Hypertriglyceride Induced Acute Pancreatitis

Pancreatitis is a common clinical entitiy with multiple contributing etiologies1. Triglyceride (TG) levels greater than 1000 mg/dL are seen in a small but significant number of cases of acute pancreatitis (AP), with estimates ranging between 1-7% of all cases and perhaps slightly higher in patients who present during pregnancy2-4. The clinical presentation of hypertriglyceridemic pancreatitis (HTGP) is similar to other causes of acute pancreatitis, but some evidence suggests that there may be an increased severity and risk of complications5,6. Multiple etiologies of highly elevated TG levels have been implicated, including congenital disorders, metabolic perturbations and certain medications but a definitive treatment regimen for profoundly elevated serum TG in association with acute, and often severe, pancreatitis has yet to be demonstrated7-10. Dietary restriction is the cornerstone of therapy. Additional treatment modalities have included insulin and heparin to stimulate the synthesis, release and activation of lipoprotein lipase (LPL) from capillary endothelial cells to promote TG degradation into free fatty acids for further metabolism or storage11. We present a case of HGTP managed with insulin, heparin and octreotide with dramatic results; a logarithmic decrease in serum TGL magnitude and a significant reduction in the time to resolution as compared with previous reports of treatment with insulin and heparin alone. Recent advances in the management of HGTP, including proposed mechanisms, will be reviewed. Adjunctive therapies, including plasmapheresis and more chronic therapy with lipid lowering agents and dietary modification will be discussed.


Introduction
Pancreatitis is a common clinical entitiy with multiple contributing etiologies 1 . Triglyceride (TG) levels greater than 1000 mg/dL are seen in a small but significant number of cases of acute pancreatitis (AP), with estimates ranging between 1-7% of all cases and perhaps slightly higher in patients who present during pregnancy [2][3][4] . The clinical presentation of hypertriglyceridemic pancreatitis (HTGP) is similar to other causes of acute pancreatitis, but some evidence suggests that there may be an increased severity and risk of complications 5,6 . Multiple etiologies of highly elevated TG levels have been implicated, including congenital disorders, metabolic perturbations and certain medications but a definitive treatment regimen for profoundly elevated serum TG in association with acute, and often severe, pancreatitis has yet to be demonstrated [7][8][9][10] . Dietary restriction is the cornerstone of therapy. Additional treatment modalities have included insulin and heparin to stimulate the synthesis, release and activation of lipoprotein lipase (LPL) from capillary endothelial cells to promote TG degradation into free fatty acids for further metabolism or storage 11 . We present a case of HGTP managed with insulin, heparin and octreotide with dramatic results; a logarithmic decrease in serum TGL magnitude and a significant reduction in the time to resolution as compared with previous reports of treatment with insulin and heparin alone. Recent advances in the management of HGTP, including proposed mechanisms, will be reviewed. Adjunctive therapies, including plasmapheresis and more chronic therapy with lipid lowering agents and dietary modification will be discussed. Table 1.

Laboratory Values at Presentation and While Hospitalized
The patient was diagnosed with HTGP and initial management included elimination of enteral intake, aggressive fluid repletion, and opiate analgesia. Subsequent therapy included a continuous insulin infusion, a 10% dextrose infusion titrated to maintain euglycemia, 60 U/kg unfractionated heparin intravenous (IV) bolus every 4 hours, and 100g octreotide bolus subcutaneously every 8 hours. TG fell by 2 orders of magnitude in 2 days, falling from 21,000 to 355 mg/dL, the rest of the laboratory values were improved (Table 1), and the lipemia resolved. The clinical course was uncomplicated and the patient was discharged after 4 days.

Clinical presentation of hypertriglyceridemic pancreatitis
The clinical features of acute HTGP are similar to that of other causes of pancreatitis 12 . Patients may present with sudden and severe epigastric abdominal pain often accompanied by anorexia and profound nausea lasting hours to days 13 . Other less common findings, more indicative of chronic hyperlipidemia, include the presence of eruptive xanthomas over the extensor surfaces, lipemia retinalis, arcus and hepatospenomeglay due to fatty infiltration of the liver. 14 Frequently, those presenting with significant TG elevations and pancreatitis have an underlying metabolic abnormality in lipid metabolism 15,16 . Patient presentations where HTGP is encountered include poorly controlled diabetics with or without a history of HTG, alcoholics with hypertriglyceridemia or lactescent serum on admission, non-diabetic, nonobese patients with drug or diet-induced HTG and patients presenting with AP without secondary risk factors; the first three of these comprise the majority of clinical presentations of HTGP 12,17,18 . Following the onset of HTGP, TGL tend to fall rapidly over 72 hours in the fasting state as a result of decreased supply and absorption of chylomicrons 19 . In addition, VLDL secretion from the liver is reduced secondary to the administration of hypocaloric intravenous fluids, thus leading to a direct reduction in TGL 20 .

Lipid physiology
Lipoproteins are macromolecules containing both organic proteins and bound lipids that are found in plasma in varying proportions and can be separated by density via ultracentrifugation. In increasing order of density, these separate into layers of chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density proteins (LDL) and high density lipoprotein (HDL) 21 . Fig. 1. Fat metabolism http://www.britannica.com/bps/media-view/92255/0/0/0 TG are a major lipid constituent of chylomicrons and VLDL. The former contains Apo B-48 and is derived from dietary sources while the latter contains Apo B-100 and is liver generated 22,23 . Cholesterol is the primary component of IDL and LDL 24 . Dietary TG are absorbed through the brush border of intestinal enterocytes, incorporated into chylomicrons and pass through the basolateral aspect where they enter the lymphatics before entering the venous circulation via the thoracic duct, ultimately acquiring apolipoprotein C-II, a critical cofactor for lipoprotein lipase (LPL) 25 .
Both chylomicrons and VLDL are transported to muscle and adipose tissue where they are metabolized by LPL to meet energy demands or stored for future use 26,27 . LPL is secreted into the venous circulation by parenchymal cells in many tissues, migrates through the vasculature and anchors to the capillary endothelium via a heparan sulfate chain. Upon activation, it facilitates lipoprotein binding and TG degradation 28 . This process results in the release of fatty acids and acylglycerols which can then be utilized directly by myocytes to meet metabolic demands or be reincorporated into triglyceride for storage in adipocytes 29 .

Diagnosis and laboratory evaluation
The clinical presentation and course of HTG pancreatitis does not differ greatly from other causes of AP 30 . Lipemic serum, frequently associated with an underlying metabolic abnormality or compromising medications, is the single most reliable clue that the pancreatitis is associated with or precipitated by hyperlipidemia 31 . Although the serum triglyceride threshold for considering HTGP is generally considered to be in the range of 1000 mg/dL, the severity, clinical course and complication rate do not correlate with lipid levels. In a study of 43 patients with HTGP, no correlation was observed between admission HTG and APACHE II score, nor was there a relation between TG level and pancreatic inflammatory complications or ultimate patient outcome 32 . Historically, clinicians have relied on increases in levels of serum amylase, and/or lipase to secure the diagnosis of acute pancreatitis. Newer diagnostic modalities, such as urine trypsinogen, procarboxypeptidase A and carboxypeptidase A, are becoming more available and may become more relevant [33][34][35] . Some patients with HTG pancreatitis and lipemic serum present with spurious laboratory values that can complicate the diagnosis 36 but a serum lipase sensitivity and specificity of 67% and 97% respectively, argue that this test remains a valuable diagnostic tool 37 .

Pathophysiology of hypertriglyceridemic pancreatitis
The mechanism by which elevated levels of plasma TG lead to the development of AP is not fully understood. It is generally accepted that levels greater than 1000 mg/dL are required to precipitate an episode of pancreatitis, but such levels of TG do not always cause HTGP. 38 The most recent ATP III guidelines suggest that a normal TG level is considered to be less than 150 mg/dl, while those greater than 500 mg/dl are considered very high 39 . Pancreatic lipase, a digestive enzyme concentrated in the exocrine pancreas which participates in TG degradation, may be liberated in AP and act in an unregulated fashion to contribute to tissue breakdown 40 . Additionally, if the local plasma TG level increases beyond the enzymatic capacity of the pancreas, free fatty acids begin to accumulate and can lead to injury of pancreatic acinar cells and surrounding tissues 41,42 . Altered pancreatic blood flow, perhaps aggravated by the hyperviscosity of chylomicronemia, may also create a more acidic environment in which free fatty acids become more toxic to the surrounding tissue [43][44][45][46] . The resultant cellular injury leads to further pancreatic inflammation, injury and destruction.

Causes of hypertriglyceridemia
Primary Causes: Primary causes of HTG consist of a series of genetic disorders leading to abnormalities in lipid metabolism and patients presenting with HTG or lipemic serum should be evaluated for Frederickson classification dyslipidemias types I, IV and V as they are strongly associated with highly elevated serum TG 47,48 .

Secondary Causes:
Diabetes -Poorly controlled, or uncontrolled, diabetes is a common cause of HTGP 49 . In type 1 diabetes mellitus, the paucity of insulin reduces LPL synthesis and thus compromises effective TG hydrolysis and release of free fatty acids. The latter are already accumulating in the absence of insulin-facilitated storage 50,51 . Similarly, in type 2 diabetes mellitus, increased insulin resistance leads to enhanced production and reduced clearance of TGs 52 . The causal role of diabetic ketoacidosis (DKA) in HTG was evaluated in a prospective study of 100 patients with DKA, 11 of whom had AP, and of these, HTG was the only attributable cause in 4 cases 53 . Serum TG levels normalized in these patients after control of the acidosis.  Table 2.

Common Etiologies of HTG
Alcohol -Ethanol compromises fuel and energy metabolism, thereby resulting in decreased serum glucose levels with elevated levels of lipids due to increased production and decreased utilization of energy sources. Alcohol can aggravate HTG and the liberated free fatty acid esters can promote calcium influx which leads to calcium-mediated pancreatic necrosis 57 . Nutritional deficiencies, including hypoglycemia, activated counterregulatory mechanisms and reduced cofactor availability reduce or inhibit insulin secretion, thus further compromising energy metabolism and exacerbating hyperlipidemia 58 .
Medications-Several medications are known to increase plasma TG levels, including isotretinoin 59 , propofol 60 , protease inhibitors 61 and furosemide 62 . Estrogens and Tamoxifen are two well studied drugs in which the tendency to promote HTG and steatohepatitis is well described 63 .
Estrogen -Exogenous estrogens increase serum TG and fatty acids primarily by reducing levels of lipoprotein and hepatic lipases which subsequently decreases clearance and aggravates insulin resistance, perhaps by as much as 40% [64][65][66] . Goldenberg et al., evaluated 56 female patients at a Cholesterol Center because of TG >400 mg/dl and/or HTGP, and/or failure of TG-lowering therapy. Of that cohort, 17 females (30%) had a history of AP and of those, 9 (53%) had taken, or were concurrently taking exogenous steroid hormones 67 . The authors concluded that hormone therapy remain relatively contraindicated with plasma TG>300mg/dl and strictly contraindicated when TG greater than >500 mg/dl in order to avoid an episode of pancreatitis.
Tamoxifen -Tamoxifen is a non-steroidal anti-estrogen commonly used in the treatment of patients with breast cancer and has shown the ability to decrease LDL and total cholesterol levels. There is frequently an increase in VLDL synthesis and subsequent rise in plasma TG levels due to reductions in lipoprotein lipase activity 68,69 . Elisaf, et al., reported 12 patients with serum TG >1000 mg/dl who were observed after administration of 20mg/day of tamoxifen 70 . Four of these patients, two of whom had a personal or family history of hyperlipidemia, developed HTGP. This led them to the conclusion that, like synthetic estrogens, the tamoxifen-mediated rise in TGs may be either contributory or causative in the development of AP. Pregnancy -Gestational AP is an uncommon condition, with studies ranging incidence between 1 in 3,500-4,000 pregnancies 71 . Most cases of AP during pregnancy are mild and are most often attributable to biliary disease, while severe AP most commonly results from hypertriglyceridemia and tends to occur in the second and third trimesters 72 . During pregnancy there is a physiologic increase in plasma lipids. Cholesterol and TG increase due to an increased production of VLDL and the decreased actions of LPL and hepatic lipase 73 . HTGP tends to develop in women with an underlying disorder in lipid metabolism, such as LPL 74 or apolipoprotein C-II deficiency 75 . Maternal mortality in cases complicated by HGTP is estimated to be near 20% and cause of death has been linked to the pancreatitis itself, or, rarely, has been associated with HELLP syndrome. 76 The mainstay of treatment, as in the non-pregnant state, is early recognition and intervention 77,78 . A major difference in long term management is that the use of HMG-CoA reductase inhibitors (statins) is contraindicated in pregnancy as they are a teratogenic category X pharmaceutical 79 .  Hypothyroidism -HTG is common in hypothyroidism, having been reported in up to 35% of cases 80 . Decreased free thyroid hormone increases the synthesis of LPL and decreases hepatic lipase activity with a net tendency toward increased plasma TG levels, perhaps further complicated by the down-regulation of LDL receptors [81][82][83][84] . One patient with central hypothyroidism secondary to a craniopharyngioma developed HTG with a level of (3,300 mg/dL) which precipitated an episode of AP 85 .

Treatment
Initial Management -Initial management of patients presenting with HTGP mirrors that of other causes of AP 86 . Patients should be placed on bowel rest, receive nothing by mouth and undergo aggressive fluid resuscitation due to third space losses 87 . Adequate pain control is essential, often through the use of opioid narcotics [88][89][90] . Some controversy still remains about the potential for medication-induced sphincter of Oddi dysfunction aggravating the clinical picture although low dose transdermal fentanyl patches appear do not to compromise sphincteric function 91,92 . Meperidine has been used as an alternative analgesic to treat pain in those suffering from acute pancreatitis, but concern for the production of toxic metabolites has altered prescribing practices [93][94][95] . Enteral nutrition should be resumed as soon as is practical, recognizing that the reintroduction of fats, the building blocks of chylomicrons, may be deleterious [96][97][98][99][100] . Assessment of exocrine function prior to refeeding may be prudent, given that pancreatic destruction has the potential to compromise secretion of digestive enzymes 101 . Beyond initial management, HTGP therapy must include measures to reduce serum TG, both acutely and following the episode to minimize the risk of recurrence 102 . Laboratory tests including liver function tests, glucose, renal function, thyroid stimulating hormone and urine protein should be obtained to rule out secondary causes of HTG 103 . Specific tests documenting LPL or Apo C-II deficiency should be obtained if type I hyperlipidemia is suspected [104][105][106][107] . No standard treatment guidelines yet exist in the specific treatment of HTGP although a rational treatment strategy should include rapidly lowering serum TG, blocking the induction of pro-inflammatory mediators that lead to pancreatic destruction and reducing the likelihood of recurrence by eliminating offending agents, as is possible, and through the use of antihyperlipidemic medications [108][109][110][111] .
Insulin -Intravenous insulin administration is an effective therapy for patients diagnosed with HTG induced pancreatitis, including those with and without diabetes mellitus 112,113 . VLDL is a triglyceride-rich lipid moiety and the use of insulin decreases hepatic production of apolipoprotein B-100 rich VLDL1 and intestinal production of VLDL2, rich in apoprotein B-48 while also increasing hydrolysis of TG by LPL 114,115 . Insulin promotes storage of both glucose and fatty acids, thus a continuous infusion of insulin should reduce serum levels of both of these fuels 116,117 . Intravenous (IV) insulin may be considered more effective and easier to titrate than subcutaneous (SQ) administration based upon absorption and delivery kinetics, although both have been used with some success 104,118,119 . Insulin has been used alone, but is commonly used in conjunction with other TG lowering modalities 120 Heparin -Heparin is an effective treatment in the management of elevated TG in the presence of HTGP 123 . LPL, the enzyme which hydrolyzes TG rich lipoproteins, is normally bound by a heparan sulfate proteoglycan chain to the capillary endothelium 124 . Heparin, when administered in a bolus dose, has a stronger affinity for the LPL binding site than does the heparan sulfate, leading it to dissociate from the endothelium tissue into the plasma as a heparan-LPL complex. 125 This surge of "free" LPL is then able to bind and metabolize lipoproteins at an accelerated rate, thus lowering serum TG levels 126 . Although there is an initial rise in available LPL, there is also a peaking of activity, after which, LPL activity begins to wane as the enzyme is transported and degraded in the liver 127 . This heparinstimulated increase and then reduction in LPL activity can be minimized by the use of intermittent heparin dosing and results in an initial drop in serum TGs, but then followed by a gradual increase 128,129 . This phenomenon tends to be more pronounced with the use of LMW heparin, versus un-fractionated heparin, although studies have shown both preparations capable of lowering severely elevated TG in the setting of HTGP. 130 Heparin has been used as successful monotherapy in treatment of profound HTG in previous studies [131][132][133] ; however, more dramatic results have been achieved when used in combination with other modalities (  Octreotide™ -Somatostatins, also called somatotropin release inhibitory factors (SRIFs) are cyclic peptide hormones which exist in 2 forms, SRIF14 (14 amino acids) and SRIF28 (28 amino acids) 135 , and are synthesized in several sites within the body, including the central nervous system, pituitary, gastrointestinal (GI) tract, liver, pancreas, and urogenital system 135,136 . SRIFs bind to 6 subpopulations of somatostatin receptors (sstrs) (1, 2 A , 2 B , 3, 4, 5) located both peripherally and centrally 137 . The sstr 2 B receptor has been demonstrated in rodents but not unequivocally in humans 138 . Binding of somatostatins to each of these receptors leads to the inhibition of adenylate cyclase via a pertussis toxin sensitive Gprotein (Gαi) and, at agonist concentrations greater than 1-nM, there is stimulation of phospholipase C which increases calcium ion mobilization 139 . In neuroendocrine cells, sstrs 2,3,4 and 5 bind to inward rectifying potassium channels 140 . SRIFs inhibit the secretion of several GI tract hormones including insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin and also inhibit exocrine gastric acid, pepsin, pancreatic enzymes, bile and intestinal fluid secretions 141 . The pancreas expresses sstrs on both acinar cells (sstr4, sstr5) 142 and islet cells (sstr1 > sstr5 > sstr2 > sstr3 > sstr4) 143 . In rodents, sstr2 in the dorsal vagal complex exerts some control of pancreatic exocrine secretion 144 . Octreotide, a somatostatin analog, has particular affinity for types 2 A , 2 B and somewhat for sstr5 145 . Octreotide has been used in the treatment of pancreatitis with varying degrees of success 146 . The evidence that pancreatic sstrs are down-regulated in acute pancreatitis suggests that the mechanisms of action of octreotide therapy may include both receptor and non-receptor mediated mechanisms 147 . Secretion of insulin and glucagon are inhibited by agonists of sstr2, sstr5, and sstr1 148 . Inhibition of glucagon secretion with octreotide therapy may potentiate the fatty acid storing action of insulin and lead to a greater reduction of serum TG 149 . Octreotide's effect on the hypoglycemic counter regulatory system, notably the hyperglycemic actions of glucagon, necessitates the co-administration of dextrose and frequent monitoring of glucose levels to maintain euglycemia.

Long-term management
Diet and General Precautions -Primary causes of hyperlipidemia often require medications but, where possible, reducing the impact of secondary causes with therapeutic lifestyle changes such as reducing alcohol intake, weight reduction, improved diabetic control and discontinuing precipitating medications are all vital steps 158 . Dietary advice should be obtained through a certified nutritionist, but fat consumption should be reduced to 7% of total caloric intake, cholesterol limited to 200mg and trans fatty acid intake should be limited 159 . Medium chain TG are an improved source of fat calories as they are absorbed directly into portal circulation and do not require chylomicrons for hepatic uptake and lower TG levels at the cost of a slightly elevated cholesterol level 160 . A meta-analysis performed by Dattilo and Kris-Etherson observed a strong correlation between weight loss and decrease in plasma TG levels. 161 Medications: Fibrates -Fibric acid derivatives are a class of medications which bind to peroxisome proliferator alpha (PPARα) receptors and are capable of increasing serum HDL while simultaneously lowering TG and are an effective adjunct in treating patients with HTGP who cannot be managed with diet alone 162 . They are typically used in treating primary HTG and include drugs such as gemfibrozil, bezafibrate and fenofibrate 163 . Fibrates lower serum TG by increasing the levels of LPL and hepatic lipase, reducing levels of Apo CIII, which down-regulates LPL activity, and by increasing fatty acid uptake by the liver 164,165 . Toxicities include elevated liver enzyme levels, cholelithithiasis, myalgias and rhabdomyolysis; the last two of these are more common when used in patients with impaired renal function 166 . Two cases have been reported where patients developed pancreatitis while taking fibrate or fibrate-statin combinations. 167,168 It is unclear whether the cause of the pancreatitis was directly related to the drug itself, a failure of treatment or possibly through the formation of biliary sludge or gallstone formation. Niacin -Niacin, a B vitamin somewhat less potent than the fibric acids, decreases TG levels by reducing hepatic secretion of VLDL and TG while raising HDL and lowering LDL levels, an overall positive impact on the lipid profile 169 . When used as doses of 1,500mg/day, no adverse impact on glucose metabolism is seen but significant prostaglandin D2-mediated flushing limits the clinical utility of this drug 170 .
Statins -HMG-CoA reductase inhibitors (statins) are not the preferred method for lowering serum TG as their role in lipid management remains in prevention (primary and secondary) of coronary artery disease in the presence of elevated cholesterol, but only mild to moderate triglyceride elevations 171 . Statins are not suitable monotherapy for long-term management of HTG, however, they may have some synergistic benefit when combined with fibrates 172,173 . Omega 3 Fatty Acids -Fish oils and omega-3 fatty acids are effective adjuncts to other drug therapy as they lead other drug therapy as they lead to a decrease in VLDL and lower endogenously derived TG-rich lipoproteins 174,175 . Active TG lowering molecules in these supplements include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 176 . Omega-3 fatty acids were studied in a prospective, double-blinded trial and were able to lower TG levels, ranging from 500-2,000 mg/dL, by an average of 45% 177 . The minimum effective dose is approximately 1 g/d; however, a dose of 3 to 4 g/d has shown to reduce serum TG by 30-50% in hyperlipidemic patients 178 .

Conclusion
HTG is a significant cause of AP, with most estimates ranging from 1-7% of all cases. Presentation is often similar to other forms of AP, with lipemic serum usually the only distinguishing initial sign. Clinicians should routinely test TG levels in patients with suspected or confirmed AP, especially those who have a history of diabetes, alcoholism, obesity, are taking a known precipitating medication, are pregnant or display normal amylase in the presence of elevated lipase.
To date, there are no official guidelines for the treatment of HTGP, although a number of different treatment modalities have been employed to rapidly lower the serum TG, including insulin, heparin, fibric acids and omega 3 fatty acids. Plasmapheresis can also rapidly lower serum TG levels, but significant potential side effects and lack of rigorous proof of efficacy have yet to clarify its role in treatment of HTGP. Long term management with diet modification and anti-hyperlipidemic medications such as statins, niacin and omega-3 fatty acids are excellent adjuncts in controlling TGs in patients with HTGP and preventing potential recurrences. We have achieved dramatic effects with the combination of insulin, heparin and octreotide, a reduction in TG levels of two orders of magnitude in 48 hours, results unprecedented in the literature. These results, while impressive, have yet to be reproduced and one must remain appropriately circumspect when interpreting this case report. It is also important to note that the positive barbiturate level may have unmasked an inducible porphyria and that rapid resolution of HTGP was aided by the removal of this compound from the metabolic milieu. No clear treatment algorithm exists for the management of HTGP and welldesigned, controlled, prospective studies are needed to clearly delineate the ideal regimen.

Disclaimer
The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Armed Forces, Department of Defense, or the U.S. Government