Chronic Pancreatitis Guidelines

2017 United European Gastroenterology guidelines

In March 2017, the United European Gastroenterology (UEG) released their updated recommendations for the diagnosis and therapy of chronic pancreatitis (CP).

A diagnosis of cystic fibrosis needs to be ruled out in all patients with CP onset before the age of 20 yr, as well as in patients with so-called idiopathic CP, regardless of the age of onset.

All patients with a family history or early onset disease (< 20 yr) should be offered genetic testing for associated variants. In patients with alcoholic CP, routine genetic testing cannot be recommended. Variants in SPINK1 and CTRC and, to a lesser extent, common single-nucleotide polymorphisms (SNPs) in the PRSS1 and CLDN2-MORC4 loci, are associated with alcoholic CP.

In pediatric patients, cystic fibrosis needs to be ruled out by chloride iontophoresis, while genetic causes seem to be much more important in children than in adults. Laboratory evaluation needs to include Ca²⁺ and triglyceride levels. Recommended imaging modalities are abdominal ultrasound or magnetic resonance cholangiopancreatography (MRCP). Testing should include PRSS1 (sequencing of exon 2 and 3 to cover mainly p.A16V, p.N29I and p.R122H), SPINK1 (all 4 exons, mainly p.N34S and IVS3 + 2T > C in exon 3 and intron 3), CPA1 (several variants, mainly in exons 7, 8, and 10), CTRC (especially exon 7), and CEL (hybrid allele only), and may include screening for variants in CFTR. In every pediatric patient, cystic fibrosis has to be ruled out, since 10-15% of cystic fibrosis patients with pancreatic sufficiency (comprising 1-2% of all patients with cystic fibrosis) present clinically with recurrent attacks of acute pancreatitis.

EUS, MRI, and CT are the best imaging methods for establishing a diagnosis of CP. CT examination is the most appropriate method for identifying pancreatic calcifications, while for very small calcifications, non-enhanced CT is preferred. The presence of typical imaging findings for CP with MRI/MRCP is sufficient for diagnosis; however, a normal MRI/MRCP result cannot exclude the presence of mild forms of the disease.

Abdominal US can only be used to diagnose CP at an advanced stage. EUS is the most sensitive imaging technique for the diagnosis of CP, mainly during the early stages of the disease, and its specificity increases with increasing diagnostic criteria. EUS is an essential tool in the differential diagnosis of CP with other pancreatic masses or cystic lesions. EUS-guided fine-needle biopsy can be considered as the most reliable procedure for detecting malignancy.

Pancreatic exocrine insufficiency (PEI) refers to an insufficient secretion of pancreatic enzymes (acinar function) and/or sodium bicarbonate (ductal function).

Mild PEI is defined as the reduced secretion of one or more enzymes with normal bicarbonate concentration in duodenal juice and normal fecal fat excretion; moderate PEI is defined as having a reduced enzyme output and bicarbonate concentration but normal fecal fat excretion; while severe PEI has a reduced enzyme output and bicarbonate concentration plus steatorrhoea.

The main causes of PEI are loss of the pancreatic parenchyma, obstruction of the main pancreatic duct, decreased stimulation of the exocrine pancreas, and inactivation of pancreatic enzymes.

For exocrine pancreatic insufficiency, in a clinical setting, a noninvasive pancreatic function test (PFT) should be performed. The fecal elastase (FE-1) test is feasible and widely available and is therefore most frequently used in this setting, while the ¹³C mixed triglyceride breath test (¹³C-MTG-BT) offers an alternative. The s-MRCP test may also be used as an indicator of PEI but provides only semiquantitative data.

A pancreatic function test is required for the diagnosis of CP. Every patient with a new diagnosis of CP should be screened for PEI.

Surgery is superior to endoscopy in terms of mid-term and long-term pain relief in patients with painful CP.

To achieve optimal long-term pain relief in patients suffering from CP, early surgery is favored over surgery at a more advanced stage of the disease.

A total pancreatectomy should be considered in CP patients without duct system dilatation, who are resistant to conventional medical, endoscopic, and previous surgical treatment and who have severe pain.

Pancreatic enzyme replacement therapy (PERT) is indicated for patients with CP and PEI in the presence of clinical symptoms or laboratory signs of malabsorption. An appropriate nutritional evaluation is recommended to detect signs of malabsorption.

The optimal dose of pancreatic enzymes for PEI in CP is a minimum lipase dose of 40,000–50,000 PhU with main meals, and half that dose with snacks. The addition of a PPI to oral pancreatic enzymes is of help in patients with an unsatisfactory response to PERT.

In patients with uncomplicated painful CP and a dilated main pancreatic duct (MPD), endoscopic therapy (ET) is recommended as the first-line treatment after failed medical therapy following discussions by a multidisciplinary team (MDT). The clinical response should be evaluated at 6-8 wk; if it appears unsatisfactory, the patient’s case should be discussed again by a multidisciplinary team of endoscopists, surgeons, and radiologists, and surgical options should be considered, in particular for patients with a predicted poor outcome following ET.

ET is performed first in most cases, with surgery reserved for the minority of patients whose painful symptoms do not respond well to ET.

Pain is the first presentation of CP in the majority of patients. Paracetamol is the preferred level I analgesic because of its limited side effects, while nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because of their gastrointestinal toxicity. If necessary, PPIs should be used in patients with CP who are at high risk of developing peptic ulcers.

Tramadol is the preferred level II analgesic and was shown to be superior to morphine in patients with CP, with fewer gastrointestinal side effects for the same level of analgesia.

Level III analgesia constitutes the group of strong opioids, such as morphine, which are widely used for pain relief in CP. In general the lowest possible dose should be used and the drug should always be taken orally to avoid dose escalation and addiction. Note: in many patients (up to 50% of chronic pain patients in general), opioids do not alleviate pain, and treatment should be stopped.

ET is effective in patients with an obstructive type of pancreatic pain and in patients with a pancreatic duct dilatation.

Extracorporeal shock wave lithotripsy (ESWL) therapy is effective for disintegrating stones in the main pancreatic duct.

Resection, decompression, or mixed surgical techniques achieve pain relief in CP that is maintained over time in approximately 80% of patients.

Parenteral nutrition is indicated in patients with gastric outlet obstruction secondary to duodenal stenosis, in patients with complex fistulating disease, and in patients with apparent severe malnutrition prior to pancreatic surgery if enteral feeding is not possible.

Enteral nutrition is indicated in patients with malnutrition who are not responding to oral nutritional support.

2017 Working Group for the International (IAP-APA-JPS-EPC) Consensus Guidelines for Chronic Pancreatitis

In September 2017, the Working Group for the International Consensus Guidelines for Chronic Pancreatitis published their guidelines for understanding and management of pain in chronic pancreatitis. ^[15]

Although abdominal pain is the most frequent symptom of CP, the severity, temporal nature, and natural history of pain varies greatly.

In addition to administering adequate treatment, strongly advise patients with CP to abstain from alcohol and smoking.

Routinely refer all patients with presumed or established CP to expert pancreatic centers for workup and management of their disease.

Pain in CP remains poorly understood and inadequately correlated with neurobiologic mechanisms. Although CP is defined by inflammation, few therapeutic attempts have been made to target this aspect of its pathophysiology. In addition, the presence of striking changes in peripheral and central nervous system structure and function suggests a maladaptive state that includes both neuropathic and dysfunctional pain. In the absence of effective anti-inflammatory approaches, it is clearly important to focus on the alteration of function that accompanies these changes in the nociceptive system as a potential therapeutic target.

Assessment of pain in CP follows the guidelines for other types of chronic pain, taking into account the multidimensional nature of symptom presentation. Although few validated instruments exist for subjective CP pain assessment, there are appropriate measures available, albeit not rigorously validated in this population.

An initial attempt with pancreatic enzyme therapy with high protease content is reasonable for pain relief in patients with CP. Include a combination of antioxidants in sufficient dosages as options for pain treatment.

The current standard guideline for analgesic therapy in CP follows the principles of the “pain relief ladder” provided by the World Health Organization (WHO) adjusted to the pain characteristics of this condition.

The best candidates for successful treatment of painful CP with first-line endoscopic therapy are those with distal obstruction of the main pancreatic duct (single stone and/or single stricture in the head of the pancreas) and in the early stage of the disease. Endoscopic therapy can be combined with extracorporeal shock wave lithotripsy (ESWL) in the presence of large (>4 mm) obstructive stone(s) located in the pancreatic head, and with ductal stenting in the presence of a dominant main pancreatic duct stricture that induces a markedly dilated duct.

In cases of uncomplicated painful calcified CP, ESWL alone is a safe and effective treatment. Best candidates for benefiting from initial first-line ESWL are patients with obstructive calcifications, more than 4 mm confined to the head of pancreas. It is not cost effective nor is it likely to improve pain outcomes to combine systematic endoscopical therapy with ESWL.

ESWL for pancreatic stones is indicated for patients with all of the following:

• Recurrent attacks of pancreatic pain
• Moderate to marked changes in the pancreatic ductal system
• Obstructing ductal stones (minimal diameter: 2-5 mm, calcified or radiolucent)

Neurolytic interventions can be used in selected patients with painful CP refractory to endoscopic and surgical treatment. Thoracoscopic splanchnic denervation is more effective regarding long-term pain relief in patients who are not on chronic opioid treatment. Include behavioral interventions as part of the multidisciplinary approach in CP pain, particularly in patients who experience psychological impact of pain and reduced quality of life. Early intervention in children may be particularly important.

Depending on the morphologic changes of the pancreas and pain processing status a (partial) resection, decompression of the pancreatic duct or combined interventions can be performed to reduce pain. Although long-term effects vary, success rates up to 80% have been reported. Total pancreatectomy is emerging as a promising initial surgical treatment but needs further investigation.

Current evidence on the timing of surgery for painful CP suggests a beneficial role for early surgery, ie, 1) within the first 2-3 years after diagnosis or symptom onset, 2) for patients who had equal to or fewer than five endoscopic procedures, and 3) for patients who have not yet required opioid analgesics for medical pain treatment.

Current evidence suggests that the first step for the management of pain relapse should be exclusion of obstructing stones or strictured anastomosis via imaging, followed by a limited number endoscopic interventions, and early consideration of resurgery to achieve pain control.

2015 American Gastroenterological Association guidelines

The American Gastroenterological Association (AGA) recommends the following in the diagnosis and management of asymptomatic neoplastic pancreatic cysts ^[16] :

• For asymptomatic mucinous cysts, a 2-year interval is recommended for a cyst of any size undergoing surveillance, with surveillance being stopped after 5 years if there is no change.

• Perform surgery only if there is more than one concerning feature on MRI confirmed on endoscopic ultrasonography (EUS) and only in centers with high volumes of pancreatic surgery, and there should be no surveillance after surgery if there is no invasive cancer or dysplasia.

• The risk of malignant transformation of pancreatic cysts is approximately 0.24% per year, and the risk of cancer in cysts without a significant change over a 5-year period is likely to be lower.

• The small risk of malignant progression in stable cysts is likely to be outweighed by the cost of surveillance and the risks of surgery.

• Positive cytology on EUS-guided fine-needle aspiration (FNA) has the highest specificity for diagnosing malignancy; if there is a combination of high-risk features on imaging, then this is likely to increase the risk of malignancy even further. Similarly, if a cyst has both a solid component and a dilated pancreatic duct (confirmed on both EUS and MRI), the specificity for malignancy is likely to be high even in the absence of a positive cytology.

• There is lower immediate postoperative mortality, as well as long-term mortality, for patients who undergo surgery in high-volume pancreatic centers.

• It seems sensible to offer screening even after the cyst has been resected, provided the patients have not undergone total pancreatectomy. Surveillance should continue as long as the patient remains a good candidate for surgery. MRI every 2 years may be a reasonable approach for these patients. The clinician may elect to offer more frequent surveillance in the case of invasive cancer resection, particularly if there is concern that the lesion has not been fully resected.