• 
  

  Disease summary:

  
  
  
  
  • 
    

    Pancreatitis is a syndrome of multiple etiologies with strong genetic influences. Genetic variants and environmental factors affect susceptibility to injury and modify the inflammatory response.

    
    
  • 
    

    Acute pancreatitis (AP) describes the clinical syndrome associated with sudden onset of pancreatic inflammation, usually associated with pancreatic injury. The majority of cases are caused by gallstones or alcohol withdrawal and multiple less-common etiologies. Approximately 20% of AP is idiopathic and/or genetic.

    
    
  • 
    

    Recurrent acute pancreatitis (RAP) describes a condition in which AP occurs more than once. The etiology of RAP is similar to AP, except for a lower incidence of treatable causes (eg, gallstones), and higher incidence of idiopathic etiologies.

    
    
  • 
    

    Chronic pancreatitis (CP) is a syndrome of pancreatic inflammation lasting over 6 months. Until recently, alcohol was considered to be the etiology in 70% to 90% of cases, but this has been disproven. There is no consensus on classification of subtypes, in part because of overlap of etiologies (eg, smoking and heavy chronic alcohol use). All of the known susceptibility genes for CP are linked to dysregulation of intrapancreatic trypsinogen. Unusual subsets of CP include autoimmune pancreatitis (~5%), and some rare congenital syndromes.

    
    
  • 
    

    Alcoholic pancreatitis (ACP) is pancreatitis associated with excessive alcohol ingestion, usually greater than 60 g per day. Smoking is common in alcohol drinking patients, and the effects of the two are likely synergistic. Genetic factors increase the risk of alcoholic pancreatitis (unpublished).

    
    
  • 
    

    Hereditary pancreatitis (HP) is an autosomal dominant disorder usually caused by mutations in the cationic trypsinogen gene (PRSS1) that begins with typical AP, RAP, and eventually CP. The high penetrance rate and early age of onset are useful in distinguishing HP from other forms of CP.

    
    
  • 
    

    CFTR-related pancreatitis is used to describe patients with CP that is linked to variant mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) but who do not meet diagnostic criteria for cystic fibrosis. Atypical CF (aCF) is a general term that covers the mild CF spectrum, including recurrent bronchitis, or lung infections with no pancreatic involvement. aCF includes late age of diagnosis and borderline or low sweat chloride levels (<60 mEq/L). Symptoms may be limited to the pancreas, but male infertility and chronic sinusitis are also common overlapping features. Complex genotypes with CFTR plus pancreatic secretory trypsin inhibitor gene (SPINK1) variants are common and associated with pancreatitis only.

    
    
  • 
    

    Autoimmune pancreatitis (AIP) is inflammation of the pancreas driven by immune dysregulation rather than pancreatic injury. It is often associated with elevated IgG4 level and may have a dramatic response to steroid treatment.

  
  
• 
  

  Differential diagnosis:

  
  
  
  
  • 
    

    Acute pancreatitis is usually suspected with sudden, severe abdominal pain. Differential diagnosis includes myocardial infarction, dissecting aortic aneurysm, mesenteric thrombosis and/or ischemia, volvulus, intussusceptions, penetrating gastric or duodenal ulcer, biliary colic and acute cholecystitis. The correct diagnosis is usually made by abdominal imaging and/or marked elevation of digestive enzymes in the blood.

    
    
  • 
    

    Chronic pancreatitis is diagnosed with different criteria by different groups. In more advanced cases evidence of chronic pancreatitis include pancreatic atrophy, distortion, dilated pancreatic ductal systems, calcifications, and fibrosis. Other common features are diabetes mellitus and various patterns and severity of pain. The differential diagnosis includes pain from nonpancreatic sources, vascular calcifications, pancreatic duct dilatation from other causes (eg, intraductal papillary mucinous neoplasm [IPMN]) pancreatic insufficiency syndromes, and pancreatic cancer.

  
  
• 
  

  Monogenic forms:

  
  
  
  
  • 
    

    Three different genes that cause typical AP and CP: PRSS1, CFTR, and SPINK1. Additional genes cause syndromes that affect the pancreas to various degrees.

  
  
• 
  

  Family history:

  
  
  
  
  • 
    

    HP is an autosomal dominant form of recurrent acute pancreatitis with strong family histories. Phenotypic penetrance is between 60% and 80%, with median age of onset at 10 years. About half of the affected subjects will develop chronic pancreatitis with both pancreatic exocrine and pancreatic endocrine failure. There is an increased risk of pancreatic cancer, calculated to be a 70-fold increase in relative risk in some families.

    
    
  • 
    

    Familial pancreatitis is used to describe families in which pancreatitis occurs at greater frequency than would expected in the general population by chance alone. Many families have been found to have genetic variants that cluster in complex ways.

  
  
• 
  

  Twin studies:

  
  
  
  
  • 
    

    Monozygotic twins with disease-causing PRSS1 mutations appear to have similar disease penetrance of 80%, but the age of onset of symptoms and severity of disease appear to be highly similar in twins compared to the variance among unrelated subjects.

  
  
• 
  

  Environmental factors:

  
  
  
  
  • 
    

    Alcohol and smoking are the most common and well established.

  
  
• 
  

  Genome-wide associations: First GWAS has been published. Whitcomb, D.C., et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nature genetics ePub.(2012).

  
  
• 
  

  Pharmacogenomics: None

Diagnostic Criteria for Acute Pancreatitis

Diagnostic evaluation should include at least two of the following:

• 
  

  History consistent with acute pancreatitis, focused on the context, timing, character and location of pain, and the differential diagnosis.

  
  
• 
  

  Serum amylase and lipase levels.

  
  
• 
  

  Computed tomographic (CT) scan with or without contrast demonstrating pancreatic inflammation, peripancreatic fluid collections, or fat stranding. For acute pancreatitis, CT is a secondary test used to make the diagnosis if there is clinical suspicion but the patient does not have pain or elevated amylase or lipase or to rule our other causes for the clinical symptoms or to evaluate complications. It should only be done after fluid resuscitation and with consideration of renal function.

Diagnostic Criteria for Chronic Pancreatitis

Diagnostic evaluation should include at least two of the following:

• 
  

  Symptoms lasting greater than 6 months.

  
  
• 
  

  Histology demonstrating chronic inflammation and irregular fibrosis with destruction and loss of exocrine parenchyma with an irregular and patchy distribution in the interlobular spaces; intralobular fibrosis alone is not specific for chronic pancreatitis.

  
  
• 
  

  CT scan demonstrating pancreatic structural abnormalities including any of the following: pancreatic ductal dilation, pancreatic parenchymal atrophy, pancreatic fibrosis, inflammatory mass, bile duct structure, pseudocysts, pancreatic calcifications, and absence of any evidence of pancreatic cancer or IPMN.

  
  
• 
  

  Pancreatic function test that demonstrates exocrine insufficiency: Tests include human fecal elastase-1, fecal chymotrypsin levels, elevated fecal fat (steatorrhea), decreased pancreatic bicarbonate levels coming from the pancreatic duct (requiring intubation of the duodenum), decreased serum trypsinogen levels.

  
  
• 
  

  Genetic testing includes the PRSS1, CFTR and the SPINK1, the chymotrypsin C gene (CTRC), and the calcium sensing receptor (CASR) with any of the above criteria. Genetic risk is not sufficient to make a diagnosis of chronic pancreatitis.

Diagnostic Criteria for Autoimmune Pancreatitis

Diagnostic evaluation should include at least two of the following:

• 
  

  Histology: AIP is distinguished from other forms of pancreatitis by periductal lymphoplasmacytic infiltrate, inflamed cellular stroma with storiform fibrosis, obliterative phlebitis, and granulocytic epithelial lesions (GEL). Two types of AIP have been defined: type 1 typically has abundant (>10 cells/hpf) IgG4-positive cells (see below) and type 2 has GEL.

  
  
• 
  

  Serum IgG4 greater than 2 × upper limits of normal. IgG4 levels may be normal or dramatically elevated. About 7% of pancreatic cancers have mildly elevated IgG4 levels.

  
  
• 
  

  Pancreatic imaging: Features that are highly suggestive of AIP include a diffusely enlarged gland with featureless borders and delayed enhancement with or without a capsule-like rim. Focal areas of enlargement of pancreatic tissue without other features of pancreatic cancer are also common in AIP but are only considered consistent with AIP.

  
  
• 
  

  Other organ involvement: AIP can be part of a systemic syndrome that includes involvement of the biliary tract, liver, salivary and lachrymal glands, kidneys, intestine or retroperitoneal fibrosis. There is also a common overlap with inflammatory bowel disease.

  
  
• 
  

  Response to corticosteroids: AIP typically has a dramatic improvement in signs and symptoms with corticosteroid treatment. Extrapancreatic systems should also improve.

Clinical Characteristics

Both acute and chronic pancreatitis are inflammatory syndrome definitions largely by clinical criteria. Acute pancreatitis can be subclinical or mild, with vague abdominal pain and/or nausea. More severe disease is reflected by increasing pain and evidence of local inflammation with leukocyte elevation and elevation of digestive enzymes in the blood. Over the first 24 to 48 hours a subset of patients progress to systemic inflammation, manifest as the systemic inflammatory response syndrome (SIRS), defined as two or more features of (1) temperature greater than 38°C or less than 36°C, (2) HR greater than 90 BPM, (3) RR greater than 20/min or PCO₂ less than 32 mm Hg, (4) WBC less than 4000 or greater than 12,000 or 10% bands (immature neutrophils). About half of these patients will develop persistent SIRS (>24 hours), develop a vascular leak syndrome, pulmonary edema (from vascular leak, not from fluid overload), and multiorgan failure. Early goal-oriented fluid resuscitation and early enteral feeding are the only therapy known to shorten the duration of SIRS and reduce organ failure.