Hypertriglyceridemic pancreatitis

Dec. 15, 2018

Severe hypertriglyceridemia is the third most common cause for acute pancreatitis, and has been estimated to account for nearly 9 percent of patients with acute pancreatitis. Vinaya Simha, M.B.B.S., M.D., with Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic's campus in Rochester, Minnesota, says: "Limited evidence suggests that hypertriglycerdemic pancreatitis is more severe than other forms of acute pancreatitis and that the severity depends on the degree of hypertriglyceridemia. While this is not established, it is quite clear that the risk of pancreatitis increases with higher serum triglyceride (TG) levels.

"While the risk of acute pancreatitis in the general population is about 0.5 to 1 percent, and about 5 percent in people with alcoholism, the risk increases to 10 percent in those with serum TG above 1,000 mg/dL. The risk increases further, to above 50 percent, when serum TG is greater than 5,000 mg/dL. Hypertriglyceridemic pancreatitis is unlikely when serum TG is below 1,000 mg/dL, and in a large study of people with acute pancreatitis, the median TG level at presentation was around 2,600 mg/dL. It is, however, important to recognize that even extreme elevations of serum TG can occur as an epiphenomenon in patients with other forms of acute pancreatitis as well."

Kristen M. Gonzales, M.D., a clinical fellow with Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minnesota, explains: "The pathogenesis of hypertriglyceridemic pancreatitis is not clear, but likely involves free fatty acid-mediated cellular damage. Large TG-rich lipoprotein particles, primarily chylomicrons, impede capillary circulation and cause ischemic damage to pancreatic acinar cells. Damaged cells release lipase and other enzymes into the interstitium, leading to TG hydrolysis and free fatty acid release. Free fatty acid aggravates cellular damage through a variety of mechanisms, including endothelial damage, vascular leak, mitochondrial toxicity, platelet aggregation and activation of coagulation cascade."

Maria (Daniela) D. Hurtado Andrade, M.D., Ph.D., a clinical fellow with Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minnesota, adds: "Homozygous deficiency of lipoprotein lipase causing familial chylomicronemia syndrome is the most common primary monogenic disorder responsible for hypertriglyceridemic pancreatitis. Many other genetic defects involving lipoprotein lipase-mediated TG hydrolysis, such as mutations in apolipoproteins C-II and A-V, LMF1, and GPIHBP1, also have been described in a few pedigrees. However, these are extremely rare disorders, including lipoprotein lipase deficiency, which has an estimated prevalence of one in a million. Secondary exacerbating factors in patients with an underlying lipid disorder, often polygenic, are more commonly responsible for hypertriglyceridemic pancreatitis. It is therefore very important to seek and address these secondary causes for elevated TG, which include uncontrolled diabetes, alcohol use, weight gain, and high intake of saturated fats and refined carbohydrates. Drug-induced hypertriglyceridemia is another important cause for acute pancreatitis. The list of offending agents includes estrogen, retinoic acid derivatives, sirolimus, L-asparaginase, capecitabine, protease inhibitors and propofol."

Tiffany M. Cortes, M.D., a clinical fellow with Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic's campus in Minnesota, highlights: "Treatment of hypertriglyceridemic pancreatitis, similar to other forms of acute pancreatitis, primarily involves intravenous hydration and other supportive measures, adequate analgesia, and fasting. The NPO state not only helps decrease pancreatic secretion and inflammation but also decreases further generation of chylomicrons. Pharmacotherapy to lower serum TG with fibrates is unlikely to be beneficial in the initial stages, and attention has focused on other measures to achieve this. Therapeutic plasma exchange is clearly effective in rapidly decreasing serum TG by nearly 60 to 80 percent, but it is not clear if this results in significant clinical benefit.

"Small uncontrolled studies and retrospective analysis have shown only minimal improvement in scores assessing pancreatitis severity with no change in mortality or complications. Similarly, a randomized controlled trial showed no benefit of high-volume hemofiltration, which reduced serum TG to below 500 mg/dL in less than 12 hours, when compared with intravenous (IV) insulin and low molecular weight heparin. In fact there was a higher incidence of organ failure in the hemofiltration group with no difference in mortality, local complications or length of stay."

Dr. Simha adds: "IV insulin infusion is an effective but underutilized intervention to reduce serum TG. Insulin is not only an activator of lipoprotein lipase but also suppresses free fatty acid release, thus limiting further generation of TG-rich lipoproteins from the liver. It is also the optimal therapy for hyperglycemia and should clearly be the treatment of choice for patients with hypertriglyceridemic pancreatitis secondary to uncontrolled diabetes.

"Drs. Gonzales, Hurtado Andrade, Cortes and I retrospectively reviewed the clinical course of 94 adult patients with hypertriglyceridemic pancreatitis admitted to Mayo Clinic in Rochester, Minnesota, from 2001-2016, to gain insight into the role of IV insulin therapy. Sixty-four patients received IV insulin infusion. Nine patients were additionally treated with plasma exchange therapy and 21 patients received only conservative treatment. Plasma exchange therapy was associated with a more rapid decline in serum TG as expected, but there was no difference in the length of hospital stay or overall complications between IV insulin and plasma exchange therapy. Baseline TG and pancreatitis severity were comparable between the two groups. Of the 64 patients who received IV insulin, nine did not have diabetes. Serum TG declined more rapidly in these patients, but overall clinical outcomes were similar.

"These limited observations on the benefits of IV insulin infusion in hypertriglyceridemic pancreatitis need to be confirmed by larger clinical trials. The optimal dose and duration of IV insulin infusion also need to be determined. Meanwhile, it is important for clinicians to recognize IV insulin infusion as a safe, effective and economical therapeutic option compared with plasma exchange therapy when treating hypertriglyceridemic pancreatitis."

Dr. Simha advises: "To prevent hypertriglyceridemic pancreatitis, it is reasonable to target fasting serum TG below 500 mg/dL, employing both pharmacologic and lifestyle interventions. Strict adherence to a diet low in saturated fat and refined carbohydrates is likely to be beneficial in most patients. There is considerable interest in novel TG-lowering therapies involving anti-sense oligonucleotides targeting apolipoprotein C-III and ANGPTL3-4, but their safety and long-term efficacy need to be established."