Acute pancreatitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Dutch physician and anatomist, Nicholaes Tulp, gave the first clear description of acute pancreatitis in 1652. The first systemic analysis of acute pancreatitis was presented by Reginald Huber Fitz in 1889. During the 20th century, there were many theories about whether surgery should be the preferred initial approach to the treatment of acute pancreatitis. Hans Chiari in 1896 proposed that the basic mechanism of the disease was autodigestion of pancreas. The father of modern anatomical pathology, Giovanni Battista Morgagni, gave the first description of pancreatic pseudocysts.

The historical landmarks in the diagnostic evaluation and management of acute pancreatitis are as follows:^{[1] [2]}

• In the 16th century, Sylvius Franciscus de la Boe Sylvius found that the pancreas discharged a fluid that mixed with the partly digested food and bile in the intestine causing an effervescence (“effervescentia intestinalis”) which liquefied food.
• In the 16th century, Regnier de Graaf of Delft devised novel surgical techniques to create pancreatic fistulas (center) to collect this juice for analysis.
• In 1642, Johannes Wirsung of Padua first described the pancreatic duct and the concept of the pancreas as a secretory organ.
• In 1652, Nicholaes Tulp of Amsterdam is credited with the first description of acute pancreatitis.
• In 1737, Giovanni Santorini of Venice identified a second, accessory duct and was credited with primacy in the discovery of the ampulla of Vater.
• In 1761, Giovanni Morgagni described the clinical syndrome of severe upper abdominal pain, vomiting, and collapse (acute pancreatitis). He is also credited with the earliest pathological recognition of cancer of the pancreas.
• In 1842, Karl von Rokitansky, the premier pathologist of Vienna (Wiener Allgemeines Krankenhaus) was the first one to recognize acute hemorrhagic pancreatitis.
• In 1887, Rugero Oddi published his observations of the structure and function of the choledochal sphincter in Archives Italiennes de Biologie that laid the basis for understanding its role in pancreatic and biliary disease.
• In late 18th century, Reginald Fitz described 3 forms of acute pancreatitis (hemorrhagic, suppurative, and gangrenous) and proposed that fat necrosis was a sequel of severe pancreatitis
• In late 18th century, Nicholas Senn of Chicago, not only addressed the mechanisms of acute pancreatitis but also provided rational insight into the validity of surgical techniques for its treatment.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Acute pancreatitis may be classified according to the severity of the disease into 2 subtypes: mild (interstitial or edematous) and severe (necrotizing or organ failure) pancreatitis.

The definitions of severity in acute pancreatitis according to the revised Atlanta classification are as follows:^[1]

The revised Atlanta classification for acute pancreatitis classifies it as:^{[2][3][4][5][6][7][8][9]}

• Mild pancreatitis (interstitial or edematous): inflammation of parenchyma of pancreas without local or systemic complications.
• Severe pancreatitis (necrotizing or organ failure): severe pancreatitis causing local and systemic manifestations.^[10]

Acute pancreatitis is further distinguished clinically into:

• Early phase (1st week).
• Late phase (after the 1st week).

• Interstitial Edematous Pancreatitis

▸ Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but without recognizable tissue necrosis

CECT criteria

▸ Pancreatic parenchyma enhancement by intravenous contrast agent.

▸ No findings of peripancreatic necrosis.

• Necrotizing Pancreatitis

▸ Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis

CECT criteria

▸ Lack of pancreatic parenchymal enhancement by intravenous contrast agent

▸ Presence of of peripancreatic necrosis.

• Infected Pancreatic Necrosis:

▸ It should be considered in patients with necrotizing pancreatitis who deteriorate or fail to improve after 7–10 days of hospitalization.^[1]

▸ It may be presumed by the presence of extraluminal gas on CECT or when fine-needle aspiration is positive for bacteria and/or fungi on Gram stain and culture.^[11]

▸ Antibiotics are able to penetrate pancreatic necrosis (such as carbapenems, quinolones, and metronidazole) and may be useful in delaying or completely avoiding intervention.^[12][13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]

Acute pancreatitis may be either idiopathic or caused by alcohol, gallstones, trauma, steroids, mumps, autoimmune diseases, ERCP, hypercalcemia, hyperlipidemia, hypertriglyceridemia or certain medications. Gallstones are the most common cause of acute pancreatitis, followed by chronic alcohol consumption (4-5 drinks daily for ~5 years). There are numerous primary and secondary causes of acute pancreatitis that must be considered in a patient’s work up.

Gallstones are the most common cause of acute pancreatitis, followed by chronic alcohol consumption (4-5 drinks daily for ~5 years).^[1] However; there are numerous primary and secondary causes of acute pancreatitis that must be considered in a patient’s work up.^[2]

The following table summarizes the most common causes of acute pancreatitis:^[3]

Sphincter of Oddi dysfunction and pancreas divisium have been traditionally associated with the development of acute pancreatitis; however, recent data suggests otherwise.^[4] Pancreas divisium has been associated with genetic mutations that may be the true underlying cause of pancreatitis. Alternatively, the presence of the abnormal anatomy alone may not predispose patients to acute pancreatitis; however, in lieu of a genetic mutation may superimpose on the existing anatomical variation to contribute in the pathogenesis of acute pancreatitis.^[5][6]

Chronic alcoholism and smoking have been associated with the development of acute pancreatitis. Though alcohol has been proposed to be pathogenic in combination with the presence of an underlying genetic mutation. Alcoholism causing pancreatitis is more common in males than females. This may be due to the propensity of males to consume alcohol more than females, or due to the genetic mutations occurring more commonly in males.^[7][8]

Common iatrogenic causes of pancreatitis include ERCP procedures as well as use of medication. Hundreds of medications have been implicated in causing pancreatitis; however, the most common drugs include:^[9][10]

• Steroid use
• Azathioprine
• 6-Mercaptopurine
• Didanosine
• Valproic acid
• Angiotensin Converting Enzyme inhibitors (ACEi)
• Mesalamine

It is extremely difficult to identify a particular drug which may be responsible for the development of pancreatitis as there are usually multiple possibilities to the underlying etiology of the pancreatitis in patients with comorbidities; however, patients hospitalized for acute pancreatitis are often found to be using one or more drugs associated with the development of the disease.^[11][12]

Several genes have been proposed to play a role in the pathogenesis of acute pancreatitis. While the exact role of every implicated genetic mutation is not fully understood, the following genes have been associated with the development of acute pancreatitis:^[13][14]

• CFTR
• PRSS-1
• SPINK-1
• Chymotrypsin C
• Claudin-2
• Calcium sensing receptors

A common mnemonic for the causes of pancreatitis spells “I get smashed”, an allusion to heavy drinking (one of the many causes):

• I – idiopathic
• G – gallstone. Gallstones that travel down the common bile duct and which subsequently get stuck in the ampulla of vater can cause obstruction in the outflow of pancreatic juices from the pancreas into the duodenum. The back-flow of these digestive juices causes lysis (dissolving) of pancreatic cells and subsequent pancreatitis.
• E – ethanol (alcohol) – Alcohol has been proposed to cause acute pancreatitis in combination with genetic factors. It is more commonly a cause in males than females. This may be due to the propensity of males to chronically abuse alcohol, or by genetic factors more commonly present in males.
• T – trauma
• S – steroids – Commonly used in patients with autoimmune diseases. Type I presents with obstructive jaundice and elevated IgG4 levels. Type II presents in younger patients with no increase in IgG4 levels.
• M – mumps (paramyxovirus) and other viruses (Epstein-Barr virus, Cytomegalovirus)
• A – autoimmune disease (Polyarteritis nodosa, Systemic lupus erythematosus)
• S – scorpion sting – Tityus Trinitatis – Trinidad/ snake bite
• H – hypercalcemia, hyperlipidemia/hypertriglyceridemia and hypothermia
• E – ERCP (Endoscopic Retrograde Cholangio-Pancreatography – a procedure that combines endoscopy and fluoroscopy)
• D – drugs (SAND – steroids & sulfonamides, azathioprine, NSAIDS, diuretics such as furosemide and thiazides, & didanosine) and duodenal ulcers. Drugs often present with mild pancreatitis and rarely are associated with signs of drug allergy such as rash.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]; Iqra Qamar M.D.[4]

Acute pancreatitis must be differentiated from gallstones, pancreatic cysts, pancreatic pseudocysts, and chronic pancreatitis.

The following table outlines the major differential diagnoses of abdominal pain.

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram, US = Ultrasound

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]

The annual incidence of acute pancreatitis in the U.S. is 18 to 49 per 100,000 population. In several European studies, the incidence of acute pancreatitis is reported at 12.4 to 31.2 per 100,000. A consistent increase in the incidence of pancreatitis has been reported in different geographical regions. Acute pancreatitis commonly affects adults of all ages. As of late, there is a significant increase in incidence among hospitalized children and has been reported as high as 3.5 per 100,000 hospitalized children.

The incidence of acute pancreatitis is variable and fluctuates between 12.4 to 31.2 per 100,000 depending on the population and time period studied. More importantly, there is a consistent trend of increasing incidence across different studies.^{[1][2] [3][4][5]}

A UK study reports increased incidence from the mid-1990s to 2013, in both males and females from ~14.5 to ~30 per 100,000. ^[6]

The reason for this increased incidence is not well understood with some reporting an increase in alcoholic pancreatitis, while others reporting a decrease in this etiology. An increase in gallstone and gallbladder associated conditions has been reported.

The mortality associated with acute pancreatitis has decreased significantly over the years with improvements in medical care. Currently the mortality is about ~2%. This figure increases depending on the subgroup studied. Subgroups associated with a higher mortality include the elderly, the morbidly obese, and patients who acquire hospital infections. Mortality has been reported as high as 30% in some patient groups.^[7][8][5]

Acute pancreatitis commonly affects adults of all ages. As of late, there is a significant increase in incidence among hospitalized children and has been reported as high as 3.5 per 100,000 hospitalized children.^[9][5]

Acute pancreatitis affects both men and women. Most studies report a slightly higher incidence in men than women.^[5]

Blacks carry a 2-3 fold risk of developing pancreatitis than other races ^[3][4][5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]

The most potent risk factor in the development of acute pancreatitis is alcoholism. Other common risk factors include diabetes mellitus, morbid obesity, abdominal trauma, family history, hypertriglyceridemia, cystic fibrosis, renal failure, SLE, and certain medications.

Risk factors for acute pancreatitis include:^[1][2][3]

• Abdominal injury
• Alcoholism
• Cystic fibrosis
• Diabetes mellitus
• Morbid obesity
• Family history of pancreatitis
• Hypertriglyceridemia – high triglycerides
• Family history of Hypertriglyceridemia
• Renal failure
• SLE
• Drugs
• Male gender

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: ; Tarek Nafee, M.D. [2]

There is no established screening recommendations for pancreatitis in the general population.

There is no established screening recommendations for pancreatitis in the general population.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]

Pancreatitis can be mild or severe, and the natural history will depend on the severity of the condition, and the timeliness of intervention. Acute pancreatitis can result in complications such as hemorrhagic pancreatitis, multisystem organ failure, infection, SIRS, ARDS, hyperglycemia, hypocalcemia, shock, hemorrhage, thrombosis, common bile duct obstruction, and the development of chronic pancreatitis. In predicting the prognosis, there are several scoring indices that have been used as predictors of survival. ^[1] These scoring systems combine radiographic, laboratory, and clinical findings in an attempt to predict prognosis. Some of these include the Ranson criteria, APACHE II, APACHE-O (APACHE with Obesity), Glasgow score, HAPS, PANC-3, JSS, POP, and BISAP. These scoring systems are extremely cumbersome to use and are associated with a high false positive rate. While imaging studies are a vital component of patient work-up and follow-up, they often lack the clinical presentation. None of the scoring systems are able to replace an experienced, attentive physician’s ongoing clinical assessment of the patient.

Acute pancreatitis can be further divided in mild and severe pancreatitis. Mostly the Atlanta classification (1992) is used. In severe pancreatitis a serious amount of necrosis determine the further clinical outcome. About 20% of the acute pancreatitis are severe with a mortality of about 20%. This is an important classification as severe pancreatitis will need intensive care therapy whereas mild pancreatitis can be treated on the common ward.^[2][3]

There are several ways to help distinguish between these two forms. One is the above mentioned Ranson Score.

Determinants of the natural course of acute pancreatitis are:

• Multisystem organ failure,
• Pancreatic parenchymal necrosis,
• Extrapancreatic retroperitoneal fatty tissue necrosis,
• Biologically active compounds in pancreatic ascites,
• Infection after necrosis,
• Clinical factors, including age and obesity.

Early in the course of acute pancreatitis, multiple organ failure is the consequence of various inflammatory mediators that are released from the inflammatory process and from activated leukocytes attracted by pancreatic injury, the so-called systemic inflammatory response syndrome (SIRS). SIRS is the cause of bacterial (gram negative) translocation from the patients colon. Local and systemic septic complications, when they occur, typically do so at least a week after presentation.

Complications can be systemic or locoregional.

• Systemic complications include:

• ARDS (Acute respiratory distress syndrome)
• Pleural effusion
• Atelectasis
• Mediastinal fluid
• Pneumonitis
• Hypotension
• Hypovolemia
• Nonspecific ST-T changes in electrocardiogram simulating myocardial infarction
• Pericardial effusion
• Peptic ulcer disease
• Erosive gastritis
• Hemorrhagic pancreatic necrosis with erosion into major blood vessels
• Oliguria (<300 mL/d)
• Azotemia
• Renal artery and/or renal vein thrombosis
• Acute tubular necrosis
• Multiple organ dysfunction syndrome
• DIC
• Exacerbation of COPD
• Exacerbation of CHF
• Exacerbation of Hepatitis
• Hypocalcemia (from fat saponification)
• Hyperglycemia
• Hypertriglyceridemia
• Sudden blindness (Purtscher’s retinopathy)
• Psychosis
• Fat emboli
• Insulin dependent diabetes mellitus (from pancreatic insulin producing beta cell damage)
• Shock

• Locoregional complications include:
  • Pancreatic pseudocyst or walled off pancreatic necrosis
  • Phlegmon / abscess formation,
  • Splenic artery pseudoaneurysm
  • Hemorrhage from erosions into splenic artery and vein
  • Thrombosis of the splenic vein, superior mesenteric vein and portal veins (in descending order of frequency)
  • Duodenal obstruction
  • Common bile duct obstruction
  • Progression to chronic pancreatitis
  • Pancreatic enteric fistula
  • Bowel infarction
  • Obstructive jaundice
  • Disruption of main pancreatic duct or secondary branches
  • Pancreatic ascites

According to the American College of Gastroenterology, the following are the guidelines for initial assessment and risk stratification for acute pancreatitis:^{[4][5][6][7][8][9][10][11][12][13][14][15][16]}

In predicting the prognosis, there are several scoring indices that have been used as predictors of survival. ^[1] These scoring systems combine radiographic, laboratory, and clinical findings in an attempt to predict prognosis. Some of these include the Ranson criteria, APACHE II, APACHE-O (APACHE with Obesity), Glasgow score, HAPS, PANC-3, JSS, POP, and BISAP. These scoring systems are extremely cumbersome to use and are associated with a high false positive rate. While imaging studies are vital component of patient work-up and follow-up, they often lack the clinical presentation. ^[17]

None of the scoring systems are able to replace an experienced, attentive clinicians assessment of the patient. In general, prognostic factors may be classified as follows:^{[5][18][1][19][20][21][4][22][17]}

Cross-sectional imaging should be utilized in assessing the progression of the complications, though imaging findings may lack the clinical presentation:

Severity scoring systems can be cumbersome to utilize and no single system has been established as a gold standard. Nevertheless, clinicians may find utility in using the following scoring systems, in conjunction with serial CT scans, and regular and thorough clinical assessments of the patient.^{[5][18][1][19][20][21][4][22][17]}

“Acute Physiology And Chronic Health Evaluation” (APACHE II) score > 8 points predicts 11% to 18% mortality ^[23] Online calculator

• Hemorrhagic peritoneal fluid
• Obesity
• Indicators of organ failure
• Hypotension (SBP <90 mmHG) or tachycardia > 130 beat/min
• PO₂ <60 mmHg
• Oliguria (<50 mL/h) or increasing BUN and creatinine
• Serum calcium < 1.90 mmol/L (<8.0 mg/dL) or serum albumin <33 g/L (<3.2.g/dL)>

The death rate is high with:

• Hemorrhagic pancreatitis
• Liver, heart, or kidney impairment
• Necrotizing pancreatitis

The APACHE score has been combined with a higher weight given to Obesity, in what is now defined as the APACHE-O score.

The Glasgow criteria is valid for both gallstone and alcohol induced pancreatitis. If a patient scores 3 or more, it indicates severe pancreatitis and the patient should be transferred to ITU.

• PaO2 <8kPa
• Age >55 years old
• Neutrophilia – WCC >15×10(9)/L
• Serum calcium <2mmol/L
• Renal function, Urea >16mmol/L
• LDH >600iu/L; AST >200iu/L
• Albumin <32g/L (serum)
• Blood glucose >10mmol/L

Bedside index for severity in acute pancreatitis (BISAP), has been proposed as an accurate method for early identification of patients at risk for in-hospital mortality. Criteria used in this score are as follows:

• Blood urea nitrogen – >25
• Impaired mental status
• Systemic inflammatory response syndrome(SIRS) – (>/= 2 criteria)
• Age – >60 yrs
• Pleural effusion on CT

Scoring system:

The advantages of BISAP score over other scoring systems are:

• Accuracy
• Simple
• Easy to obtain
• Prognostic efficacy similar to other scoring systems

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