Chronic pancreatitis overview

# Overview
Chronic pancreatitis is a long-standing inflammatory disease of the pancreas characterized by irreversible changes in pancreatic structure and function leading to inflammation and fibrosis. The concept of pancreas and pancreatic duct was first described by Johannes Wirsung of Padua in 1642. The classification systems that have been used up til now for chronic pancreatitis include; Marseille, Marseille-Rome, Cambridge, TIGAR-O, ABC grading system, and Manchester system. The pathogenesis is still unclear and multifactorial but decreased bicarbonate secretion and intrapancreatic activation of digestive enzymes is thought to play an important role in the pathogenesis of chronic pancreatitis. Other factors that are thought to play an important role in the pathogenesis of chronic pancreatitis may include intraductal plugging and obstruction, direct injury to pancreatic cells induced by toxins and toxic metabolites, antioxidants, ischemia, autoimmune disorders, the sentinal acute pancreatitis event (SAPE) hypothesis, necrosis and fibrosis. Genes involved in the pathogenesis of chronic pancreatitis include CFTR-cystic fibrosis gene mutation, SPINK-1, which encodes for trypsin inhibitor, PRSS-1 gene linked to hereditary pancreatitis, claudin-2 (CLDN2), and carboxypeptidase A1 (CPA1) genes. TIGAR-O may be used for the etiologic classification of chronic pancreatitis. Chronic pancreatitis needs to be differentiated from other diseases presenting with similar complaints such as abdominal pain, diarrhea, and weight loss. The incidence of chronic pancreatitis and the number of hospital admissions secondary to chronic pancreatitis is increasing in most countries worldwide. Alcoholic pancreatitis is more prevalent in developed or industrialized countries. Idiopathic and tropical pancreatitis is more prevalent in developing and underdeveloped countries. The M-ANNHEIM multiple risk factor classification of chronic pancreatitis includes multiple risk factors such as alcohol consumption, nicotine consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors, rare metabolic factors, and miscellaneous factors. The risk of progression of chronic pancreatitis to pancreatic cancer is approximately 4% at 20 years. Common complications of chronic pancreatitis usually include pseudocyst formation and mechanical obstruction of the duodenum and common bile duct. The diagnostic study of choice for chronic pancreatitis is magnetic resonance cholangiopancreatography (MRCP). The diagnosis is difficult to establish as the laboratory results and the imaging may be normal. Patients with chronic pancreatitis usually present with persistent abdominal pain with episodic flares that may or may not be associated with food intake, steatorrhea, pancreatic diabetes, nausea and weight loss. A secretin stimulation test is considered the gold standard functional test for diagnosis of chronic pancreatitis. Fecal tests may include sudan staining of feces, 72-hour quantitative fecal fat (gold standard), and faecal elastase measurement (test of choice). CT scan findings suggestive of chronic pancreatitis may include dilatation of the main pancreatic duct, calcifications, pancreatic gland enlargement, changes in pancreatic size, shape, and contour, and pancreatic pseudocysts. MRI findings may include parenchymal atrophy or enlargement, pseudocyst formation, dilatation and beading of the pancreatic duct with intraductal calcifications giving an appearance of 'chain of lakes'.  ERCP findings diagnostic of chronic pancreatitis may include beaded appearance of the main pancreatic duct and ectatic side branches from the main pancreatic duct. Presence of stones is the most predictive finding seen on endoscopic ultrasonography. Other diagnostic studies may include genetic testing such as CFTR-Cystic fibrosis gene mutation, SPINK-1, which encodes for trypsin inhibitor and PRSS-1 gene linked to hereditary pancreatitis. Medical therapy includes pancreatic enzyme supplementation, analgesics and antioxidants. Specialized approaches include celiac nerve block, endoscopic therapy, extracorporeal shock wave lithotripsy (ESWL), and radiation. Steatorrhea can be managed by dietary modification, lipase supplementation, vitamin supplementation, and medium chain triglycerides (MCTs). Surgery for chronic pancreatitis tends to be divided into two resectional and drainage procedures. Dilated pancreatic duct may be managed with lateral pancreaticojejunostomy (LPJ) and lateral pancreaticojejunostomy with localized pancreatic head resection. Nondilated pancreatic duct is usually manages with pancreaticoduodenectomy, duodenal-preserving pancreatic head resection (DPPHR), distal pancreatectomy (DP) and total pancreatectomy (TP).

# Historical Perspective
The concept of pancreas and pancreatic duct was first described by Johannes Wirsung of Padua in 1642. In 1761, Giovanni Morgagni described the clinical syndrome of severe upper abdominal pain, vomiting, and collapse. He is also credited with the earliest pathological recognition of cancer of the pancreas. In 1948, Eliason and Welty described distal pancreatectomy (DP). In 1980, Beger described duodenal-preserving pancreatic head resection (DPPHR) technique for chronic pancreatitis to decrease the morbidity of pancreatic head resection.

# Classification
Chronic pancreatitis may be divided based upon underlying morphology into large-duct type or small-duct type with or without calcification. The classification systems that have been used up til now for chronic pancreatitis may include ; Marseille, Marseille-Rome, Cambridge, TIGAR-O, ABC grading system and Manchester system.

# Pathophysiology
Chronic pancreatitis is a progressive inflammatory process leading to irreversible structural damage to pancreas resulting in exocrine and endocrine dysfunction. The pathogenesis is still unclear and multifactorial but decreased bicarbonate secretion and intrapancreatic activation of digestive enzymes is thought to play an important role in the pathogenesis of chronic pancreatitis. Other factors that are thought to play an important role in the pathogenesis of chronic pancreatitis may include intraductal plugging and obstruction, direct injury to pancreatic cells induced by toxins and toxic metabolites, antioxidants, ischemia, autoimmune disorders, the sentinal acute pancreatitis event (SAPE) hypothesis, necrosis and fibrosis. Genes involved in the pathogenesis of chronic pancreatitis include CFTR-cystic fibrosis gene mutation, SPINK-1, which encodes for trypsin inhibitor, PRSS-1 gene linked to hereditary pancreatitis, claudin-2 (CLDN2), and carboxypeptidase A1 (CPA1) genes. Associated conditions may include autoimmune conditions, primary biliary cirrhosis, primary sclerosing cholangitis, sjogren syndrome, and renal tubular acidosis. Gross pathology may include enlarged or atrophic pancreas, cysts, calcifications, fibrosis and patchy focal necrosis. Microscopic histopathological analysis may show patchy focal disease characterized by a mononuclear infiltrate.

# Causes
TIGAR-O may be used for the etiologic classification of chronic pancreatitis. Toxic causes may include alcohol, tobacco smoking, hypercalcemia, hyperlipidemia, chronic renal failure, medications, and toxins. Genetic causes of chronic pancreatitis may include cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator gene (CFTR), calcium-sensing receptor (CASR), chymotrypsin C gene (CTRC) and pancreatic secretory trypsin inhibitor gene (SPINK1). Less common causes may include hypertriglyceridemia, scorpion sting, tropical pancreatitis and medications such as metronidazole, ercaptopurine, valproate, isoniazid and corticosteroids.

# Differentiating Chronic pancreatitis overview from Other Diseases
Chronic pancreatitis needs to be differentiated from other diseases presenting with similar complaints such as abdominal pain, diarrhea and weight loss.

# Epidemiology and Demographics
The incidence of chronic pancreatitis and the number of hospital admissions is increasing in most countries worldwide. The incidence of chronic pancreatitis is approximately 1.6 to 23 cases per 100,000 individuals per year worldwide. A rising level of per capita alcohol consumption is correlated with an increasing prevalence of chronic pancreatitis. Changes in lifestyle modifications such as smoking and alcohol cessation may result in slowing the progression and reducing the incidence of chronic pancreatitis. Alcoholic pancreatitis is more prevalent in developed or industrialized countries. Idiopathic and tropical pancreatitis is more prevalent in developing and underdeveloped countries.

# Risk Factors
The M-ANNHEIM multiple risk factor classification of chronic pancreatitis includes multiple risk factors, alcohol consumption, nicotine consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors, miscellaneous and rare metabolic factors. Common risk factors may include alcohol abuse, cigarette smoking, genetic mutations (PRSS1 mutations, SPINK1 mutations, CFTR mutations, and CTRC mutations), obstructive causes and hypercalcemia. Less common risk factors may include sphincter of Oddi dysfunction, hyperlipidemia, metabolic diseases such as branched-chain organic aciduria, and chronic renal failure.

# Screening
Patients with chronic pancreatitis should be screened for diabetes annually and should be followed up with fasting glucose and HbA1c levels.

# Natural History, Complications, and Prognosis
The natural history of pain is highly variable and mostly involves intermittent pain attacks that decrease or resolve over 5-25 years while a few patients may have chronic pain. The risk of progression of chronic pancreatitis to pancreatic cancer is approximately 4% at 20 years. Common complications usually include pseudocyst and mechanical obstruction of the duodenum and common bile duct. Less common complications may include pancreatic ascites, pleural effusion, pseudoaneurysm formation, and splenic vein thrombosis. Prognostic factors associated with chronic pancreatitis may include the age at diagnosis, smoking status, continued use of alcohol, and presence of liver cirrhosis. In chronic pancreatitis, the overall survival rate is 70% at 10 years and the 10-year mortality rate is 30%.

# Diagnosis

## Diagnostic study of choice:
The diagnostic study of choice for chronic pancreatitis is magnetic resonance cholangiopancreatography (MRCP). The diagnosis is difficult to establish as the laboratory results and the imaging may be normal. Diagnostic findings confirmatory for chronic pancreatitis may include pancreatic calcifications seen on abdominal plain films or CT scan, beaded appearance of main pancreatic duct seen on pancreatogram, abnormal pancreatogram showing ecstatic side branches from the main pancreatic duct and abnormal pancreatic function tests (Secretin test).

## Diagnostic criteria:
The M-ANNHEIM diagnostic criteria for chronic pancreatitis can be used to identify and differentiate various forms of chronic pancreatitis. M-ANNHEIM pancreatic imaging criteria for US, CT, MRI/MRCP, and EUS based on imaging features as defined by the Cambridge classification includes normal, equivocal, mild, moderate and marked changes.

## History and Symptoms:
Patients with chronic pancreatitis usually present with persistent abdominal pain with episodic flares that may or may not be associated with food intake steatorrhea, pancreatic diabetes, nausea, and weight loss. According to M-ANNHEIM clinical staging of chronic pancreatitis, it can be classified into asymptomatic and symptomatic chronic pancreatitis. M-ANNHEIM scoring system for the grading of clinical features of chronic pancreatitis include features such as pain control, surgical intervention, exocrine insufficiency, endocrine insufficiency, morphologic status on pancreatic imaging and severe organ complications.

## Physical Examination:
Patients with chronic pancreatitis may assume a characteristic position in an attempt to relieve their abdominal pain such as lying on the left side, flexing the spine, drawing the knees up toward the chest. Patients with steatorrhea or advanced disease may present as loss of subcutaneous fat, temporal wasting and sunken supraclavicular fossa. Skin findings may include jaundice, pallor, and bruises.

## Laboratory Findings:
The diagnosis of chronic pancreatitis is typically based on tests on pancreatic structure and function. Serum amylase and lipase are usually normal but may be slightly elevated. Serum calcium and triglyceride levels may be elevated in hypertriglyceridemia induced pancreatitis. A secretin stimulation test is considered the gold standard functional test for diagnosis of chronic pancreatitis. Fecal tests may include sudan staining of feces, 72-hour quantitative fecal fat (gold standard), and faecal elastase measurement (test of choice).

## Abdominal X-ray:
An x-ray may be helpful in the diagnosis of chronic pancreatitis. Finding on an x-ray suggestive of chronic pancreatitis includes pancreatic calcification.

## CT scan:
CT scan findings suggestive of chronic pancreatitis may include dilatation of the main pancreatic duct, calcifications, pancreatic gland enlargement, changes in pancreatic size, shape, contour, and pancreatic pseudocysts. Contrast enhanced CT scan may be helpful in ruling out other diseases with similar presentation such as malignancy and pseudocysts. The sensitivity of CT scan is 75 to 90 percent and specificity is 85 percent.

## MRI:
MRI findings for chronic pancreatitis may be classified as early and late findings. Early findings may include low-signal-intensity pancreas on T1-weighted fat-suppressed images, decreased and delayed enhancement after IV contrast administration and dilated side branches. Late findings may include parenchymal atrophy or enlargement, pseudocyst formation, dilatation and beading of the pancreatic duct with intraductal calcifications giving an appearance of 'chain of lakes'.

## Ultrasound:
Ultrasound findings suggestive of chronic pancreatitis may include dilatation of the main pancreatic duct, calcifications, pancreatic gland enlargement, changes in pancreatic size, shape, and contour, pancreatic pseudocysts, hyperechogenicity suggesting fibrotic changes, pseudoaneurysms and ascites. The sensitivity of ultrasound is 60 to 70 percent and the specificity of ultrasound is 80 to 90 percent. The pancreas might appear atrophic, calcified or fibrotic (advanced stages).

## Other imaging findings:
Other imaging findings may include MRCP, ERCP, and endoscopic ultrasonography. MRCP is the diagnostic study of choice. MRCP findings suggestive of chronic pancreatitis may include calcifications and pancreatic duct obstruction. ERCP findings diagnostic of chronic pancreatitis may include beaded appearance of the main pancreatic duct and ectatic side branches from the main pancreatic duct. Presence of stones is the most predictive finding seen on endoscopic ultrasonography. Other findings suggestive of chronic pancreatitis may include visible side branches, cysts, lobularity, an irregular main pancreatic duct, hyperechoic foci, dilation of the main pancreatic duct and hyperechoic margins of the main pancreatic duct. Pancreatic function tests may include direct tests such as secretin stimulation tests and indirect tests.

## Other diagnostic studies:
Other diagnostic studies may include genetic testing such as CFTR-cystic fibrosis gene mutation, SPINK-1, which encodes for trypsin inhibitor and PRSS-1 gene linked to hereditary pancreatitis. Routine genetic testing is usually not recommended for CFTR and SPINK-1 genes as it is expensive, do not alter the management and false positive results.

# Treatment

## Medical Therapy
The goals of chronic pancreatitis management include pain control, management of pancreatic insufficiency by pancreatic enzyme replacement and management of complications. Pain is managed in a stepwise approach of general recommendations, pancreatic enzyme replacement, analgesics and invasive procedures. General recommendations usually include smoking cessation, cessation of alcohol intake, small meals and hydration. Medical therapy includes pancreatic enzyme supplementation, analgesics and antioxidants. Specialized approaches include celiac nerve block, endoscopic therapy, extracorporeal shock wave lithotripsy (ESWL), and radiation. Steatorrhea can be managed by dietary modification, lipase supplementation, vitamin supplementation, and medium chain triglycerides (MCTs). Diabetes is usually managed with a trial of oral hypoglycemic agents followed by insulin therapy.

## Surgery
Surgery is usually considered when pain management fails with medical and endoscopic therapies. The goals of surgery include effective pain relief, and to preserve long-term pancreatic function. Surgery for chronic pancreatitis tends to be divided into two areas - resectional and drainage procedures. Dilated pancreatic duct may be managed with lateral pancreaticojejunostomy (LPJ) and lateralpancreaticojejunostomy with localized pancreatic head resection. Nondilated pancreatic duct is usually managed with pancreaticoduodenectomy, duodenal-preserving pancreatic head resection (DPPHR), distal pancreatectomy (DP) and total pancreatectomy (TP).

## Primary Prevention

## Secondary Prevention
Effective measures for the secondary prevention of Hereditary pancreatitis include low-fat diet, multiple small meals, good hydration, antioxidants and cessation/abstinence from smoking and alcohol use. Patients should be managed appropriately and timely with glucocorticoids and immunomodulatory drugs to prevent complications.