Hypertriglyceridemia (HTG) is a disorder where a patient's serum triglyceride level is greater than 150 mg/dL (normal, less than 150 mg/dL).1 In the US, about 200,000 hospital admissions annually are due to acute pancreatitis, and this figure has been increasing.2 HTG is an important cause of acute pancreatitis and hypertriglyceridemia-induced pancreatitis (HTGP) occurs in 1% to 14% of patients diagnosed with acute pancreatitis.3,4 The risk of developing pancreatitis significantly increases when triglyceride levels are above 200 mg/dL.5
Both primary (genetic) and secondary disorders of lipoprotein metabolism are associated with HTGP. Primary disorders include type I dyslipidemia, also known as familial chylomicronemia. Secondary disorders include poorly controlled diabetes mellitus (types 1 and 2) and diabetic ketoacidosis.4
Pancreatitis is an inflammation of the pancreas. In pancreatitis, intra-acinar activation of pancreatic enzymes (including trypsin, phospholipase A2, and elastase) can lead to autodigestion of the pancreas.6 These pancreatic enzymes damage tissue and activate the complement system and inflammatory cascade resulting in cytokine production, edema, inflammation, and sometimes necrosis. Injury occurs to the pancreatic cells with subsequent activation of the trypsinogen inside of the pancreas instead of in the duodenum; trypsinogen is then activated to trypsin by enterokinase. Normally, trypsin inhibitors in the pancreas inactivate the trypsin produced, but this fails to occur in an individual with pancreatitis, as digestive enzymes are secreted improperly leading to inflammation and autodigestion of the pancreas.6
The literature states that the processes leading to pancreatitis are not clear; however, pancreatitis is believed to be related to the discharge of excess free fatty acids and lysolecithin from the chylomicrons.5 This surpasses the attachment capacity of albumin in pancreatic capillaries. The unbound free fatty acids are presumed to form micellar structures with detergent properties, causing injury and ischemia, resulting in pancreatitis. There is also backflow of bile acids into the pancreatic ducts through a malfunctioning sphincter of Oddi.5,6 Ischemia occurs in the pancreas where the ducts are obstructed. Ischemia, along with gut barrier compromise, allows bacteria to enter the bloodstream, which increases the risk of infection.6 Patients with severe pancreatitis are at high risk for developing pancreatic necrosis, organ failure, and sepsis. Circulating triglycerides are broken down into toxic free fatty acids by pancreatic lipases, which causes lipotoxicity seen in acute pancreatitis.1 The severity of acute pancreatitis is dependent on the inflammatory response from pancreatitis and injury caused by lipotoxicity from the breakdown of triglycerides. The higher the triglyceride level, the more severe the disease.6
The risk of pancreatitis significantly increases with triglyceride levels above 200 mg/dL. HTG should be considered the underlying cause of pancreatitis when the serum triglyceride level is greater than 1,000 mg/dL.2 Risk factors for HTGP include poorly controlled diabetes, alcoholism, obesity, pregnancy, prior pancreatitis, and a personal or family history of HTG. HTG is classified based on the degree of triglyceride elevation. (See HTG classifications.)
Abdominal pain is often located in the left upper quadrant, or in the midepigastrium and may radiate to the back because of the retroperitoneal location of the pancreas. The pain is described as severe, deep, piercing, aggravated by eating, and can occur when lying in the recumbent position.6
Other signs and symptoms include nausea, vomiting, low-grade fever, tachycardia, abdominal tenderness/guarding, and hypoactive bowel sounds.6 The abdominal distension and hypoactive bowel sounds may occur due to an ileus and secondary inflammation.7
A patient with severe pancreatitis can also present with mental status changes, fever, tachypnea, hypoxemia, and hypotension.7 In 3% of patients with acute pancreatitis, ecchymosis may be present in the periumbilical region (Cullen sign) or along the flank (Grey Turner sign). These findings, although nonspecific, suggest the presence of retroperitoneal bleeding in the setting of pancreatic necrosis.7
HTGP should be suspected in patients with acute pancreatitis and risk factors for HTG. A serum triglyceride level >1,000 mg/dL is necessary to consider HTG as the underlying etiology of acute pancreatitis.4
The primary diagnostic studies for acute pancreatitis are serum lipase and amylase levels.6 Serum lipase rises within 4 to 8 hours of the onset of symptoms, peaks at 24 hours, and returns to normal within 8 to 14 days.7 Serum amylase rises within 6 to 12 hours of the onset of acute pancreatitis. Amylase has a shorter half-life of approximately 10 hours and in uncomplicated pancreatitis returns to normal within 3 to 5 days.7
Patients with pancreatitis may have leukocytosis and an elevated hematocrit from hemoconcentration attributable to extravasation of intravascular fluid into third spaces. Metabolic abnormalities include elevated blood urea nitrogen and hypocalcemia. Acute pancreatitis is associated with elevations in C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor, and polymorphonuclear elastase. A CRP level above 150 mg/L (normal, 0 to 2 mg/L) at 48 hours is associated with severe pancreatitis.7
The diagnosis of acute pancreatitis in patients with HTG is the same as other etiologies of acute pancreatitis but requires the presence of two of the following three criteria: acute onset of persistent, severe, epigastric pain often radiating to the back, elevation in serum lipase or amylase to three times or greater than the upper limit of normal, and characteristic findings of acute pancreatitis on imaging study (such as contrast-enhanced computed tomography [CT], magnetic resonance imaging, or transabdominal ultrasonography).4
In most patients with acute pancreatitis, the disease is mild in severity and patients recover in 3 to 5 days without complications or organ failure. However, 20% of patients have moderately severe or severe acute pancreatitis with local or systemic complications or organ failure.7 (See Local complications.) Recognizing and preventing these complications can improve the outcome for patients with acute pancreatitis.
When a patient presents with HTGP, early management by treating the acute pancreatitis and bringing the serum triglyceride levels to lower than 500 mg/dL is priority.1 With acute pancreatitis, an assessment of the initial severity of pancreatitis should be made. This includes the assessment for evidence of organ failure, particularly, respiratory, cardiovascular, or renal compromise. There are several scoring systems that can be used to predict the severity of acute pancreatitis. Ranson's criteria consist of 11 parameters. Five parameters are assessed on admission, and the other six are assessed 48 hours after admission. One point is given for each positive parameter for a maximum score of 11. Mortality increases with an increasing score. (See Ranson's criteria.)
In patients with HTGP, it is important to monitor for signs of hypocalcemia, lactic acidosis, signs of worsening systemic inflammation or organ dysfunction, or multiorgan failure in patients with a serum triglyceride level higher than 1,000 mg/dL and a lipase level more than three times the upper limit of normal value.1 If the preceding signs are present, treatment with apheresis, explicitly, therapeutic plasma exchange should be initiated. Check triglyceride levels when beginning apheresis; apheresis should be discontinued when the triglyceride levels are below 500 mg/dL.
When patients present with worrisome features (hypocalcemia, lactic acidosis, or worsening systemic inflammation), start an I.V. infusion of regular insulin as prescribed. If the blood glucose level is 150 to 200 mg/dL, administer an I.V. glucose infusion (5% dextrose) as prescribed, with hourly checks of serum glucose. The dextrose and insulin infusions are titrated depending on the serum glucose level. Monitor serum triglyceride levels every 12 hours. Insulin should be discontinued when triglyceride levels are lower than 500 mg/dL.
In patients with HTGP, as soon as the triglyceride levels are lower than 500 mg/dL, pursue long-term treatment goals to prevent pancreatitis relapse and HTG complications. Long-term treatment is defined by pharmacologic therapy (for example, gemfibrozil) and dietary modifications such as restriction of fat and simple carbohydrates. Educate the patient on the importance of committing to nonpharmacologic interventions such as weight loss if obese, aerobic exercise, avoidance of concentrated sugars and medications that raise serum triglyceride levels, and strict glycemic control in patients with diabetes.1
Mr. H, a 35-year-old, White male with a history of hypertension and HTG presented to a rural hospital ED after developing an acute onset of persistent, severe epigastric pain associated with nausea and vomiting. Mr. H rates his abdominal pain intensity as a 6 out of 10 (0 = no pain, 10 = worst pain). His medications include gemfibrozil, a lipid-regulating agent that decreases serum triglycerides and very low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol.9 He states he frequently forgets to take it as prescribed.
Vital signs were temperature 97.7°F, pulse 77 beats/minute, respirations 18 breaths/minute, BP 161/88 mm Hg, oxygen saturation 97% on room air, and body mass index of 37.2 (obese; normal, 18.5-24.9).6,10
Physical assessment findings included a distended abdomen with hypoactive bowel sounds and tenderness to light palpation. No rebound tenderness or guarding was noted.
Mr. H's lab results were within normal limits, with the exception of:
- serum triglycerides of 8,300 mg/dL (See Serum triglyceride levels.)
- fasting plasma glucose of 250 mg/dL (normal, 70-80 mg/dL)11
- A1C of 10.8% (normal, 4%-5.6%)11
- corrected calcium of 6.7 mg/dL (normal, 8.5-10.2 mg/dL)11
- lipase of 218 U/L (normal, 0-160 U/L)11
- amylase (not measured). Lipase levels are more specific to the pancreas than amylase. Because lipase is elevated for a longer time than amylase, it provides a larger diagnostic window.12 Evidence-based guidelines recommend the use of lipase over amylase.
Imaging studies included CT of the abdomen that confirmed acute pancreatitis of the pancreatic head. Based on Mr. H's history and clinical presentation, he was diagnosed with HTGP and type 2 diabetes mellitus (T2DM). Management in the ED included N.P.O. status, adequate fluid resuscitation, antiemetics, and analgesics.
Mr. H had a Ranson score of four points, which is associated with a 15% mortality.7 He was admitted to the CCU for continued observation and management.
While in the CCU, Mr. H was managed by an intensivist and a gastroenterologist. Mr. H's management included treating the acute pancreatitis and reducing the serum triglyceride level with the goal of preventing necrotizing pancreatitis and organ failure.4
In the CCU, aggressive fluid resuscitation was continued. Central venous pressure monitoring was used to guide adequate fluid replacement along with accurate intake and output.
It is important to rest the pancreas by suppressing pancreatic enzymes.6 Mr. H was placed on N.P.O. status; a nasogastric tube was inserted and attached to low intermitted wall suction, which helped reduce gastric distension and vomiting, and prevent contents from entering the duodenum.
In order to lower the high triglyceride level rapidly, discussions focused on the use of apheresis or an insulin infusion, both of which have been used successfully in HTGP management.10
The efficacy of these two treatment modalities are supported by randomized trials.1 The approach to the decision on these two modalities of treatment is based on severity of acute pancreatitis and worrisome clinical features including: signs of hypocalcemia, lactic acidosis, two or more signs of worsening systemic inflammation, temperature >38.5°C or <35.0°C, heart rate >90 beats/minute, respiratory rate of >20 breaths/minute or PaCO2 of <32 mm Hg, white blood cell count >12,000 cells/mL, <4,000 cells/mL, or >10% immature (band) forms, or signs of organ dysfunction or multiorgan failure.1
The treatment team decided to start a regular insulin infusion titrated by the blood glucose level dictated by a protocol. It is believed that insulin works by increasing lipoprotein lipase activity, which degrades chylomicrons, thereby reducing the triglyceride level. Because HTGP often presents in patients with uncontrolled diabetes, as in Mr. H, insulin can decrease both triglyceride and glucose levels. Triglyceride levels were monitored every 12 hours and the I.V. insulin was stopped when triglyceride levels were <500 mg/dL.
After 2 days, Mr. H showed significant improvement in his serum triglyceride level with clinical improvement such as reduction in abdominal pain and ability to tolerate oral nutrition.6
Long-term management of HTG
Acute pancreatitis in patients with HTG can be prevented by lowering the serum triglyceride level to 200 mg/dL.4 Pharmacotherapy to reduce serum triglyceride levels includes gemfibrozil. After discussing the reason that Mr. H stopped taking his medication, he was educated on the need to consistently take gemfibrozil as prescribed.
Weight loss, dietary fat restriction, aerobic exercise, avoiding concentrated sugars, and glycemic control were also discussed with Mr. H.6 Because alcohol intake can precipitate future attacks, he was counseled on the importance of maintaining abstinence. Cigarette smoking was discouraged, as this can trigger acute pancreatitis. The patient was also educated to report signs of infection or steatorrhea as these could indicate further damage to pancreatic tissue.6
This patient with a history of HTG was diagnosed with HTGP, complicated by a new diagnosis of T2DM, an A1C of 10.8%, and hypocalcemia. Besides supportive care for acute pancreatitis, care in the CCU included administering an insulin infusion, monitoring triglyceride levels, and preventing and treating infections promptly, thus decreasing mortality in these patients. In order to prevent future acute pancreatitis, patient education is also important for appropriate long-term care.
- acute peripancreatic fluid collections
- pancreatic pseudocyst
- acute necrotic collection
- walled-off necrosis
- peripancreatic vascular complications
- splanchnic venous thrombosis
- abdominal compartment syndrome
- systemic complications
- alcohol withdrawal
- exacerbation of underlying comorbidities (coronary artery disease, chronic lung disease)
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2. Mohy-ud-din N, Morrissey S. Pancreatitis. In: Stat Pearls (Internet). Treasure Island, FL: Stat Pearls Publishing; 2019.
3. Zhu Y, Pan X, Zeng H, et al. A study on the etiology, severity, and mortality of 3260 patients with acute pancreatitis according to the revised Atlanta classification in Jiangxi, China over an 8-year period. Pancreas
4. Gelrud A, Whitcomb DC. Hypertriglyceridemia-induced acute pancreatitis. UpToDate. 2019. www.uptodate.com
5. Karanchi H, Wyne K. Hypertriglyceridemia. In: Stat Pearls (Internet). Treasure Island, FL: Stat Pearls Publishing; 2019.
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. 10th ed. St. Louis, MI: Elsevier; 2017.
7. Vege SS. Clinical manifestations and diagnosis of acute pancreatitis. UpToDate. 2019. www.uptodate.com
8. Vege SS. Management of acute pancreatitis. UpToDate. 2020. www.uptodate.com
9. Pfizer Medical Information. LOPID (gemfibrozil): clinical pharmacology. 2020. www.pfizermedicalinformation.com/en-us/lopid/clinical-pharmacology
10. Centers for Disease Control and Prevention. About adult BMI. 2020. www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html
11. Pagana K, Pagana T. Mosby's Manual of Diagnostic and Laboratory Tests
. 6th ed. St. Louis, MI: Elsevier; 2017.
12. Khan R, Jehangir W, Regeti K, Yousif A. Hypertriglyceridemia-induced pancreatitis: choice of treatment. Gastroenterol Res