Hereditary pancreatitis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]
Overview
In 1642, Johannes Wirsung of Padua first described the pancreatic duct and the concept of the pancreas as a secretory organ. In 1996, a gene for hereditary chronic pancreatitis was mapped to chromosome 7. Hereditary pancreatitis may be classified on the basis of mode of inheritance into autosomal dominant, autosomal recessive and hereditary pancreatitis with complex genetics. Hereditary pancreatitis is caused by genetic mutations in the regulatory regions present on trypsin. Mutations in PRSS1, SPINK1, CTRC, and CFTR gene result in weakening of defense mechanisms against pancreatitis. Defense mechanisms against pancreatitis include control of trypsin activity via prevention of premature activation of trypsinogen to trypsin and destruction, inhibition, or elimination of trypsin from the pancreas. Premature activation of digestive enzymes resulting in pancreatic injury, immune system activation, acute pancreatitis, and chronic pancreatitis. The incidence of hereditary pancreatitis is approximately 3.5–10 per 100,000 individuals in the USA. The median age at which the symptoms develop is 10 years. The symptoms of hereditary pancreatitis usually develop in the first or second decade of life. Patients with hereditary pancreatitis usually present with recurrent episodes of acute pancreatitis and may develop exocrine and endocrine insufficiency. If left untreated, patients with hereditary pancreatitis may progress to develop pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and pancreatic cancer. Mortality rate is found to be increased in patients who develop pancreatic cancer. There are no established criteria for the diagnosis of Hereditary pancreatitis but the diagnosis is usually made on the basis of clinical findings, a typical medical and family history, imaging methods, and pancreatic function tests. Pancreatic function tests include direct and indirect tests. Genetic testing is generally done for the following genes; PRSS1, CFTR, SPINK1 and CTRC. Contrast enhanced CT scan may be helpful in ruling out other diseases with similar presentation such as malignancy and pseudocysts. 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. The goals of management for hereditary pancreatitis 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. 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).
Historical Perspective
In 1642, Johannes Wirsung of Padua first described the pancreatic duct and the concept of the pancreas as a secretory organ. In 1952, Comfort and Steinberg were the first to identify a genetic background associated with hereditary pancreatitis and they found hereditary pancreatitis in six family members spanning 3 generations. In 1996, a gene for hereditary chronic pancreatitis was mapped to chromosome 7.
Classification
Hereditary pancreatitis may be classified on the basis of mode of inheritance into autosomal dominant, autosomal recessive and hereditary pancreatitis with complex genetics.
Pathophysiology
Hereditary pancreatitis is caused by genetic mutations in the regulatory regions present on trypsin. Mutations in PRSS1, SPINK1, CTRC, and CFTR gene result in weakening of defense mechanisms against pancreatitis. Defense mechanisms against pancreatitis include control of trypsin activity via prevention of premature activation of trypsinogen to trypsin and destruction, inhibition, or elimination of trypsin from the pancreas. Premature activation of digestive enzymes resulting in pancreatic injury, immune system activation, acute pancreatitis, and chronic pancreatitis. Hereditary pancreatitis may be associated with Shwachman-Diamond syndrome (SDS), Pearson marrow pancreas syndrome, CEL maturity-onset diabetes of the young (CEL-MODY) and Johanson-Blizzard syndrome. Gross examination may show enlarged or atrophic pancreas, Cysts, Calcifications and Fibrosis. On microscopic histopathological analysis, non-invasive dysplastic intraductal lesions, called pancreatic intraepithelial neoplasia (PanIN), may be noticed. Common risk factors in the development of Hereditary pancreatitis include smoking, alcohol consumption, lack of antioxidants, genetic mutations such as increased PRSS1 gene expression and CTRC gene mutations. Patients with hereditary pancreatitis should be screened for pancreatic cancer as they are at markedly increased risk of pancreatic cancer.
Causes
Hereditary pancreatitis may be caused by mutation in any one of the following genes PRSS1, SPINK1, CFTR and CTRC gene.
Differentiating Hereditary pancreatitis from Other Diseases
Hereditary 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 hereditary pancreatitis is approximately 3.5–10 per 100,000 individuals in Europe and the USA. In Western countries, the prevalence was found to be 0.3/100 000. Hereditary pancreatitis commonly affects younger age group. The median age at which first diagnosis is made is 19 years. The median age at which the symptoms develop is 10 years.
Risk Factors
Common risk factors in the development of Hereditary pancreatitis include smoking, alcohol consumption, lack of antioxidants, genetic mutations such as increased PRSS1 gene expression and CTRC gene mutations.
Screening
Patients with hereditary pancreatitis should be screened for pancreatic cancer as they are at markedly increased risk of pancreatic cancer.
Natural History, Complications, and Prognosis
The symptoms of hereditary pancreatitis usually develop in the first or second decade of life. Patients with hereditary pancreatitis usually present with recurrent episodes of acute pancreatitis and may develop exocrine and endocrine insufficiency. If left untreated, patients with hereditary pancreatitis may progress to develop pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and pancreatic cancer. Mortality rate is found to be increased in patients who develop pancreatic cancer.
Diagnosis
Diagnostic Criteria
There are no established criteria for the diagnosis of Hereditary pancreatitis but the diagnosis is usually made on the basis of clinical findings, a typical medical and family history, imaging methods, and pancreatic function tests.
History and Symptoms
Patients with hereditary pancreatitis usually have a positive family history of recurrent acute pancreatitis or chronic pancreatitis occurring in two first degree relatives or three or more second degree relatives, in two or more generations in the absence of precipitating factors after negative work-up for known chronic pancreatitis aetiology. The majority of patients with hereditary pancreatitis are asymptomatic. The most common presentation is recurrent acute pancreatitis.
Physical Examination
Patients with hereditary 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
Serum amylase and lipase are usually normal but may be slightly elevated (neither diagnostic nor prognostic). Serum bilirubin and alkaline phosphatase levels may be elevated in case of intra-pancreatic biliary duct obstruction. Fecal tests include Sudan staining of faeces, 72-hour quantitative fecal fat, and faecal elastase measurement. Pancreatic function tests include direct and indirect tests. Genetic testing is generally done for the following genes; PRSS1, CFTR, SPINK1 and CTRC.
Electrocardiogram
There are no ECG findings associated with Hereditary pancreatitis.
X-ray
Pancreatic calcification can often be seen on plain abdominal X-rays.
Ultrasound
Ultrasound findings suggestive of hereditary 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.
CT scan
Contrast enhanced CT scan may be helpful in ruling out other diseases with similar presentation such as malignancy and pseudocysts. 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. The sensitivity of CT scan is 75 to 90 percent and specificity is 85 percent.
MRI
MRI findings for hereditary 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'.
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
Genetic testing is generally done for the following genes PRSS1, SPINK1, CFTR and CTRC . Predictive testing is done only after expert genetic counseling and may be considered for patients who have a first-degree relative with a known PRSS1 mutation. Predictive testing is not done for patients below 16 yr age. Predictive testing is usually not recommended for patients with SPINK1 or CFTR mutations.
Treatment
Medical Therapy
The goals of management for hereditary pancreatitis 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
There are no established measures for the primary prevention of hereditary pancreatitis.
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.