Journal of Clinical Gastroenterology:
Liver, Pancreas, and Biliary Tract: Clinical Reviews: Pancreatic and Biliary Diseases
Issues in Hyperlipidemic Pancreatitis
Yadav, Dhiraj M.D.; Pitchumoni, C. S. M.D., M.A.C.G.
From Our Lady of Mercy University Medical Center, New York Medical College, Bronx, New York.
Address correspondence and reprint requests to Dr. C.S. Pitchumoni, Department of Medicine, 4th Floor, GI Department, Our Lady of Mercy Medical Center, 600 East 233rd Street, Bronx, NY 10466. E-mail: email@example.com.
Hypertriglyceridemia (HTG) is a rare cause of pancreatitis. Pancreatitis secondary to HTG, presents typically as an episode of acute pancreatitis (AP) or recurrent AP, rarely as chronic pancreatitis. A serum triglyceride (TG) level of more than 1,000 to 2,000 mg/dL in patients with type I, IV, or V hyperlipidemia (Fredrickson's classification) is an identifiable risk factor. The typical clinical profile of hyperlipidemic pancreatitis (HLP) is a patient with a preexisting lipid abnormality along with the presence of a secondary factor (e.g., poorly controlled diabetes, alcohol use, or a medication) that can induce HTG. Less commonly, a patient with isolated hyperlipidemia (type V or I) without a precipitating factor presents with pancreatitis. Interestingly, serum pancreatic enzymes may be normal or only minimally elevated, even in the presence of severe pancreatitis diagnosed by imaging studies. The clinical course in HLP is not different from that of pancreatitis of other causes. Routine management of AP caused by hyperlipidemia should be similar to that of other causes. A thorough family history of lipid abnormalities should be obtained, and an attempt to identify secondary causes should be made. Reduction of TG levels to well below 1,000 mg/dL effectively prevents further episodes of pancreatitis. The mainstay of treatment includes dietary restriction of fat and lipid-lowering medications (mainly fibric acid derivatives). Experiences with plasmapheresis, lipid pheresis, and extracorporeal lipid elimination are limited.
HYPERLIPIDEMIA IN PANCREATITIS VERSUS PANCREATITIS OF HYPERLIPIDEMIA
Since Speck in 1865 1 noted the association between hyperlipidemia and acute pancreatitis (AP), the interrelationship has been studied by many, 2–8 most importantly by Cameron and associates. 9 The serum in patients with AP may be lactescent in 4% to 20% of patients, and lipid levels increase above the normal in up to 50% of patients with AP of any cause. 4–8 The wide variation in lipid levels observed is explained by the criteria used to diagnose hyperlipidemia, type of population studied, causes of AP, and the timing of the serum sample obtained in relation to the acute attack. Mild to moderate hyperlipidemia in AP—particularly in alcoholic pancreatitis—is observed much more often than the entity of hyperlipidemic pancreatitis (HLP). The clinicians should not confuse the mild to moderate hyperlipidemia secondary to AP with the marked hypertriglyceridemia (HTG) that causes AP. Hypercholesterolemia, in contrast to HTG, does not cause AP.
Of the many causes for pancreatitis, HTG is a rare but well-recognized association. Studies on patients with familial HTG and their long-term follow-up have shown that in the absence of other causes for pancreatitis, extreme elevations of triglycerides (TG) occur during episodes of AP and the so called “hyperlipidemic abdominal crisis.”10,11 It is generally believed that a TG level of more than 1,000 mg/dl is needed to precipitate an episode of AP. 12
This review is an extension of many previous excellent reviews on the topic. 12,13 In this review, we emphasize the physiology of lipids and hyperlipidemia and the clinical issues in the diagnosis and management of patients with HLP, and we discuss the interrelationship of AP with HTG. Throughout the article, the terms HLP and hypertriglyceridemic pancreatitis are used interchangeably.
PHYSIOLOGY OF LIPIDS AND HYPERLIPIDEMIA
Lipoproteins, a family of molecules containing the same basic constituents but in different proportions, can be separated into five classes by ultracentrifugation, from the least dense and largest to the most dense and smallest. Chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins, low-density lipoproteins (LDL), and high-density lipoproteins (HDL) are the components. 14 Triglyceride is the major lipid component in VLDL, whereas cholesterol is the major component of LDL. Intermediate-density lipoproteins are catabolic products of chylomicrons and VLDL and contain similar amounts of both lipid components. The source of plasma TG can be exogenous or endogenous. In healthy individuals, dietary intake accounts for the majority of TG input. Triglycerides present in dietary fat are hydrolyzed in the gut and absorbed by enterocytes where they are converted into TG-containing chylomicrons. Chylomicrons are secreted into lymphatic vessels and subsequently enter the venous system via the thoracic duct. In the plasma, they acquire apoprotein C-II (apo C-II), which is a cofactor for lipoprotein lipase (LPL). Endogenous synthesis of TG occurs in the liver, and they are secreted in the form of VLDL. Chylomicrons and VLDL are transported to muscle and adipose tissue for storage and use that is regulated by LPL. Cells in all parenchymal tissues secrete LPL, which migrates to endothelial cells of local capillary beds where it hydrolyzes TG and surface components of chylomicrons and VLDL to release fatty acids, which are used by the muscle cells for combustion and by adipose tissue for resynthesis and storage of TG. 15 Chylomicrons usually appear in the serum within 1 to 3 hours of a meal and normally are cleared within 8 hours. 16 They are almost always present when TG levels exceed 1,000 mg/dL.
Hyperlipoproteinemia, the excessive accumulation in the blood of one or more of the lipoprotein-transporting macromolecules can be defined as plasma levels of lipids or lipoproteins above the 95th percentile of those found in the reference population. Hyperlipoproteinemia states are classified as primary (hereditary or sporadic genetic disorder of metabolism) or secondary (associated with an identifiable disease or condition and is reversible with control or eradication of that disease or condition) or both.
Patients who present with significant HTG and pancreatitis usually have a preexisting abnormality in lipoprotein metabolism. The clinical features of AP secondary to HTG are no different from AP of other causes. The common scenarios in which a clinician would encounter a patient with HTG pancreatitis include a poorly controlled diabetic with or without a history of HTG, an alcoholic patient admitted with AP who is found to have a lactescent serum, a nondiabetic, nonalcoholic, non-obese patient who has HTG secondary to diet or drugs, and a patient with one of the familial hyperlipidemias presenting with AP in the absence of a secondary factor. 17 The first three types constitute the majority of patients with HLP. These patients have a secondary precipitating factor that independently would not increase the TG levels to significant proportions to be a risk factor for pancreatitis. However, if a preexisting defect in lipoprotein metabolism is present, marked elevation of TG occurs, causing AP.
Within 24 to 48 hours of the onset of AP, in the majority of patients, TG levels fall rapidly as a result of fasting status, when the supply of chylomicrons from the intestinal absorption to the blood is cut off. Also, once therapy with hypocaloric intravenous fluids is started, there is a decrease in the secretion of VLDL from the liver, which further reduces the TG pool and causes a decrease in the levels. 18 If a lipoprotein analysis is performed within the first 24 to 48 hours of the onset of AP, it would reflect type V or I hyperlipoproteinemia, indicating elevated chylomicrons with or without VLDL. When lipoprotein analysis is repeated several weeks after the episode of AP, the profile usually changes to type IV, V, or III. 19
In a patient with AP, the strongest clue to HLP is the presence of lipemic serum. Other features that should raise suspicion are preexisting medical conditions or medications known to cause HTG and family history of HTG.
The diagnostic hallmark of AP is elevated amylase and/or lipase in the absence of which clinicians seldom consider AP in the differential diagnosis. Interestingly, serum and urinary amylase levels are spuriously low in patients with HTG pancreatitis and may be normal in more than 50% patients at the time of admission or during the hospital course. 20–22 This has been attributed to an interference of plasma lipids with the assay 20 or to the presence of an inhibitor in the plasma and urine that inhibits the assay. 21,22 Although the exact inhibitor is not known, it does not seem to be TG itself, as the removal of excess serum lipids by ultracentrifugation does not eliminate the inhibition of amylase activity. 22 If the serum is diluted, the increase in amylase can be appreciated and the diagnosis of AP can be made. 21,22 Urinary amylase creatinine clearance ratio has also been suggested to be accurate in the diagnosis of these patients 21; however, this method has lost popularity. Lipase levels usually parallel the amylase levels, but there has not been much literature on lipase activity in patients with HLP.
MECHANISM OF PANCREATITIS IN HYPERTRIGLYCERIDEMIA
The mechanism by which HTG leads to pancreatitis is not clear. A well-accepted mechanism proposed initially by Havel 23 is as follows: hydrolysis of TG in and around the pancreas by pancreatic lipase seeping out of the acinar cell leads to accumulation of free fatty acids in high concentrations. Unbound free fatty acids are toxic and could produce acinar cell or capillary injury. Increased concentration of chylomicrons in the pancreatic capillaries causes capillary plugging and leads to ischemia and acidosis, and in the acidotic environment, free fatty acids cause activation of trypsinogen and initiate AP. This hypothesis was supported by experimental studies by Saharia et al., 24 in which they perfused the pancreas preparations with TG and free fatty acid (oleic acid) infusions that resulted in edema of the pancreatic preparation, weight gain, and elevation of serum amylase. The injury caused by free fatty acids was similar to that seen with TG infusion, but it occurred more rapidly.
TYPES OF HYPERTRIGLYCERIDEMIA
There are two forms of HTG: genetic and acquired (Table 1). Acquired forms by themselves do not cause significant HTG that can be a risk factor for pancreatitis. However, in the presence of an underlying abnormality in lipoprotein metabolism, they increase TG to a significant level that can result in pancreatitis. Although the major source of TG in healthy individuals is dietary intake, the most frequent cause of HTG is an abnormality in the regulation of endogenous production of TG-rich VLDL. This can cause either elevation of VLDL alone (type IV hyperlipidemia) or VLDL and chylomicrons (type V hyperlipidemia). Endogenous HTG is usually related to hyperinsulinemia and insulin resistance, most often caused by obesity, ingestion of excess calories or alcohol use, or the use of estrogens or certain medications. Some of the important secondary causes will be discussed later in this review.
The classification of lipoproteins into five types was initially proposed by Fredrickson and Lees 25 based on their electrophoretic pattern. Patients with types I, IV, and V hyperlipidemia in which HTG is an association are predisposed to develop pancreatitis. The majority of adult patients with familial hyperlipidemia and pancreatitis would have a type V or IV defect. Types I and V can present with spontaneous pancreatitis in the absence of a secondary factor; however, type IV almost always requires a secondary factor to increase TG levels substantially.
Type I hyperlipidemia, also known as familial chylomicronemia, is a rare genetic disorder inherited as an autosomal recessive trait. It occurs because of LPL or apo C-II deficiency and almost always presents in infancy and early childhood. The classic triad is eruptive xanthomas, lipemia retinalis, and pancreatitis. These patients have fasting HTG and the degree of chylomicronemia depends upon the amount of fat intake.
Familial combined hyperlipidemia and familial HTG—both inherited as autosomal-dominant—are much more common than familial chylomicronemia and usually manifest in adulthood. The genetic mutations in these conditions are yet unknown, and the diagnosis is a clinical one, mainly by demonstration of lipoprotein abnormalities by family history or family studies. In familial combined hyperlipidemia, in addition to TG, cholesterol levels may also be elevated. The lipoprotein abnormality may vary at different times in an individual or in family members (electrophoretic pattern IIa, IIb, or IV). These patients are at risk for premature coronary artery disease. They usually do not have xanthomas or xanthelasmas. Patients with familial HTG have elevation of TG alone. Their TG levels usually range from 200 to 500 mg/dL, which are increased because of a secondary factor. Coronary artery disease is not a feature in familial HTG, and xanthomas are usually absent, except when chylomicronemia is precipitated. The differentiation of familial HTG from familial combined hyperlipidemia is based on elevated TG levels with a normal cholesterol level in an individual and family members and an absence of family history of premature coronary disease. This can be difficult at times as some patients with familial combined hyperlipidemia may not have elevated cholesterol levels. The clinical characteristics of familial hyperlipidemias are summarized in Table 2. 26
Chait and Brunzell 27 studied 123 patients who were referred to their lipid clinic for elevated TG levels (>2,000 mg/dL). Although all patients had a genetic basis for their HTG, 110 out of 123 had an associated secondary factor contributing to the elevated TG levels, whereas only 13 patients had primary abnormality of the lipid metabolism as the sole cause for their HTG. Multiple family members of these patients had abnormal lipid levels, but their TG levels were much lower than the index cases. The authors attributed this to the lack of associated secondary factors in the relatives. Thus, identifying presence of secondary factors in managing a patient with severe HTG or HLP is important.
SECONDARY CAUSES OF HYPERTRIGLYCERIDEMIA
Hypertriglyceridemia in an alcoholic patient is always an enigma (Table 1). When an alcoholic patient presents with AP and has either an elevated TG level or a lactescent serum, it is difficult for the physician to decide whether HTG or pancreatitis was the initial event. Increase in plasma TG levels occurs in many, but not all, patients with alcohol intake. 28 Association of alcohol and HTG was initially investigated by Cameron et al. 19 They found that a baseline abnormality of lipoprotein metabolism was present in the majority of alcoholic patients who were detected to have HTG during admission for AP. In the acute phase of AP, the lipoprotein analysis showed type V pattern that changed to type IV when repeated after several weeks to months.
To further investigate the role of hyperlipidemia in the development of pancreatitis, Cameron and colleagues 29 administered a high-fat diet to these patients during the quiescent phase (several weeks to months after resolution of pancreatitis episode). Eleven of 12 patients in their study developed TG levels of more than 500 mg/dL; seven had abdominal pain similar to their episodes of pancreatitis that resolved once the TG levels returned to normal. Serum amylase was elevated in four of the seven patients. 29 The authors concluded that in some alcoholic patients, the development of AP is secondary to the HTG initiated by the intake of alcohol. Normalization of fasting TG levels occurs in many alcoholics after discontinuation of their alcohol intake, 30 particularly in those with type V hyperlipidemia.
In a patient who does not have an underlying lipid abnormality, alcohol per se does not increase the TG concentrations to the significant levels needed to precipitate an episode of pancreatitis. 12 Also, in the absence of a high fat intake, alcohol alone does not cause an increase in TG level. 31 The lipemic response to a combination of alcohol and fat is exaggerated in patients with underlying HTG, indicating an abnormal lipoprotein metabolism as compared with those with normal TG levels. 31 Binge drinking or consumption of moderate to large amounts of alcohol leads to an increase in serum TGs, primarily because of increased VLDL secretion. 32,33
Thus, alcohol use induces HTG by competing with free fatty acids for oxidation, leading to increased availability of free fatty acids for TG synthesis, leading to an increased VLDL secretion by the liver. In the presence of an underlying lipid abnormality, this increased load of VLDL cannot be cleared from the blood, leading to saturation of TG removal and causing chylomicronemic syndrome.
A common scenario for HLP that clinicians would encounter is a patient with poorly controlled diabetes presenting with pancreatitis caused by HTG. Lipoprotein analysis would show an elevated VLDL (type IV hyperlipidemia). Hyperlipidemic pancreatitis occurs more often in patients with poorly controlled or untreated diabetes 17 and can be seen both in type I or II diabetes. In type I patients with diabetes, markedly reduced levels of LPL activity occurs, as insulin is required for normal synthesis of this enzyme. 34 In obese type II patients with diabetes, there is hyperinsulinemia and insulin resistance and, consequently, an enhanced production and reduced plasma clearance of TG.
We have prospectively evaluated the incidence of HTG and occult HLP in uncontrolled diabetes with diabetic ketoacidosis. 35 In our study of 100 consecutive cases of diabetic ketoacidosis, we estimated amylase, lipase, and TG levels on hospital admission and 48 hours later. Patients who either had abdominal pain, elevation of pancreatic enzymes more than three times normal, or an elevation of TG of more than 500 mg% underwent CT scan of the abdomen to screen for AP. Hypertriglyceridemia (>500 mg%) was seen in 22 (22%) patients, out of whom 8 (8%) had levels more than 1,000 mg%. Computed tomography–proven pancreatitis was seen in 11% of cases, and in almost half of them, profound and transient HTG on admission (range, 1,000–8,000 mg/dL) was the likely cause. Patients with pancreatitis had higher glucose levels, lower pH, and higher anion gap compared with those without pancreatitis. The clinical course of patients with presumed HLP was similar to AP from other causes. Triglyceride levels returned to normal after control of acidosis in all patients. Serum TG levels did not correlate with blood pH or anion gap (Table 3).
Estrogens and Pregnancy
Exogenous estrogen use either as birth-control pills or postmenopausal supplementation may cause an increase in TG. The underlying mechanism includes reduced postheparin lipolytic activity, leading to decreased removal of TG or increased endogenous TG synthesis related to increased insulin levels. 36 Elevation of TG levels from 1.5- to 2.5-fold can be seen as a dose-response phenomenon to estrogens. 37 Although this is not of clinical significance in the large majority of women taking exogenous estrogens, in the presence of a preexisting abnormality of lipoprotein metabolism, an exponential increase in TG can occur, increasing the risk for pancreatitis. 38 A recent study demonstrated that 39% women referred for evaluation of HTG (>750 mg/dL) were receiving exogenous estrogens. 39 Acute pancreatitis developed in four of seven patients with TG more than 1,500 mg/dL, and significant abdominal pain suggestive of AP was present in another two. The authors suggested that exogenous estrogen replacement should be relatively contraindicated if serum TG are more than 300 mg/dL and contraindicated if TG are more than 750 mg/dL. Thus, before initiation of estrogen replacement, it is prudent to check the fasting serum TG level and monitor it periodically on replacement. Oral estrogens are more likely to cause HTG than a combination of estrogen and progesterone, transdermal estrogens, or the injectable form of estrogens. 40 The newer low-dose estrogens have a reduced risk for HTG.
Similarly, an increase in TG levels during pregnancy is seen with peak levels in the third trimester. Although inconsequential in most, in the presence of an underlying lipid abnormality, it may cause severe HTG and chylomicronemic syndrome, precipitating pancreatitis. 41,42 Probable explanations include an enhanced adipose tissue lipolysis that facilitates the availability to the liver of substrates for the synthesis of TG, inducing high flux of VLDL into the circulation 43; a simultaneous reduction in LPL activity causes inadequate TG removal. 42,44 It is recommended that a fasting lipid profile be obtained early in pregnancy. 41,42 Because AP in pregnancy can have dire consequences both for the mother and the baby, HTG should be ruled out in all pregnant patients with pancreatitis of unexplained etiology.
Several medications can induce marked increase in HTG to precipitate AP, usually in the presence of a preexisting lipoprotein abnormality (Table 1). In addition to exogenous estrogens as mentioned previously, the most important ones to be recognized are oral retinoids, diuretics, β-blockers, and anti-HIV medications. 45–51 Discontinuation of the offending medication will lead to reduction of TG to baseline levels.
DOES HYPERTRIGLYCERIDEMIA AFFECT THE SEVERITY OF ACUTE PANCREATITIS?
A few animal studies have shown that HTG intensifies the course of pancreatitis (both edematous and necrotizing). 52,53 Other studies indicated that HTG could have a role in the development of respiratory insufficiency associated with AP. 54,55 However, the clinical course of HLP has been reported to be no different from other forms of pancreatitis. 17 Patients with HLP can have severe necrotizing pancreatitis, pseudocysts, abscesses, and all other complications that are seen in other types of pancreatitis.
NATURAL HISTORY OF HYPERTRIGLYCERIDEMIA PANCREATITIS
Studies on the natural history of patients with type V hyperlipidemia have indicated that reduction of TG to less than 2,000 mg/dL prevents abdominal pain and pancreatitis. 10 A recent study on long-term follow-up of patients with acute HLP demonstrated effectiveness of dietary and pharmacologic therapies in controlling TG to prevent relapses. 56 It is recommended that TG levels be reduced to less than 500 mg/dL to prevent episodes of pancreatitis and hyperlipidemic abdominal crisis. 12 Whether HTG causes chronic pancreatitis remains controversial. Several case reports and some small series of cases have reported patients who have documented exocrine or endocrine insufficiency and also calcifications. 57,58 The senior author has not seen a case of pancreatic calculi or exocrine insufficiency secondary to HLP. In view of the earlier reported association between alcoholism and HTG, it is even likely that some of these patients may have combined injury to the pancreas.
CAN WE PREDICT WHO WILL DEVELOP PANCREATITIS?
It is difficult to predict which hyperlipidemic patient is likely to develop an episode of pancreatitis. Several studies have looked at either oral lipid tolerance 29,59,60 or intravenous lipid tolerance in patients with a prior episode of pancreatitis, but they have conflicting results. 61,62 In two studies in which oral lipid load was given, the lipid clearance was impaired, 29,59 and some patients developed abdominal pain and elevation of enzymes. 29 Haber et al. 60 found lipid tolerance to be the same in alcoholic (with or without pancreatitis) and gallstone pancreatitis. Durrington et al. 61 on the other hand used an intravenous lipid load and found that only 12% of their patients with pancreatitis demonstrated impaired fat clearance. Similarly, another study showed mixed results with intravenous lipid load. 62
These studies are inconclusive in predicting which patient with HTG would develop pancreatitis and why some patients with HTG seldom develop pancreatitis, even with marked elevation of TG levels. Better methods need to be devised in the future to answer this question.
Management of Acute Pancreatitis
The initial treatment of AP should be similar to that for other causes of AP, including bowel rest, nothing by mouth, intravenous hydration, and analgesics. Triglyceride levels rapidly decrease within 24 to 48 hours of the onset of AP in the majority of patients. Thus, if HLP is suspected, estimation of serum TG levels should be performed as soon as possible after onset of abdominal pain. If total parenteral nutrition is needed to provide nutrition in the presence of prolonged fasting status, lipid infusions should be avoided, as they will cause an increase in TG levels. Family history of lipid disorders and personal history of alcohol and medication use should be carefully obtained. Laboratory tests (e.g., glucose, liver functions, renal functions, urine protein, and TSH levels) should be performed to rule out secondary causes of HTG. Other laboratory abnormalities that can occur with hyperlipidemia are hyponatremia and hyperbilirubinemia. 16
If type I hyperlipidemia is suspected, tests to document LPL or apo C-II deficiency may be performed. These tests can either quantify in vitro postheparin LPL activity or absence from patients plasma of a functional apo C-II that is able to activate LPL in vitro.63,64 The underlying genetic defects can now be identified by sequence analysis of the LPL or apo C-II gene. 63,64
PREVENTION OF RECURRENT PANCREATITIS
Diet, General Measures, and Control of Secondary Factors
Control of secondary factors like avoidance of alcohol, weight reduction, discontinuation of offending drug, control of diabetes, and hypothyroidism form an important part of long-term management of patients with HLP. Several studies have shown that reducing the alcohol intake in hypertriglyceridemic individuals lowers TG levels. 65,66
Dietary interventions form an important part of patient management once the acute episode has resolved, and dietary advice may be obtained from a nutritionist. The role of exercise and weight reduction in association with dietary interventions should be stressed. Step I and II diets in the absence of weight reduction lead to an increase in plasma TG levels. 67,68 However, weight reducing step I and II diets favorably affect TG levels along with other lipoproteins. Two recent meta-analyses have shown a significant correlation between weight loss and decrease in plasma TG levels. 69,70
The mainstay of treatment in type I hyperlipidemia is dietary restriction of fat. Fat intake (both saturated and unsaturated) should be reduced to approximately 10% to 15% of total calorie intake. 12 Complex carbohydrates should be substituted to correct fat deficit. Supplementation of medium-chain TGs can be used as a source of fat calories. Medium-chain TGs are absorbed directly into the portal circulation compared with long-chain TGs and do not rely on chylomicrons formation for hepatic uptake. 16,71 In other patients, restriction of dietary fat intake to less than 25% to 30% of total calorie intake may be sufficient.
Fish Oil Supplements
Fish oil supplements are effective in normalizing TG levels or as an adjunct to drug therapy. They lead to a decrease in concentrations of endogenously derived TG-rich lipoproteins, VLDL, and intermediate-density lipoproteins in a dose-dependent fashion. 72 Plasma TG levels are reduced in healthy subjects and in patients with hyperlipidemia in whom VLDL concentrations are raised, especially when diet and exercise have not helped to reduce markedly elevated TG. 73,74 The active molecules in fish oil are n-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid, in addition to other minor fatty acids. The TG-lowering effect is primarily attributed to eicosapentaenoic acid. 75 The minimum effective dose for n-3 fatty acids is slightly more than 1 g/d. A daily dose of 3 to 4 g/d decreases plasma TG by around 30% to 50% in hypertriglyceridemic patients. 72,76 Although certain types of fish are a rich source of n-3 fatty acids (e.g., salmon, herring, mackerel; mean, 2.3 g/100 g of fish; range, 1–5.3 g/100 g of fish), to achieve a therapeutic reduction of TG levels, a large amount of fish intake per day is needed. Thus, fish oil supplements are necessary to meet the levels of n-3 fatty acid intake to achieve therapeutic reduction in TG levels.
The side effects of fish oil supplements that need monitoring are weight gain and bleeding tendency. Other potential side effects are fishy odor and upset stomach.
As already mentioned, before initiation of drug therapy in any patient, potential causes of secondary hyperlipidemia should be ascertained and treated. In type I hyperlipidemia, dietary restriction of fat intake is the mainstay of treatment. Drug therapy is largely ineffective, however, drug therapy may be required to decrease VLDL production and prevent severe HTG.
Fibric acid derivatives or fibrates (gemfibrozil, fenofibrate, clofibrate) are a class of drugs that reduce plasma TG and concurrently raise HDL levels. They are first-line drugs for the treatment of primary HTG. Fibrates, predominantly gemfibrozil, are extensively used in the United States. The Helsinki heart study, primarily aimed to look at its efficacy in reducing the risk of coronary artery disease, has demonstrated the safety and efficacy of gemfibrozil as a lipid-modifying agent. 77 Fibric acid derivatives act through different mechanisms to lower levels of TG. One distinct action of fibrates appears to be an increase in the levels of LPL. Further, fibrates decrease hepatic TG synthesis by inducing hepatic fatty acid uptake, increasing removal of LDL particles, reducing neutral lipid (cholesterol-ester and TG) exchange between VLDL and HDL, and stimulating reverse cholesterol transport. 78 In addition to the side effects listed in the Table 5, pancreatitis has been reported in patients taking fibrates. 79,80 This may be interpreted as failure of efficacy, a distinct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation. Because the physicians—particularly the noncardiologists—may be less familiar with the use of fibrates, it is important to become thoroughly familiar with the use of these medications, and if clinical experience is limited, it is prudent to seek the help of an endocrinologist or a cardiologist with more experience in using fibrates.
The HMG-CoA (3-hydroxy-3-methyl glutaryl coenzyme A) reductase inhibitors, also popularly called statins, are not the primary drugs of choice for hypertriglyceridemic states. Rather, they are extremely popular in the prevention of coronary artery disease for the management of patients with elevated total cholesterol, LDL cholesterol, and mild to moderate elevations of TG. The currently available statins are atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin. Cervistatin was withdrawn from the market recently. Although statins are well tolerated, concerns about “myopathy” (especially in combination with fibrates 81,82) as an adverse event has been widely publicized. Statins may have a role as an adjunct in certain cases.
Niacin (optimal dose, 3–6 g/d) decreases TG levels mainly by reducing VLDL secretion. It also affects LDL and HDL levels favorably. Several side effects of niacin should be kept in mind: gastric upset, flushing, pruritus, hepatotoxicity, glucose intolerance, and hyperuricemia.
Monotherapy is not all that time–effective in tackling combined hyperlipidemia. Combining drugs with different mechanisms to achieve an additional synergistic effect is an acceptable choice. Gemfibrozil and lovastatin together have been shown to be a superior combination. In one recent study on the safety and efficacy of long-term statin–fibrates combination in patients with refractory familial hyperlipidemia by Athyros et al., 83 the authors looked at the efficacy of simvastatin with gemfibrozil (20 + 1,200 mg/d), pravastatin with gemfibrozil (20 + 1,200 mg/d) and simvastatin with ciprofibrate (20 + 100 mg/d). All combinations were noted to be safe, but the combination of simvastatin and ciprofibrate was the most effective. 83 The drug combination in this study did not cause any case of myopathy or rhabdomyolysis. However, because of previous observations of these side-effects, especially with a combination of statin and fibrates, patients on statins alone or on combination therapy should be cautioned and urged to report any unusual muscle soreness and fatigue, and the therapy should be discontinued if myopathy is present.
Antioxidants were recently reported to be helpful in patients with familial HTG and chronic pain. 84 Use of plasma exchange to lower lipid and pancreatic enzymes levels and improve signs and symptoms of AP has been reported. 85 In contrast to plasma exchange, lipoprotein apheresis removes only large molecular weight complexes from plasma (such as lipoproteins) and retains immunoglobulins, albumin, and clotting factors, thus reducing the possibility of infection and bleeding. 86–88
Pancreatic enzyme therapy to cause feedback inhibition of pancreatic enzyme secretion should be considered to alleviate abdominal symptoms. 12 Once TG levels fall below 500 mg/dL, enzyme therapy could be stopped and diet and drug therapy should be continued. 12
Hypertriglyceridemia, although uncommon, is a well recognized cause of AP. An underlying lipid abnormality is present in almost all affected individuals. A TG level of more than 1,000 mg/dL is needed to cause an episode of pancreatitis. A secondary factor such as alcoholism, obesity, uncontrolled diabetes mellitus, or a number of medications prone to increase lipid levels is present in the large majority of patients and should always be identified. Reduction of TG levels to well below 1,000 mg/dL would effectively prevent further episodes of pancreatitis in all patients. The mainstay of treatment includes dietary restriction of fat and lipid-lowering medications in addition to managing the secondary or precipitating causes.
1. Speck L. Fall von lipamia. Arch Verin Wissenschaftl Heilkunde
1865;1:232. Quoted in Thannhauser SJ, ed. Lipidoses, diseases of the intracellular lipid metabolism
, 3rd ed. New York: Grune & Stratton, 1958:307.
2. Coffey RJ. Unusual features of pancreatic disease. Ann Surg 1952; 135:715–20.
3. Wang C, Aldersberg D, Feldman EB. Serum lipids in acute pancreatitis. Gastroenterology 1959; 36:832–40.
4. Greenberger NJ, Hatch FT, Drummey GD, et al. Pancreatitis and hyperlipidemia. Medicine 1966; 45:161–75.
5. Farmer RG, Winkelmann EI, Brown HB, et al. Hyperlipoporteinemia and pancreatitis. Am J Med 1973; 54:161–5.
6. Buch A, Buch J, Carlsen A, et al. Hyperlipidemia and pancreatitis. World J Surg 1980; 4:307–14.
7. Dickson AP, O'Neill J, Imrie CW. Hyperlipidemia, alcohol abuse and acute pancreatitis. Br J Surg 1984; 71:685–8.
8. Dominguez-Munoz JE, Malfertheiner P, Ditschhneit HH, et al. Hyperlipidemia in acute pancreatitis. Relationship with etiology, onset and severity of the disease. Int J Pancreatol 1991; 10:261–7.
9. Cameron JL, Capuzzi DM, Zuidema GD, et al. Acute pancreatitis with hyperlipiemia: The incidence of lipid abnormalities in acute pancreatitis. Ann Surg 1973; 177:493–9.
10. Miller A, Lees RS, McCluskey MA, et al. The natural history and surgical significance of hyperlipemic abdominal crisis. Ann Surg 1979; 190:401–8.
11. Greenberg BH, Blackwelder WC, Levy RL. Primary type-V hyperlipoproteinemia. A descriptive study in 32 families. Ann Intern Med 1977; 87:526–34.
12. Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am 1990; 19:783–91.
13. Liu Q, Prinz RA. Pancreatitis associated with hyperlipidemia and hyperparathyroidism. In: Howard JM, Idezuki Y, Ihse I, et al., eds. Surgical diseases of the pancreas
, 3rd ed. Baltimore, Williams & Wilkins, 1998:271–80.
14. Lindgren FT, Jensen LC, Hatch FT. The isolation and quantitative analysis of serum lipoproteins. In: Nelson GJ, ed. Blood lipids and lipoproteins: quantification, composition and metabolism. New York: John Wiley & Sons, 1972:181.
15. Nilsson-Ehle P. Regulation of lipoprotein lipase: triacylglycerol transport in plasma. In: Carlson LA, Pernow B, eds. Metabolic risk factors in ischemic cardiovascular disease. New York, Raven Press, 1982:49.
16. Chait A, Brunzell JD. Chylomicronemia Syndrome. Adv Intern Med 1992; 37:249–73.
17. Fortson MR, Freedman SN, Webster PD. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol 1995; 90:2134–9.
18. Brunzell JD, Bierman EL. Chylomicronemia syndrome. Med Clin N Am 1982; 66:455–8.
19. Cameron JL, Capuzzi DM, Zuidema GD, et al. Acute pancreatitis with hyperlipemia. Evidence for a persistent defect in lipid metabolism. Am J Med 1974; 56:482–7.
20. Fallat RW, Vester JW, Glueck CJ. Supression of amylase activity by hypertriglyceridemia. JAMA 1973; 225:1331–4.
21. Lesser PB, Warshaw AL. Diagnosis of pancreatitis masked by hyperlipemia. Ann Intern Med 1975; 82:795–8.
22. Warshaw AL, Bellini CA, Lesser PB. Inhibition of serum and urine amylase activity in pancreatitis with hyperlipemia. Ann Surg 1975; 182:72–5.
23. Havel RJ. Pathogenesis, differentiation and management of hypertriglyceridemia. Adv Intern Med 1969; 15:117–54.
24. Saharia P, Margolis S, Zuidema MD, et al. Acute pancreatitis with hyperlipidemia: studies with an isolated perfused canine pancreas. Surgery 1977; 82:60–7.
25. Fredrickson DS, Levy RI, Lees RS: Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. N Engl J Med 1967; 276:34–44.
26. Bushy-Whitehead MJ, Blackman MR. Clinical implications of abnormal lipoprotein metabolism. In: Barker LR, Burton JR, Zieve PD, eds. Principles of ambulatory medicine
, 5th ed. Baltimore, Williams & Wilkins, 1999:1122–49.
27. Chait A, Brunzell JD. Severe HTG. Role of familial and acquired disorders. Metabolism 1983; 32:209–13.
28. Ginsberg H, Olefsky J, Farquhar JW, et al. Moderate ethanol ingestion and plasma triglyceride levels: a study in normal and hypertriglyceridemic persons. Ann Intern Med 1974; 80:143–9.
29. Cameron JL, Zuidema GD, Margolis S. A pathogenesis of alcoholic pancreatitis. Surgery 1975; 77:754–63.
30. Erkelens W, Brunzell JD. Effect of controlled alcohol feeding on triglycerides in patients with outpatient “alcohol hypertriglyceridemia.” J Hum Nutr 1980; 34:370–5.
31. Pownall HJ, Ballantyne C, Kimball K, et al. Effect of moderate alcohol consumption on HTG: a study in the fasting state. Arch Intern Med 1999; 159:981–7.
32. Pownwall HJ. Dietary alcohol is associated with reduced lipolysis of internally derived lipoproteins. J Lipid Res 1994; 35:2105–13.
33. Taskinen MR, Valimaki M, Nikkila EA, et al. Sequence of alcohol induced initial changes in plasma lipoproteins (VLDL and HDL) and lipolytic enzymes in humans. Metabolism 1985; 34:112–9.
34. Havel RJ. Approach to the patient with hyperlipidemia. Med Clin North Am 1982; 66:319–33.
35. Nair S, Yadav D, Pitchumoni, CS. Association of Diabetic Ketoacidosis and Acute Pancreatitis: Observations in 100 consecutive episodes of DKA. Am J Gastroenterol 2000; 95:2795–800.
36. Hazzard WR, Spiger MJ, Bagdade JD, et al. Studies on the mechanism of increased plasma triglyceride levels induced by oral contraceptives. N Engl J Med 1969; 280:471–4.
37. Knopp RH, Walden CE, Wahl PW, et al. Oral contraceptive and postmenopausal estrogen effects on lipoprotein triglyceride and cholesterol in an adult female population: relationship to estrogen and progestin potency. J Clin Endocrinol Metab 1981; 53:1123–32.
38. Glueck CJ, Scheel D, Fiskback J, et al. Estrogen-induced pancreatitis in patients with previously covert Familial type V hyperlipoproteinemia. Metabolism 1972; 21:657–66.
39. Glueck CJ, Lang J, Hames T, et al. Severe hypertriglyceridemia and pancreatitis when estrogen replacement is given to hypertriglyceridemic women. J Lab Clin Med 1994; 123:59–64.
40. Crook D, Cust MP, Ganger KF, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effect on serum lipids and lipoproteins. Am J Obstet Gynaecol 1992; 166:950–5.
41. De Chalain TMB, Michell WL, Berger GMB. Hyperlipidemia, pregnancy and pancreatitis. Surg Gynaecol Obstet 1988; 167:469–73.
42. Gleuck CJ, Christopher C, Mishkel MA, et al. Pancreatitis, familial HTG and pregnancy. Am J Obstet Gynecaol 1980; 136:755–61.
43. Herrera E, Gomez-Coronado D, Lascuncion MA. Lipid metabolism in pregnancy. Biol Neonate 1987; 57:70–7.
44. Herrera E, Lascuncion MA, Gomez-Coronado D, et al. Role of lipoprotein-lipase activity on lipoprotein metabolism on fate of circulating triglycerides in pregnancy. Am J Obstet Gynaecol 1988; 158:1575–83.
45. Bershad S, Rubinstein A, Paterniti JR, et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985; 313:981–5.
46. Flynn Wj, Freemann PG, Wickboldt LG. Pancreatitis associated with isotretinoin-induced HTG. Ann Intern Med 1987; 107:63.
47. Noguchi M, Taniya T, Tajiri K, et al. Fatal hyperlipidemia in a case of metastatic breast cancer treated by tamoxifen. Br J Surg 1987; 74:586–7.
48. Lasser NL, Grandits G, Caggiula AW, et al. Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984; 76:52–66.
49. Lardinos CK, Neuman SL. The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med 1988; 148:1280–8.
50. Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother 1999; 33:859–63.
51. Kumar AN, Schwartz DE, Lim KG. Propofol-induced pancreatitis: recurrence after rechallenge. Chest 1999; 115:1198–9.
52. Hofbauer B, Friess H, Weber A, et al. Hyperlipemia intensifies the course of acute oedematous and acute necrotizing pancreatitis in the rat. Gut 1996; 38:753–8.
53. Haig THB. Experimental pancreatitis intensified by a high fat diet. Surg Gynecol Obstet 1970; 131:914–8.
54. Warshaw AL, Lesser PB, Rie M, et al. The pathogenesis of pulmonary edema in acute pancreatitis. Ann Surg 1975; 182:505–10.
55. Kimura T, Toung JK, Margolis S, et al. Respiratory failure in acute pancreatitis. A possible role for triglycerides. Ann Surg 1979; 189:509–14.
56. Athyros V, Gioulene OI, Nikolaidis NL, et al. Long-term follow-up of patients with acute hypertriglyceridemia-induced pancreatitis. J Clin Gastroenterol 2002; 34:472–5.
57. Hacken JB, Moccia RM. Calcific pancreatitis in a patient with type 5 hyperlipoproteinemia. Gastrointestinal Radiol 1979; 4:143–6.
58. Krauss RM, Levy AG. Subclinical chronic pancreatitis in type I hyperlipoproteinemia. Am J Med 1977; 62:144–9.
59. Guzman S, Nervi F, Llanos O, et al. Impaired lipid clearance in patients with previous acute pancreatitis. Gut 1985; 26:888–9.
60. Haber PS, Wilson JS, Apte MV, et al. Lipid intolerance does not account for susceptibility to alcohol and gallstone pancreatitis. Gastroenterology 1994; 106:742–8.
61. Durrington PN, Twentyman OP, Braganza JM, et al. HTG and laboratory abnormalities of triglyceride catabolism persisting after pancreatitis. Int J Pancreatol 1986; 1:195–203.
62. Dominguez-Munoz JE, Junemann F, Malfertheiner P. Hyperlipidemia in acute pancreatitis. Cause or epiphenomenona? Int J Pancreatol 1995; 18:101–6.
63. Fojo SS, Brewer HB. Hypertriglyceridemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. J Intern Med 1992; 23:669–77.
64. Fojo SS, Brewer Jr. HB The familial hyperchylomicronemia syndrome. JAMA 1991; 265:904–8.
65. Chait A, Mancini M, February AW, et al. Clinical and metabolic study of alcoholic hyperlipemia. Lancet 1974; 2:62–4.
66. De Mann FH, van der Laarse A, Hopman EG, et al. Dietary counseling effectively improves lipid levels in patients with endogenous hypertriglyceridemia: emphasis on weight reduction and alcohol limitation. Eus J Clin Nutr 1999; 53:413–8.
67. Ginsberg HN, Kris-Etherton P, Dennis B, et al. Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA study, protocol 1. Arterioscler Thromb Vasc Biol 1998; 18:441–9.
68. Kris-Etherton PM, Pearson TA, Wan Y, et al. High-monounsaturated fatty acids lower both plasma cholesterol and triacylglycerol concentrations. Am J Clin Nutr 1999; 70:1009–15.
69. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992; 56:320–8.
70. Yu-Poth S, Zhao G, Etherton T, et al. Effects of the National Cholesterol Education Program's Step I and II dietary intervention programs on cardiovascular disease risk factors: a meta analysis. Am J Clin Nutr 1999; 69:632–46.
71. Santamarina-Fojo S, Brewer HB. The familial hyperchylomicronemia syndrome: new insights into underlying genetic defects. JAMA 1991; 265:904–8.
72. Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997; 65(suppl. 5):1645s–54s.
73. Connor WE, DeFrancesco CA, Connor SL. N-3 fatty acids from fish oil: Effects on plasma lipoproteins and hypertriglyceridemic patients. Ann N Y Acad Sci 1993; 683:16–34.
74. Harris WS, Rothrock DW, Fanning A, et al. Fish oils in hypertriglyceridemia: a dose-response study. Am J Clin Nutr 1990; 51:399–406.
75. Rambjor GS, Walen AI, Windsor SL, et al. Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids 1996; 31:S45–9.
76. Harris WS. Fish oils and lipoprotein metabolism in humans. J Lipid Res 1989; 30:785–807.
77. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary prevention with gemfibrozil in middle aged men with dyslipidemia. N Engl J Med 1987; 317:1237–45.
78. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:2088–93.
79. Gang N, Langevitz P, Livneh A. Relapsing acute pancreatitis induced by re-exposure to the cholesterol lowering agent bezafibrate. Am J Gastroenterol 1999; 94:3626–8.
80. Abdul-Ghaffar NU, el-Sonabaty MR. Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy. J Clin Gastroenterol 1995; 21:340–1.
81. Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis. Ann Intern Med 1988; 109:682–3.
82. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264:71–5.
83. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997; 80:608–13.
84. Heaney AP, Sharer N, Rameh B, et al. Prevention of recurrent pancreatitis in familial lipoprotein lipase deficiency with high-dose antioxidant therapy. J Clin Endocrin Metabol 1999; 84:1203–5.
85. Piolot A, Nadler F, Cavallero E, et al. Prevention of recurrent acute pancreatitis in patients with severe HTG: value of regular plasmapheresis. Pancreas 1996; 13:96–9.
86. Archad JM, Westeel PF, Moriniere JD, et al. Pancreatitis related to severe acute HTG during pregnancy: treatment with lipoprotein apheresis. Intensive Care Med 1991; 17:236–7.
87. Roberts IM. Hyperlipidemic gestational pancreatitis. Gastroenterology 1993; 104:1560–2.
88. Swoboda K, Derfler K, Koppensteiner R, et al. Extracorporeal lipid elimination for treatment of gestational hyperlipidemic pancreatitis. Gastroenterology 1993; 104:527–31.
Hypertriglyceridemia; Hyperlipidemia; Pancreatitis
© 2003 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read