Acute Pancreatitis

Epidemiology and Etiology

Epidemiology

• Incidence:
  • United States: 40–50 cases per 100,000 adults
  • Worldwide: 5–80 per 100,000 adults
• Men > women
  • Men: likely due to alcohol
  • Women: related to biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the "corners" of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract disease
• Mortality is approximately 5%, overall:
  • Necrotizing pancreatitis: 17%
  • Interstitial pancreatitis: 3%

Etiology

• Biliary tract disease: 
  • Approximately 40% of cases
  • Caused by biliary obstruction due to a stone
• Alcohol use:
  • Approximately 30% of cases
  • Often an exacerbation of chronic pancreatitis Chronic pancreatitis Chronic pancreatitis is due to persistent inflammation, fibrosis, and irreversible cell damage to the pancreas, resulting in a loss of endocrine and exocrine gland function. The most common etiologies are alcohol abuse and pancreatic duct obstruction. Patients often present with recurrent epigastric abdominal pain, nausea, and features of malabsorption syndrome (diarrhea, steatorrhea, and weight loss). Chronic Pancreatitis
  • Usually seen with habitual consumption over 5–15 years, but may be seen after a binge
• Endoscopic retrograde cholangiopancreatography (ERCP):
  • Can cause accidental lodging of stone into the sphincter of Oddi
  • Increased risk in sphincter of Oddi dysfunction
• Abdominal trauma:
  • More often in penetrating injuries
  • Blunt trauma may lead to ductal injury
• Drugs:
  • Azathioprine
  • Sulfonamides
  • Tetracycline
  • Valproic acid
  • Estrogens
  • Thiazide and loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics
  • Corticosteroids
  • Octreotide
  • Pentamidine
• Idiopathic: 
  • Approximately 10%–30% of cases
  • Occult microlithiasis may be responsible.
• Less common causes:
  • Infections: 
    • Mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps
    • Hepatitis
    • Cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus
    • Coxsackievirus Coxsackievirus Coxsackievirus is a member of a family of viruses called Picornaviridae and the genus Enterovirus. Coxsackieviruses are single-stranded, positive-sense RNA viruses, and are divided into coxsackie group A and B viruses. Both groups of viruses cause upper respiratory infections, rashes, aseptic meningitis, or encephalitis. Coxsackievirus
    • Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella
    • Parasites
  • Genetic predispositions (e.g., CFTR mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, as in cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis)
  • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
  • Hypertriglyceridemia
  • Tumors
  • Toxins: 
    • Organophosphates 
    • Scorpion bite
  • Vascular or ischemic
  • Autoimmune pancreatitis (IgG4)
  • Developmental:
    • Pancreatic ductus divisum: failure of the dorsal and ventral pancreatic ducts to fuse
    • Annular pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: a band of pancreatic tissue surrounds the 2nd part of the duodenum
    • Sphincter of Oddi dysfunction

Pathophysiology

Normal pancreatic function

• The pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas has endocrine ( insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin) and exocrine (digestive enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes) functions.
• Digestive enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes made in acinar cells → stored as zymogens (inactive form) → released in the pancreatic duct and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine → activation by trypsin
• Protective mechanisms against organ injury (autodigestion) include:
  • Negative feedback mechanism (↑ trypsin in duodenum → ↓ cholecystokinin (CCK) and secretin → ↓ pancreatic secretion)
  • Zymogens are controlled with protease inhibitors.
  • ↓ Acinar cell pH and calcium concentrations → prevent premature activation of trypsin
• Anything that disrupts the homeostasis of normal pancreatic function can cause acute pancreatitis.

Acute pancreatitis pathogenesis

1. Initiated through acinar cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death from:
   • Biliary obstruction → increased pancreatic duct pressure → acinar cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death
   • Direct injury (e.g., toxins, alcohol)
2. Changes in acinar cell pH and calcium concentrations → allows intrapancreatic activation of trypsin → activation of zymogens → autodigestion
3. Inhibited secretion on zymogens into the pancreatic ducts → exocytosis into the interstitium → not fully understood, but believed to lead to attraction of inflammatory cells
4. Inflammatory cells arrive → cytokine release → pancreatic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
5. Cytokine release and vascular injury from enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes → vasodilation and vascular permeability → fluid shifting to the interstitial space (3rd spacing) → decreased perfusion and hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension → can result in:
   • Shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock
   • Acute renal failure
   • Pancreatic necrosis

Clinical Presentation

Symptoms

• Acute abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain:
  • Epigastric
  • Dull and steady
  • Sudden onset, increasing in severity
  • Radiation to the back (approximately 50% of patients)
• Nausea and vomiting
• Anorexia
• Diarrhea
• Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever

Physical examination

• General:
  • Tachycardia
  • Abdominal tenderness
  • Abdominal distention
  • Diminished bowel sounds → ileus
• Evidence of severe disease:
  • Fever
  • Hypotension
  • Tachypnea and crackles
  • Pale and diaphoretic
• Signs of an underlying cause:
  • Hepatomegaly → alcoholic pancreatitis
  • Scleral icterus or jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice → choledocholithiasis
  • Muscle spasms → hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia
  • Xanthomas → hypertriglyceridemia
• Warning signs of retroperitoneal bleeding in severe, necrotizing pancreatitis:
  • Cullen’s sign: bluish discoloration around the umbilicus due to blood in the peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum
  • Grey-Turner’s sign: reddish-brown discoloration on the flanks due to blood in the retroperitoneum or pancreatic exudates

Management

Acute management

• Basic treatment:
  • Aggressive intravenous fluid ( IVF IVF Intravenous fluids (IVFs) are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids) resuscitation 
  • Fluid intake and output monitoring
  • Close vital sign monitoring
  • Address electrolyte imbalances
  • Medications:
    • Analgesics (typically opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics)
    • Antiemetics Antiemetics Antiemetics are medications used to treat and/or prevent nausea and vomiting. These drugs act on different target receptors. The main classes include benzodiazepines, corticosteroids, atypical antipsychotics, cannabinoids, and antagonists of the following receptors: serotonin, dopamine, and muscarinic and neurokinin receptors. Antiemetics
  • Initial bowel rest
  • Early nutritional support:
    • Can be started as early as 24 hours, if pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain is decreasing
    • Is associated with ↓ morbidity compared to delayed or no nutrition
• Mild acute pancreatitis:
  • Can be treated on a general medical ward
  • May begin low-residue, low-fat diet as soon as tolerated
• Severe acute pancreatitis:
  • Intensive care setting is preferred.
  • May require enteral nutrition if the patient cannot tolerate oral intake: Start within 72 hours.

Treating the etiology

• Gallstones
  • ERCP:
    • Can perform sphincterotomy and stone extraction
    • Indicated for choledocholithiasis or evidence of cholangitis
  • Cholecystectomy Cholecystectomy Cholecystectomy is a surgical procedure performed with the goal of resecting and extracting the gallbladder. It is one of the most common abdominal surgeries performed in the Western world. Cholecystectomy is performed for symptomatic cholelithiasis, cholecystitis, gallbladder polyps > 0.5 cm, porcelain gallbladder, choledocholithiasis and gallstone pancreatitis, and rarely, for gallbladder cancer. Cholecystectomy: Approaches and Technique:
    • Surgical removal of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
    • Performed after recovery from pancreatitis
• Hypertriglyceridemia:
  • Goal triglyceride level is < 500 mg/dL.
  • Intravenous (IV) insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin:
    • Requires close glucose monitoring
    • May need a concurrent dextrose infusion to prevent hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia 
  • Apheresis:
    • Should be considered in patients with SIRS, hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, and multi-organ dysfunction
    • May not be available at all hospitals
• Alcohol:
  • Patient education
  • Abstinence

Differential Diagnosis

• Acute cholecystitis Cholecystitis Cholecystitis is the inflammation of the gallbladder (GB) usually caused by the obstruction of the cystic duct (acute cholecystitis). Mechanical irritation by gallstones can also produce chronic GB inflammation. Cholecystitis is one of the most common complications of cholelithiasis but inflammation without gallstones can occur in a minority of patients. Cholecystitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract resulting from sustained gallstone impaction of the cystic duct. Patients present with colicky, upper abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, nausea, and vomiting. Inflammation of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract and gallstones are seen on US or CT. Amylase and lipase are usually not elevated, which differentiates acute cholecystitis Cholecystitis Cholecystitis is the inflammation of the gallbladder (GB) usually caused by the obstruction of the cystic duct (acute cholecystitis). Mechanical irritation by gallstones can also produce chronic GB inflammation. Cholecystitis is one of the most common complications of cholelithiasis but inflammation without gallstones can occur in a minority of patients. Cholecystitis from acute pancreatitis. Treatment includes IVF IVF Intravenous fluids (IVFs) are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids, antibiotics, and cholecystectomy. 
• Perforated peptic ulcer disease Peptic ulcer disease Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease: complete erosion of an ulcer through the wall of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach or duodenum. Patients present with severe epigastric pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, tachycardia, and abdominal rigidity. Lipase and amylase may be elevated, but not to the degree seen in acute pancreatitis. Diagnosis relies on imaging, which will show extraluminal gas. Patients require antibiotics and emergency surgery for repair. 
• Acute mesenteric ischemia Mesenteric Ischemia Mesenteric ischemia is a rare, life-threatening condition caused by inadequate blood flow through the mesenteric vessels, which results in ischemia and necrosis of the intestinal wall. Mesenteric ischemia can be either acute or chronic. Mesenteric Ischemia: tissue injury caused when perfusion fails to meet the demands of the intestines, usually due to an embolism or thrombosis. Patients have periumbilical pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain out of proportion to the exam. Computed tomography with angiography is used to detect vessel stenosis or occlusion. Lipase can be elevated, but not to the degree seen in acute pancreatitis. Acute ischemia requires revascularization and resection of the infarcted bowel.
• Pancreatic cancer: a neoplasm of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas. Symptom onset is more insidious, and patients may have unrelenting epigastric pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, weight loss, and jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice. The diagnosis is confirmed with imaging. The history, exam, and imaging will differentiate pancreatic cancer from acute pancreatitis. Treatment is usually aggressive because tumors are usually found late, and includes chemotherapy, radiation, and surgery. Prognosis for survival is generally poor.