Chronic pancreatitis

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Traditionally, chronic pancreatitis (CP) is considered a progressive inflammatory disorder of the pancreas in which normal parenchymal morphology is irreversibly damaged and replaced by fibrosis and chronic inflammatory cell infiltrates. Clinical value of this histological definition is limited because some patients with histological definition of CP have no symptoms, histological features seen in CP can be present in normal aging process, social ethanol intake, smoking, chronic kidney disease, long standing diabetes mellitus, etc. Clinically CP is a constellation of chronic symptoms such as abdominal pain sometimes radiating to the back, steatorrhea, weight loss, and dysglycemia often accompanied by abnormal histological and radiological characteristics of the pancreas. Although acute and chronic pancreatitis were previously recognized as different disease entities; in the current paradigm of pathogenesis, they are considered as two ends of the same spectrum.

A patient with chronic pancreatitis typically presents with chronic epigastric pain with episodic worsening. Impaired endocrine/exocrine function may or may not be obvious. The classic triad of pancreatic calcifications, steatorrhea and diabetes is usually only seen in advanced disease.

Abdominal pain is by far the most common symptom and occurs in up to 80% of patients. The typical pancreatic pain is a dull or boring pain in the epigastric region with radiation to the back, worse with eating and often associated with nausea or vomiting. However, the presentation of pain can be variable: intermittent, frequent or persistent; mild to severe or even absent between relapses; right or left upper quadrant pain; and progressively worsening or improving (pancreatic burnout) over time.

The mechanism of pain is perhaps multifactorial including inflammation causing damage to nerve sheaths and exposure of sensory nerves to toxic substances, ductal obstruction and increased parenchymal pressure (compartment syndrome) with tissue ischemia, pseudocyst or cancer development, opioid related gastroparesis and non-visceral (somatic or central) pain.

Severe malnutrition and weight loss are common in advanced stages due to combination of poor oral intake due to fear of eating. Additionally, exocrine insufficiency leads to malabsorption of important macro and micro nutrients.

• CP is a disease of middle age with a male predominance. The estimated incidence of CP ranges from 5-12 cases per 100,000 per year worldwide. The annual incidence of CP in the United States is about 8 cases per 100,000. The prevalence of CP is about 50 cases per 100,000.
• Heavy alcohol use (over 4-5 drinks per day) over a prolonged period of time is the most common cause of chronic pancreatitis. Smoking is an independent risk factor for both acute and chronic pancreatitis, and the effects of tobacco could be synergistic to alcohol.
• Some genetic mutations like cystic fibrosis transmembrane regulator [CFTR], serine protease inhibitor Kazal type 1 [SPINK1] have been linked with this condition.
• Tropical pancreatitis (TP) is endemic to certain developing regions such as India, Africa, and South America. Episodic abdominal pain begins in childhood and often progresses to endocrine and exocrine insufficiency.
• There are other obstructive causes like pancreatic adenocarcinoma, neuroendocrine tumors, and intrapapillary tumors.
• Autoimmune chronic pancreatitis is rare and associated with other autoimmune diseases, such as Sjögren’s syndrome and primary sclerosing cholangitis. There is a rapid clinical and radiographic response to steroids.
• Hypercalcemia and chronic renal failure are less common causes of chronic pancreatitis.
• CP can be idiopathic in 10-30% of patients. It is more common in females than males. Idiopathic CP can occur in two forms. Early onset variety occurs in second or third decades of life whereas late onset idiopathic CP appears in sixth or seventh decades of life.

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Acute pancreatitis, pancreatic cancer, peptic ulcer disease, gallstone disease, irritable bowel syndrome, chronic gastritis, and chronic mesenteric ischemia.

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Very few findings are specific for CP. In chronic alcoholics with advanced disease, one may find severe weight loss and malnutrition with stigmata of chronic liver disease. There may be a palpable mass in the abdomen due to a pseudocyst. Icterus (due to alcoholic liver disease or due to compression of bile duct in the head of pancreas from fibrosis) and or palpable spleen (due to splenic vein thrombosis) may be present. There may be enlarged salivary glands or lymphadenopathy in patients with autoimmune pancreatitis.

Plain abdominal X-ray is a reliable screen. It is inexpensive and has 100% specificity if pancreatic calcifications are seen.

Qualitative testing for steatorrhea by Sudan staining of feces is nonspecific and is no longer recommended.

Quantitative 72-hour fecal fat determination is the gold standard. Fecal fat content of over 7 g/day is indicative of steatorrhea. This if accompanied with typical symptoms of longstanding abdominal pain would be diagnostic of chronic pancreatitis.

Fecal elastase level is the most sensitive and specific test for assessing pancreatic exocrine function. Values less than 200 mcg/g are suggestive of pancreatic exocrine insufficiency. Single stool sample is sufficient for testing and results are not affected by pancreatic enzyme supplements.

Direct tests involve stimulating the pancreas by meals or pharmacologic hormonal secretagogues and measuring pancreatic enzymatic content in duodenal fluid. This can diagnose early chronic pancreatitis but is performed in only a few specialized centers. Certain genetic mutations have been associated with chronic pancreatitis. These are the CFTR (cystic fibrosis), SPINK1, and PRSS1 genes linked to hereditary pancreatitis.

• Only 30% of patients with chronic pancreatitis demonstrate calcifications on plain films.
• On the other hand, computed tomography (CT), transabdominal ultrasound (US) and magnetic resonance imaging (MRI) show calcifications and other findings of ductal dilatation, pancreatic enlargements, pseudocysts, etc.
• Sensitivity and specificity of transabdominal US for diagnosis of chronic pancreatitis are 60 to 70% and 80 to 90% respectively, and that of CT are 75 to 90, and 85% respectively.
• Magnetic resonance cholangiopancreatography (MRCP) is now used frequently as a noninvasive, no radiation risk imaging modality. Besides, it demonstrates structural changes in the pancreas distinctly. A secretin-enhanced MRCP also detects impairment in exocrine function early on in chronic pancreatitis and improves sensitivity.
• Endoscopic retrograde cholangiopancreatography (ERCP) use is now limited. Findings include characteristic beading of the main pancreatic duct (PD) and ecstatic branches which are pathognomonic of chronic pancreatitis.
• Endoscopic ultrasound (EUS) has been found to be as sensitive as ERCP but requires a skilled endoscopist.
• Direct pancreatic function test: secretin stimulation test to analyse bicarbonate level and cholecystokinin stimulation test to check lipase level.
• Indirect pancreatic function test: Fecal elastase level, in advanced pancreatitis fecal elastase level is less than 100 micrograms per gram of stool.
• The American Pancreatic Association first published its practice guidelines in 2014 for the diagnosis of CP. The guidelines define the diagnostic aspect of CP as definitive, probable, and insufficient according to current knowledge. The guidelines’ main emphasis is not to mislabel the patient as having CP without sufficient evidence, but to continue with a longitudinal follow-up including serial imaging and physiological testing. The diagnostic algorithm proposed in the guidelines proceeds from noninvasive to invasive testing. After confirmation of the diagnosis of CP, it recommends an etiological, morphological, and physiological characterization of the CP. A mnemonic for predisposing factors for CP is TIGAR-O (toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, and obstructive).

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Amylase and lipase are minimally elevated and more frequently normal. This is because chronic pancreatitis is a patchy disease. In addition, structural damage resulting in fibrosis causes decreased levels of these enzymes.

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It is important to rule out acute pancreatitis which is always treated with pancreatic “rest”, and minimizing pancreatic exocrine secretion.

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This includes pain control, management of pancreatic insufficiency, and treatment of complications.

General measures involve abstinence from alcohol, cessation of smoking, and small frequent meals low in fat (restricted to 20 gm/day or less).

Non-narcotic analgesics are the first step to control pain. NSAIDs should be avoided. Acetaminophen and/or tramadol are useful in controlling pain in some patients and should be tried first unless contraindications to their use exist. Tricyclic antidepressants, SSRIs, gabapentin, and pregabalin may be tried for control. If pain persists, low dose opioids may be added. Doses can be escalated depending on response.

Pancreatic enzymes are presumed to improve pain by suppressing cholecystokinin (CCK) release from the duodenum, leading to decreased pancreatic stimulation. However, this has not been well supported by studies done thus far.

Pain from chronic pancreatitis could be visceral, nonvisceral, or somatosensory. A differential nerve blockade helps to differentiate these 2 components of pain. A CT-guided or EUS-guided celiac plexus blockade can be performed. Counseling with or without antidepressants could be used as adjuncts for treating somatosensory pain.

Obstruction of pancreatic duct from stones or strictures may contribute pain. As such, some patients may benefit from endoscopic sphincterotomy or removal of stones, or both, and decompression by placement of pancreatic stents.

Surgical options include Whipple’s procedure if the CP is concentrated mostly in the head of the pancreas. Puestow, Beger, or Frey procedures have been used with varying degrees of success for pain control. However, these have not been well studied in randomized trials, require skilled surgeons, and may lead to significant loss of pancreatic exocrine and endocrine functions. Patients with chronic pain and nondilated ducts can be managed with either CT or EUS guided celiac plexus block.

Autoimmune pancreatitis should be treated with glucocorticoids (40 mg of prednisone per day for 1-2 months followed by a slow taper).

Pancreatic enzyme supplements are usually given in a minimum dose of 40,000 U of lipase per meal. They can be taken entirely before a meal divided into 2 doses: one half before meal and the other half taken 15 minutes into a meal.

Because coated preparations may be released distally lower down the small intestine, uncoated ones are preferred. Uncoated preparations are easily degraded by the gastric acid and thus proton pump inhibitors or H2 (histamine receptor 2) blockers are usually added.

Response to enzymes supplementation can be assessed subjectively by the amount of pain control achieved, or objectively by determining 72-hour stool fat content.

Pancreatic fluid collections may result from CP. Drainage of the symptomatic collections should be performed.

Pancreatic pseudocysts may be decompressed endoscopically or surgically.

Endoscopic ultrasound may be used to facilitate the optimal site of endoscopic drainage.

Pancreatic ascites or pancreatopleural fistulas can be managed by inserting stents across the disrupted ducts endoscopically.

Biliary or gastric outlet obstruction by large pseudocysts also require drainage of the cyst or surgical cystogastrostomy or cystojejunostomy. Patients with duodenal stenosis may need surgical gastrojejunostomy.

Pancreatic ascites usually resolves with pancreatic stent placement; total parenteral nutrition aids resolution of ascites in many cases. Pancreatic ascites and pleural effusions typically are diagnosed by their high amylase content.

Splenic vein thrombosis is usually asymptomatic, however, it may cause recurrent variceal bleeding requiring splenectomy.

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Narcotic analgesics such as morphine should be used with caution – in reduced dosages.

It is worthwhile to remember that chronic kidney disease may cause histological changes in pancreas mimicking CP.

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Narcotic analgesics such as opioids should either be avoided or used at reduced dosages.

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Diabetes resulting from loss of endocrine function can be brittle due to concomitant loss of glucagon producing cells leading to frequent hypoglycemia.

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CP increases the risk of pancreatic carcinoma.

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Pleural effusion secondary to chronic pancreatitis may complicate existing lung disease.

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See ‘Treatment’ section.

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May predispose patients to developing splenic vein thrombosis which is a known complication of chronic pancreatitis. Deranged coagulation profile can also predispose patients with splenic vein thrombosis to developing variceal bleeding.

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Abstinence from alcohol and smoking may prove to be a difficult task in those with psychiatric comorbidities or dementia.

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These are mainly associated with complications. Acute worsening of abdominal pain may be indicative of splenic vein thrombosis or shortness of breath caused by pleural effusion.

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Variable.

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When adequate pain control is achieved. If any complications are detected, appropriate management should be initiated or outpatient follow-up should be arranged to address these.

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These patients should be co-managed with the primary care provider, pain specialist, psychiatrist, and a gastroenterologist. Clinic follow-up should be arranged with the appropriate provider upon discharge so that continuing issues are addressed. This approach will help patients from making repeated visits to emergency room.

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• General medicine in 2-3 weeks to ascertain good pain control with medications
• Gastroenterology to establish long-term care
• Chronic pain management referral can be initiated through general medicine clinic when deemed necessary

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Those with coexisting dementia due to alcohol abuse may need to be placed in nursing homes for ongoing care.

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• Prognosis is variable.
• Alcohol cessation is imperative to halt progression of disease.
• Smoking has been known to accelerate pancreatic calcification and CP, therefore smoking cessation should be advised.

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Alcohol and smoking cessation will decrease the progression of the disease and should be advised. Regular follow-up with interdisciplinary team of professionals consisting of the primary care provider, gastroenterologist, psychiatrist, and pain specialist will help the patient. Whether these measures will prevent or decrease the readmission rate for CP, requires further study.

Forsmark, C., Feldman, M, Friedman, LS, Brandt, LJ.. Chronic Pancreatitis: in Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. vol. 59. 2006. pp. 994-1026.

Forsmark, C, Adams, PC.. “Pancreatic function testing – valuable but underused”. Can J Gastroenterol. vol. 23. 2009 Aug. pp. 529-530.

Duggan, SN, Ní Chonchubhair, HM, Lawal, O, O’Connor, DB. “Chronic pancreatitis: A diagnostic dilemma”. World J Gastroenterol. vol. 22. 2016 Feb 21. pp. 2304-2313.

Friedman, LS, Papadakis, MA, McPhee, SJ, Rabow, MW.. Current Medical Diagnosis & Treatment 2016. 2015 Sep 8.

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