narrowing of both Wirsung’s and Santorini’s ducts at diagnosis as an independent risk factor for pancreatic stone formation, which presumably led to pancreatic juice stasis and stone development (30). A long-term follow up study showed 16 of 73 (22%) AIP patients progressed to chronic pancreatitis that fulfilled the revised Japanese clinical diagnostic criteria for chronic pancreatitis in the chronic stage (29). However, other studies have indicated a lower prevalence of pancreatic stone formation during long term follow-up (41, 42). A recent multicenter, international analysis estimated that pancreatic stones occurred in only 7% of subjects with follow-up imaging permitting evaluation for stone disease (8). Further studies are needed to explain these discrepancies, and to understand if the formation of stones can be prevented.

Disease relapse

AIP is a chronic disease that can have a relapsing clinical course. To illustrate the frequency and distribution of disease relapses we reviewed the medical charts of 84 patients with AIP, who were followed up for more than 1 year at Shinshu University Hospital. Twenty-eight of the 84 patients (33%) experienced a total of 60 recurrences, including autoimmune pancreatitis (n = 26 times), sclerosing cholangitis (n = 18), lacrimal and salivary gland lesions (n = 5), and retroperitoneal fibrosis (n = 4). Seventy-two percent of the recurrences occurred in the maintenance stage of corticosteroid therapy. Although no markers at diagnosis significantly predicted recurrence, IgG and immune complexes tended to be elevated in the relapse group compared to the non-relapse group. During clinical follow-up, the development of pancreatic stones was more frequent in the relapse group (14 patients, 50%) than in the non-relapse group (13 patients, 23%). Collectively, one-third of patients with AIP developed a pancreatic stone. Close observation with activity markers during follow-up and early intervention with corticosteroid therapy may help to prevent recurrence in such cases (22).

Published series have reported similar relapse rates in AIP ranging from 30% to 50% (9, 16, 24, 26, 40, 43). Patients with relapse generally experienced 1 or 2 episodes, although some experienced many relapses. Corticosteroid therapy was reported to significantly increase the remission rate and reduce the relapse rate of AIP (16, 26). Thus, corticosteroid therapy is currently considered the standard treatment for inducing remission in AIP (13). Although spontaneous remission occurs in some patients with AIP, these patients are usually good candidates for corticosteroid therapy (9, 13, 16, 24, 26). According to the Japanese Consensus Guidelines for Management of AIP, the indications for corticosteroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, and back pain, and the presence of symptomatic extrapancreatic lesions (15). In principle, corticosteroid therapy should be administered for all patients diagnosed with AIP (15).

Since AIP is the pancreatic manifestation of IgG4-Related Disease, other manifestations of IgG4-related disease can be seen at disease relapse (23, 38). In addition to pancreatic lesions, other common manifestations include sclerosing cholangitis, lacrimal/salivary gland lesions, retroperitoneal fibrosis, and interstitial pneumonitis (8, 24). These lesions also respond well to corticosteroid therapy. In our study population, the first, second, and third recurrences occurred at medians of 33, 66, and 122 months following steroid therapy, and 72% of recurrences occurred during the maintenance therapy stage. Other studies have shown that relapse generally occurs within the first 3 years following diagnosis (26). In those who develop a relapse, 56% relapsed within 1 year, and 92% relapsed within 3 years from the start of steroid treatment (16). Although relapse in our study occurred mostly during the maintenance stage of corticosteroid therapy, the relapse rate of patients with AIP on maintenance treatment was 23%, which was significantly lower than patients who stopped maintenance treatment (34%) (16). According to the Japanese Consensus Guidelines for Management of AIP, maintenance therapy (2.5 – 5 mg/day) is recommended to prevent recurrence, and stopping of maintenance therapy should be planned within at least 3 years in cases with serologic and radiologic improvement (15).

Previous studies indicated that various factors at diagnosis, including involvement of proximal biliary tract, diffuse pancreatic swelling, jaundice, IgG4, immune complex, soluble IL2 receptor, and complement are predictive factors of relapse (9, 21, 24, 26, 41). Specific HLA antigens were reported to predict the recurrence of AIP, and substitution of aspartic acid at position 57 of HLA DQβ1 was reported to affect the recurrence of autoimmune pancreatitis (35). We reported that serum elevation of IgG4 and immune complex preceded the clinical manifestations of recurrence (18). Accordingly, serial measurements of IgG, IgG4, and immune complex in the follow-up period may be useful to predict recurrence (13, 18, 21).

Relapse after surgical resection of the pancreas

Recently, Detlefsen et al. reported that 21 of 51 AIP patients (41.2%) who underwent surgical resection of the pancreas experienced recurrence during long term follow-up the sites of recurrence were the pancreas (n = 8) and extrapancreatic bile ducts (n = 7) (3). Recurrence rate and sites were similar to those of the non-resection group. Their results are in contrast to a previous study, which showed a decreased risk of relapse in those undergoing surgical resection (36).

Pancreatic function

Pancreatic exocrine function

AIP is associated with exocrine dysfunction in 83% – 88% of cases during the acute inflammatory stage (11, 13, 14, 34). Following corticosteroid treatment and during the chronic stage, exocrine dysfunction resolves in most patients. However, exocrine dysfunction persists or may develop during long-term follow-up in some patients, which may be associated with the transition to chronic pancreatitis (42).

Pancreatic endocrine function

Diabetes mellitus occurs in 42% – 78% of cases during the acute stage of AIP (11, 13, 14, 33, 34). Similar to exocrine dysfunction, endocrine dysfunction, especially diabetes mellitus, is often ameliorated after corticosteroid therapy (9, 31, 34, 42). Miyamoto et al. reported amelioration of diabetes mellitus in 10 of 16 (63%) AIP patients 3 years after corticosteroid therapy, indicating that corticosteroid therapy is often effective for the treatment of diabetes in AIP (31). However, corticosteroid therapy sometimes causes deterioration of glycemic control, especially in aged patients, and thus requires cautious administration (33). Ito et al. reported that 10 of 50 AIP patients who received insulin treatment experienced hypoglycemic attacks, suggesting the need for vigilance when insulin therapy is administered (12). One third of AIP patients with diabetes mellitus suffered from diabetes at the onset of AIP these patients frequently had a family history of diabetes mellitus and had poor nutritional status. Half of AIP patients are diagnosed with diabetes mellitus at AIP onset, however only 10% of AIP patients continued to have diabetes mellitus after corticosteroid therapy (12, 33).

AIP and complications of pancreatic cancer and other malignancies

Chronic pancreatitis has been regarded as risk factor for the occurrence of pancreatic cancer (27). Therefore, if AIP can progress to chronic pancreatitis, it also may be complicated with pancreatic cancer. A Japanese survey indicated that the average life expectancies of male and female patients with chronic pancreatitis were 11 and 17 years shorter than those of the general population, respectively. The major cause of the death was malignancy, indicating that the standard death rates for bile duct and pancreatic cancer were very high (3.44 and 7.84, respectively). It is possible that immunodeficiency due to corticosteroid therapy and chronic inflammation of the pancreas may contribute to the occurrence of malignancy.

There have been a few previous reports of AIP complicated with pancreatic cancer (4, 5, 10, 32, 44). Characteristic features of pancreatic cancer complicated with AIP are more frequent occurrence at body and tail regions compared with ordinary pancreatic cancer,(15) and earlier occurrence after the diagnosis of AIP compared with chronic pancreatitis. These results raise the possibility that AIP may contribute to the occurrence of pancreatic cancer, however these cases are highly subject to selection bias.

Since AIP occurs predominantly in elderly patients, deficiency of the immunosurveillance system may be associated with its pathogenesis, which in turn may be associated with the occurrence of various malignancies other than pancreatic cancer (37). In addition to AIP, IgG4-related disease was reported to be highly complicated with malignancies (45). In clinical follow-up for AIP and IgG4-related disease, caution is recommended to monitor for the occurrence of malignancy, however further studies are needed to clarify the true risk and most appropriate methods of cancer surveillance.

Long-term prognosis and outcome of type 2 AIP

The long-term prognosis and outcome of type 2 AIP have not been fully clarified. The two subtypes can be definitively distinguished based on their histology (See Histology of Autoimmune Pancreatitis). Type 2 AIP patients are younger than those with type 1 AIP, do not show the male gender bias seen in type 1 AIP, and are unlikely to have elevation of serum IgG4 or other organ involvement (39). A multicenter international analysis showed that the average ages at diagnosis were 61.4 and 39.9 years for type 1 and type 2 AIP, respectively, and the proportion of males was 77% in type 1 and 55% in type 2 AIP. In addition, type 2 AIP represented a smaller proportion of AIP in Asian countries compared with European and North American countries (8).

During the acute stage, imaging findings of type 2 AIP appear similar to those of type 1, including pancreatic swelling and irregular narrowing of the MPD. Similar to type 1 AIP, those with type 2 AIP respond favorably to corticosteroid therapy. However, the recurrence rate of type 2 AIP was significantly lower than that of type 1, and the site of type 2 AIP recurrence was limited to the pancreas. Few pancreatic stones were found in type 2 AIP during follow-up, suggesting it is uncommon for type 2 AIP to progresses to an advanced stage (8). However, another study indicated that the outcome of patients with type 2 AIP was not different from that of patients with type 1 AIP, except for diabetes, which was significantly higher in type 1 AIP (28). Further studies are therefore needed to better define the long-term prognosis and outcomes of type 2 AIP.

Type 1 AIP is a chronic, relapsing disease. Although the acute inflammatory phase is very responsive to corticosteroid therapy, there are several potential long term complications that can develop. Endocrine and exocrine pancreatic dysfunction is more typical during the acute phase. They may resolve with corticosteroid therapy, but occur later when the pancreas has atrophied. Disease relapses are common and can develop in the pancreas, biliary tree, or other distant sites associated with IgG4-RD. Careful observation of prodromal symptoms and activity markers during follow-up, as well as early intervention with corticosteroid therapy may help to limit morbidity from disease relapses. Pancreatic duct stones can develop, and are more likely in those with relapsing disease. There is a theoretical increased risk for developing pancreatic cancer, but the actual risk is not fully understood. In contrast, in type 2 AIP disease relapse and other long term complications are uncommon.

Acknowledgements

We would like to thank Drs. Takashi Muraki, Tetsuya Ito, Keita Kanai, Takaya Oguchi, Hideaki Hamano, and Norikazu Arakura for their clinical assistance and contributions to this work.


The Prevention, Recognition and Treatment of Post-ERCP Pancreatitis

*Corresponding Author: Scott Tenner
Medical Education and Research, Maimonides Medical Center,
State University of New York, 2211 Emmons Ave, Brooklyn, NY
11235, USA
Phone: +1-718.368.2960
Fax: +1-718.368.2249
E-mail: [email protected]

Received October 16th, 2008 - Accepted January 26th, 2009

Keywords

Cholangiopancreatography, Endoscopic Retrograde Pancreatitis, Acute Necrotizing Review Stents Therapeutics

INTRODUCTION

Acute pancreatitis is the most common and feared complication of endoscopic retrograde cholangiopancreatography (ERCP). It is associated with substantial morbidity and occasional mortality. The mechanisms that lead to post-ERCP pancreatitis are complex and not fully understood. Rather than having a single pathogenesis, post-ERCP pancreatitis is believed to be multi-factorial, involving a combination of chemical, hydrostatic, enzymatic, mechanical, and thermal factors. Although there is some uncertainty in predicting which patients will develop acute pancreatitis following ERCP, a number of risk factors acting independently or in concert have been proposed as predictors of post-ERCP pancreatitis [1, 2, 3, 4]. These include patient and procedure related factors. In patients at high risk for developing post-ERCP pancreatitis, numerous studies have attempted to identify endoscopic or pharmacologic interventions that might reduce the risk. The purpose of this review is to describe recent advances in the prevention and amelioration of post-ERCP pancreatitis.

Identification of Post-ERCP Pancreatitis

Regardless of the etiology, the criteria for the diagnosis of acute pancreatitis requires two of the three following criteria [5]: 1) abdominal pain (symptoms) consistent with the diagnosis 2) a serum amylase and/or lipase greater than 3 times the upper limit of normal and/or 3) cross-sectional imaging (CT and/or MRI) consistent with the diagnosis. Although using two of the three criteria will accurately lead to a diagnosis of acute pancreatitis in most patients, the criteria are not always accurate in patients following ERCP. Many patients with post-ERCP pancreatitis have two of these criteria in the absence of acute pancreatitis, pain and an elevation of amylase/lipase. The pain of pancreatitis is typically epigastric, persistent and radiating to the back and lasting for hours if not days. Episodic and fleeting pain is not related to pancreatitis. Some patients have pain following ERCP due to the large volume of air insufflated during the procedure. This results in bowel distention and painful spasm. In addition to pain, asymptomatic elevations in the amylase and/or lipase often occur following ERCP, with no clinical sequelae. Inappropriate labeling of patients with abdominal pain and mild, transient elevation of serum amylase and/or lipase as having post ERCP pancreatitis may explain why the reported incidence of post ERCP pancreatitis varies greatly, from 4% to 31% among studies [1, 2, 5, 6].

Due to the lack of specificity of pain and elevations of the amylase/lipase in patients who have undergone ERCP, imaging becomes the most important criterion in determining the diagnosis of post-ERCP pancreatitis. Post-ERCP pancreatitis should be suspected in any patient who develops pain within 6 hours of the procedure. It is much less likely to develop after 12 hours from the procedure. Post-ERCP pain with marked elevation of serum amylase and/or lipase especially when the values are greater than 1,000 IU/L, it is strongly suggestive of pancreatitis. In cases of diagnostic doubt, especially when severe pancreatitis is predicted, radiologic imaging should confirm the diagnosis.

Early recognition of post-ERCP pancreatitis may be possible by evaluating serum amylase or lipase within a few hours of the procedure [7, 8, 9]. In a study that involved 231 patients, the 2-hour serum amylase or lipase was more accurate than clinical assessment in distinguishing post-ERCP pancreatitis from other causes of abdominal pain. Values greater than 276 IU/L for serum amylase and greater than 1,000 IU/L for serum lipase obtained 2 hours after the procedure had almost 100% positive predictive value (PPV) for post-ERCP pancreatitis [7]. More recently, Ito et al. found that if the serum amylase was normal at 3 hours, only 1% of patients developed post-ERCP pancreatitis compared to 39% if the amylase was greater than 5 times the upper limit of reference [8]. A serum amylase and/or lipase alone should not guide a decision regarding the presence or absence of post-ERCP pancreatitis. However, these tests can assist clinicians in their assessment of patients with post-ERCP pain.

Risk Factors for Developing Post-ERCP Pancreatitis

Awareness of the risk factors for post-ERCP pancreatitis is essential for the recognition of high-risk cases in which ERCP should be avoided if possible, or in which protective endoscopic or pharmacologic interventions should be considered. Risk factors for developing post-ERCP pancreatitis have been assessed in various studies and include patient, procedure, and operator-related factors (Table 1).

On reviewing the literature, the general consensus of the patient related-factors include: young age, female gender, suspected sphincter of Oddi dysfunction, recurrent pancreatitis, prior history of post-ERCP pancreatitis, and patients with normal serum bilirubin. The procedure related factors include: pancreatic duct injection, difficult cannulation, pancreatic sphincterotomy, precut access, - and balloon dilatation. The operator dependant and technical factors are controversial. Although endoscopists who have a high volume of cases might be expected to have intuitively lower rates post-ERCP pancreatitis, in general this does not appear to be true [2]. However, trainee (fellow) participation has been shown to be a significant risk factor for the development of post-ERCP pancreatitis [3]

In general, the more likely a patient is to have an abnormal common bile duct and/or pancreatic duct, the less likely the patient will develop post-ERCP pancreatitis. Cheng et al. [3] created a 160 variable database that prospectively evaluated over a thousand patients from 15 referral centers in the U.S. Their study emphasized the role of patient factors, including age, sphincter of Oddi dysfunction, prior history of post- ERCP pancreatitis and technical factors, including number of pancreatic duct injections, minor papilla sphincterotomy and operator experience.

Mehta et al. [4] showed that the patient most at risk of developing post-ERCP pancreatitis was a woman with suspected choledocholithiasis, non-dilated common bile duct, but normal serum bilirubin, which undergoes a biliary sphincterotomy and no stone was found. In this patient population, more than a quarter of patients (27%) developed post-ERCP pancreatitis. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound, which do not cause pancreatitis, can provide useful information with an accuracy similar to ERCP in high risk/low yield cases and are the preferred imaging modalities in the initial evaluation of such patients.

Pharmacologic Prevention of Post-ERCP Pancreatitis

Although there has been interest in the pharmacologic prevention of post-ERCP pancreatitis, since its introduction, a large number of studies have failed to identify a consistently effective drug. However, a small number have been shown to be worthy of further study (Table 2). Our limited understanding of the pathogenesis of post-ERCP pancreatitis is a major hurdle to developing effective drug prophylaxis. Drugs that have been studied can be divided into five groups: those that 1) decrease pancreatic inflammation 2) decrease sphincter of Oddi pressure 3) attenuate systemic inflammation 4) decrease pancreatic stimulation and 5) interrupt the activity of proteases.

Drugs that Decrease Inflammation

These include antioxidants, antibiotics, steroids, and non-steroidal anti-inflammatory drugs (NSAIDS). Oxygen-derived free radicals contribute to the pathogenesis of acute pancreatitis by inducing capillary-endothelial injury, which leads to an increase in capillary permeability. Drugs that prevent the generation of, and/or inactivate, free radicals include allopurinol and n-acetylcysteine, respectively. Both have been studied in animal and human models. Initial studies in animals demonstrated a decrease in the incidence and severity of acute pancreatitis for both drugs. However, subsequent human trials failed to show any significant benefit. Four clinical trials that evaluated the efficacy of allopurinol in the prevention of post ERCP pancreatitis showed no clear benefit [10, 11, 12, 13]. One study from Greece [12] looked encouraging, but a high rate of post-ERCP pancreatitis in the control group limited interpretation of the results. Two trials have been published evaluating nacetylcysteine in the prevention of post-ERCP pancreatitis [14, 15] neither showed a benefit.

As infectious complications contribute to the morbidity and mortality in acute pancreatitis, studies evaluating the potential role of antibiotics in preventing post- ERCP pancreatitis have been performed. Only one study has appeared to show benefit. Räty et al. [16] showed reduced rates of post-ERCP pancreatitis in patients receiving 2 grams of ceftazidime 30 minutes prior to ERCP when compared to placebo (2.6% vs. 9.4%. P=0.009).

There have been seven studies evaluating the effect of corticosteroids in reducing the incidence or severity of post ERCP pancreatitis. Pooling all of these studies, 3,308 patients have been evaluated [11, 17, 18, 19, 20, 21]. An early retrospective trial [17] showed a reduced incidence of post therapeutic ERCP pancreatitis in patients with iodine sensitivity. Subsequently, 5 large trials (one randomized and four double-blind) using a variety of corticosteroids, including oral prednisolone, intravenous hydrocortisone and methyl-prednisolone, showed no benefit in reduction of severity or incidence of post ERCP pancreatitis. Of note, the two trials that showed benefit with use of corticosteroids in the prevention of post-ERCP pancreatitis used lower amylase levels (2 to 2.5 times the upper limit of reference) as the cut-off for the diagnoses of acute pancreatitis [17, 18].

In terms of attenuating the inflammatory response, the most promising results have been seen with NSAIDs. Two clinical trials have been published evaluating the role of diclofenac in reducing the incidence of post ERCP pancreatitis [22, 23]. In both trials patients received 100 mg of diclofenac by rectal suppository. Both showed a reduction in the incidence of acute pancreatitis. In the trial performed by Murray et al [22], pancreatitis occurred in 6.4% of patients in the diclofenac group compared to 15.5% in the placebo group (P=0.049). Interestingly, there appeared to be no benefit in patients with sphincter of Oddi dysfunction. Satoudehmanesh et al. [24] showed similar beneficial results with indomethacin. Although pancreatitis occurred in 3.2% of treated patients compared to 6.8% of control patients, these results were not statistically significant (P=0.06). However, a post-hoc analysis suggested a possible beneficial effect in the patients undergoing pancreatic duct injection

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that has been shown to reduce the severity of acute pancreatitis in animal models. Deviere et al. [25] showed a reduction in the incidence and severity of acute pancreatitis with administration of IL-10, 7.5% in treated patients compared to 24% in controls (P<0.05). However, in a separate double blind, prospective trial, Dumot et al. [26] found no difference in the incidence of acute pancreatitis in 200 average risk patients randomized to receive 8 &mug/kg of IL-10 versus placebo (9% vs. 11%, P=0.7). A subsequent, larger, multicenter trial, published only in abstract format at present, showed no benefit of IL-10 in patients undergoing ERCP [27].

Drugs that Secrease Sphincter of Oddi Pressure

It has been suggested that relaxation of the sphincter of Oddi following ERCP will promote pancreatic drainage and prevent acute pancreatitis. Several agents have been used in an effort to relax the sphincter of Oddi, as a way to prevent post-ERCP pancreatitis. There have been 3 recent randomized studies evaluating the use of nitroglycerin during ERCP. Sudhindran et al. [28] compared the prophylactic administration of 2 mg of sublingual nitroglycerin compared to placebo in patients undergoing ERCP. They found that the incidence of post-procedure pancreatitis was significantly less in treated patients (7.7% vs. 17.8%, P<0.05). The short duration of action of sublingual nitroglycerin raises questions about the plausibility of the proposed pharmacologic effect. In a subsequent trial by Moretó et al. [29], 144 patients were randomized to a 15 mg transdermal nitroglycerin patch or an identical placebo patch. A significant reduction in pancreatitis in the placebo arm was demonstrated (4% vs. 15%, P=0.03). However, both trials had high rate of acute pancreatitis in the control arm. In the latest and the largest of the three studies [30], 318 patients at low risk for post ERCP pancreatitis were randomized to receive either the active agent or placebo by transdermal patch. No difference in post-ERCP pancreatitis was seen between active nitroglycerin and placebo groups.

Other studies evaluating drugs to decrease sphincter of Oddi pressure for post-ERCP pancreatitis prophylaxis include: two trials of oral nifedipine [31, 32], one of sprayed lidocaine [33] and one of injected botulinum toxin [34]. Unfortunately, none of these trials demonstrated any beneficial role in the reduction of severity or incidence of post ERCP pancreatitis. In a prospective, non-placebo-controlled trial of 173 patients undergoing endoscopic balloon sphincteroplasty [35], irrigation of the dilated orifice with epinephrine, resulted in a reduced incidence of acute pancreatitis (1.2% vs. 7.6%, P<0.05).

Drug that Interrupt the Activity of Proteases

As the initiation of acute pancreatitis depends on the activation and propagation of proteases, the theoretical advantage of protease inhibitors in decreasing the incidence and severity of post ERCP pancreatitis warrants study. In experimental models, heparin has been shown to inhibit pancreatic proteases, increase microcirculation, and have anti-inflammatory properties. In a non-randomized, prospective trial of 815 patients, heparin administration was associated with a statistically significant reduction of post ERCP pancreatitis (3.4% vs. 7.9%, P=0.005) [36]. However, despite these early encouraging results, two years later the same group performed a randomized, double-blind trial that failed to show a reduction of post ERCP pancreatitis in high risk patients randomized to receive heparin [37].

Gabexate maleate (FOYTM) is a protease inhibitor with anti-inflammatory properties. Its ability to inhibit circulating trypsin is greater than most other protease inhibitors. In 1995, Messori et al. [38] published a meta-analysis of 5 trials [39, 40, 41, 42, 43] showing a statistically significant reduction in the incidence of complications in patients receiving gabexate after the development of acute pancreatitis. However, the trials were small with possibly insufficient numbers of patients. A larger double blind trial by Cavallini et al. [44] subsequently demonstrated a significant reduction in the incidence (2.4% vs. 7.6%, P=0.03) and severity of acute pancreatitis in the patients receiving gabexate versus placebo. An initial meta-analysis of 6 trials [44, 45, 46, 47, 48, 49] by Andriulli et al. [50] demonstrated statistically significant reduction rates of post ERCP pancreatitis (OR: 0.27, 95% CI: 0.13-0.57 P=0.001). Second and 3rd meta-analyses published by the same group [51, 52], which included several large prospective trials [53, 54, 55, 56, 57, 58], did not support the prophylactic use of gabexate in the prevention of acute pancreatitis. Recently, following the publication of the meta-analysis by Andriulli et al. [52], several additional trials have been published, with conflicting results [59, 60, 61, 62, 63]. Although the data are conflicting, it appears that infusions of the drug would likely need to be started 1-2 hours pre- ERCP, and continued for 12 hours following ERCP, to show a beneficial effect [1, 64]. In patients with a low risk, the costs likely outweigh any benefit.

The protease inhibitor, ulinastatin, has been long used in the management of acute pancreatitis in Japan and China [65]. In an initial, randomized, placebocontrolled trial [66], an ulinastatin bolus prior to ERCP significantly reduced the incidence (2.9% vs. 7.4% P=0.041) but not the severity of acute pancreatitis. Two subsequent, randomized, controlled trials comparing ulinastatin to gabexate, found no difference in the prevention of acute pancreatitis [60, 62]. Further study of protease inhibitors in high-risk patients is warranted.

Inhibitors of Pancreatic Secretion

Theoretically, inhibition of exocrine pancreatic secretion could prevent post-ERCP pancreatitis by &ldquoresting&rdquo a damaged gland. Although an attractive concept, there is little scientific basis to support this approach. Somatostatin and its synthetic analog, the octapeptide octreotide, are potent inhibitors of pancreatic secretion. Although several trials of somatostatin have demonstrated an efficacy in reducing the rate of post ERCP pancreatitis [67, 68, 69, 70, 71, 72], the majority of the studies do not support the routine use of this medication [73, 74, 75, 76, 77, 78, 79, 80]. In a meta-analysis published in 2007, Andriulli et al. [52] evaluated 16 trials of somatostatin [53, 55, 58, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] and concluded that this drug&rsquos only statistically significant effect is reduction of post ERCP hyperamylasemia (OR: 0.67, 95% CI: 0.57-0.81 number needed to treat equal to 12). However, when one excludes small, heterogeneous studies, somatostatin administered as a bolus and or as 12-hour infusion seems to be effective in prevention of post- ERCP pancreatitis with a risk difference of 2.1% (95% CI: 0.7-3.6, P=0.004) [64]. In 2000, Andriulli et al. [50] performed a meta-analysis of 10 trials of octreotide [78, 79, 80, 81, 82, 83, 84, 85, 86, 87] in the prevention of post ERCP pancreatitis. They concluded that, similar to somatostatin, octreotide was only effective in reducing post ERCP hyperamylasemia it did not reduce the incidence of post ERCP pancreatitis. Subsequently, multiple welldesigned trials evaluating different doses and scheduling of administration of octreotide [80, 91, 92, 93], and a meta-analysis [94] failed to demonstrate any benefit of octreotide in the prevention of post ERCP pancreatitis. However, two recently published trials [95, 96] reported a beneficial effect of octreotide in reducing the rate of post ERCP pancreatitis, (2% vs. 8.9%, P=0.03) and (2.4% vs. 5.3%, P=0.046), respectively. Further trials with octreotide are warranted. Drugs such as somatostatin, calcitonin [97], and glucagon [98], have been shown to inhibit pancreatic secretion, however none of them has been shown to have a protective effect. It is worth mentioning that a single trial has shown beneficial effects of beta-carotine administration in the reduction of severity of post ERCP pancreatitis (2.22% vs. 0% P<0.01) [99].

Stents and Guidewires to Prevent Post-ERCP Pancreatitis

Pancreatic stent placement decreases the risk of post- ERCP pancreatitis in high-risk patients [6, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111]. This technique has become a common practice during ERCP in patients who are thought to be at particular risk for post-ERCP pancreatitis (Figure 1). Stenting is thought to prevent obstruction to pancreatic duct outflow that can result from papillary edema following instrumentation. Pancreatic sphincter hypertension is a significant risk factor for post-ERCP pancreatitis, which may explain the high risk of pancreatitis in patients with sphincter of Oddi dysfunction. There is prolonged alleviation of ductal obstruction when pancreatic stents are placed. Typically, 3-5 French (Fr) gauge, unflanged, plastic pancreatic stents are used in the following settings: sphincter of Oddi dysfunction, difficult cannulation, balloon dilation (balloon sphincterotomy), and precut sphincterotomy. Thirteen trials (6 prospective, randomized, controlled trials and 7 case-control trials) have been published evaluating the role of pancreatic stent placement in the prevention of post-ERCP pancreatitis (Table 3) [6, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111]. In all of the reported studies, which cumulatively include 1,500 high-risk patients undergoing ERCP, only one patient developed severe pancreatitis after a pancreatic duct stent had been placed [1]. A meta-analysis published in 2004 by Singh et al. [112], evaluating 5 prospective trials including 483 patients, showed a three-fold reduction in the incidence of post-ERCP pancreatitis in patients with pancreatic duct stents versus no stent (15.5% vs. 5.8% P=0.001 OR: 3.2, 95% CI: 1.6-6.4). Similarly, a 2007 meta-analysis published by Andriulli et al. [113], that evaluated 4 randomized, prospective trials including 268 patients, showed a two-fold drop in the incidence of post-ERCP pancreatitis (24.1% vs. 12% P=0.009 OR: 0.44, 95% CI: 0.24-0.81). In a large, retrospective review of 2,283 patients having a total of 2,447 ERCPs, 3 Fr unflanged stents were more effective in reducing the incidence of post ERCP pancreatitis (P=0.0043), more likely to pass spontaneously (P=0.0001), and less likely to cause ductal changes (24% vs. 80%) when compared to larger 4 Fr, 5 Fr or 6 Fr stents [114]. Although prophylactic pancreatic duct stenting is a cost-effective strategy for the prevention of post-ERCP pancreatitis for high-risk patients [115], higher incidence of severe pancreatitis has been reported in patients with failed pancreatic duct stenting [116]. Also, pancreatic duct stenting is not always technically feasible with reported failure rate ranging from 4 to 10% [116].

Figure 1. Pancreatic duct stent.

The potential for pancreatic ductal and or parenchymal injury, risk of inward stent migration and fracture following stent placement is of a concern. In order to minimize pancreatic ductal and or parenchymal changes it is recommended that long 3 Fr (8-12 cm) or short 4 or 5 Fr (2-3 cm) single pigtail unflanged stents should be used, followed by removal within two to four weeks after placement [116].

Guidewire cannulation, in which the bile duct and pancreatic duct are cannulated by a guide-wire inserted through a catheter (e.g. a sphincterotome), has been shown to decrease the risk of pancreatitis [117]. By avoiding cannulation with radiocontrast agents, thus minimizing the risk of hydrostatic injury to the pancreas, the incidence of acute pancreatitis appears to be dramatically decreased. In a study of 400 consecutive patients who underwent ERCP by a single endoscopist, randomized to initial cannulation with contrast versus initial cannulation by guide-wire under fluoroscopic control, pancreatitis rates were markedly different. No case of acute pancreatitis was seen in the guidewire group compared to 8 cases in the standard contrast group (P<0.001). Cannulation success rates between the standard contrast and guide-wire techniques were comparable, 98.5% versus 97.5%. A more recent study [118] confirmed a decrease in post- ERCP pancreatitis in 300 patients prospectively randomized to guide-wire cannulation compared to conventional contrast injection. However, the reduction in post-ERCP pancreatitis appears to have been related to less need for precut sphincterotomy in patients undergoing guide-wire cannulation.

Treatment of Post-ERCP Pancreatitis

As not all patients with pain and hyperamylasemia following ERCP have acute pancreatitis, clinicians may be having difficulty in establishing the diagnosis. As a result, some patients with severe post-ERCP pancreatitis may not be identified in the early stages of their illness, when aggressive hydration is most important. Some endoscopists may have difficulty acknowledging that post-ERCP pancreatitis has occurred, as this requires accepting that there has been a complication. A sense of guilt on the part of the clinician performing the procedure is understandable. However, delay in both the diagnosis and treatment of post-ERCP pancreatitis may lead to adverse consequences.

Post-ERCP pancreatitis should be managed like other causes of acute pancreatitis. This is sometimes complicated by difficulty distinguishing mild from severe disease during the early stages. The degree of elevation of serum amylase and lipase do not always correlate with severity. Prospective systems using clinical criteria have been developed to predict severity in patients with acute pancreatitis, such as the Ranson, Imrie (Glasgow) and, APACHE scores [5]. The Ranson and Imrie scoring systems are effectively obsolete. They are cumbersome, requiring serial measurements of numerous physiologic, hematologic and biochemical indices. Additionally, it may take up to 48 hours to develop the predictive score. Although improved, the APACHE III is even more complex. In acute pancreatitis, close monitoring for signs of organ dysfunction is paramount. An apparently mild post- ERCP pancreatitis can sometimes progress to life threatening necrotizing disease. CT-based scoring systems, such as the Balthazar CT score may be helpful but also may be inaccurate within the first 24 hours of the disease process [119].

Aggressive intensive care to prevent complications of acute pancreatitis requires the early identification of patients with severe disease, and those at risk of developing severe disease. An advanced age (more than 55 years), obesity (BMI greater than 30 kg/m2), organ failure at admission, and pleural effusion and/or infiltrates are risk factors for severity that should be noted early [5]. Patients with these characteristics may require treatment in a highly supervised area, such as a step-down or intensive care unit.

Hematocrit is the best laboratory marker to follow in monitoring patients with acute pancreatitis. The role of hematocrit in determining severity is related to hemoconcentration. As the inflammatory process progresses early in the course of the disease, there is an extravasation of protein-rich intravascular fluid into the peritoneal cavity resulting in hemoconcentration. The decreased perfusion pressure into the pancreas leads to microcirculatory changes that lead to pancreatic necrosis. An admission hematocrit equal to, or greater than, 47 % and/or a failure of the admission hematocrit to decrease at 24 hours have been shown to be predictors of necrotizing pancreatitis [120].


Conclusions

Chronic pancreatitis is a fibro-inflammatory disease that can produce complications through loss of endocrine function, loss of exocrine function, and compromise of the local vascular and luminal anatomy. The primary complications include abdominal pain, diabetes mellitus, exocrine pancreatic insufficiency (namely fat malabsorption), metabolic bone disease, and pancreatic cancer. Additional anatomic complications can include pseudocysts, splanchnic venous thrombosis, and duodenal or biliary obstruction. These complications are primarily the consequence of chronic inflammation and fibrosis, and management primarily consists of screening for and treating complications after they develop. Additional efforts are needed to further understand the pathophysiology of disease progression and study therapeutic interventions to prevent the development of these end-stage complications.

Key Findings

Chronic pancreatitis is a fibro-inflammatory disease that can lead to a variety of complications due to loss of function or compromise of the adjacent vascular or luminal anatomy.

Future Unmet Needs

Better understanding of type 3c diabetes secondary to chronic pancreatitis is needed to provide optimal diabetes treatment and understand the accelerated risk of pancreatic cancer in those with chronic pancreatitis and diabetes.

The development and validation of an accurate and easily repeatable test for assessment of exocrine pancreatic insufficiency is needed.

Additional studies are needed to examine preventative strategies for the development of metabolic bone disease and pancreatic cancer in chronic pancreatitis.

Implications for the Clinician

There are several potential complications of chronic pancreatitis which require active surveillance by clinicians, including diabetes, exocrine pancreatic insufficiency, metabolic bone disease, and pancreatic cancer.


The Take-Away

As the Canine Journal puts it, “pancreatitis is like that relative that just won’t leave: Even when they’re gone, the thought of their return hovers in the back of your mind.” Unfortunately, once a dog has had a bout of pancreatitis, the chance of recurrence is high. You best defense against a repeat appearance of this unwelcome intruder is a two-pronged approach: Be on the look-out for the warning signs and control the things you can. Don’t let your dog become obese (exercise is good for both of you), follow your vet’s feeding instructions strictly, and, when relevant, administer your dog’s medication faithfully.

Mild cases of pancreatitis usually have a good prognosis. Severe cases have a more guarded prognosis, due to the potential for systemic complications. But as a vigilant, responsible, and most of all, knowledgeable dog owner, you now know what you can do to reduce the risk of pancreatitis, how to recognize it if it does strike, and how to manage it going forward.