Therapeutic plasmapheresis for hypertriglyceridemia-associated acute pancreatitis: case series and review of the literature

Abstract

Background:

Severe hypertriglyceridemia (HTG) is the third leading cause of acute pancreatitis (AP) in the United States. The current standard of care includes management of HTG using pharmacological therapy. More recently, plasmapheresis has been proposed as a therapeutic tool for decreasing triglyceride (TG) levels, especially in critically ill patients. Few studies are available to ascertain overall benefits of plasmapheresis over traditional management.

Objective:

To analyze the outcomes of patients treated with plasmapheresis for severe HTG-associated pancreatitis.

Methods:

We conducted a retrospective chart review of three patients with severe HTG- associated (TGs greater than 1000 mg/dl; 11.29 mmol/l) AP at the Methodist University Hospital. All the patients underwent plasmapheresis as part of their treatment.

Results:

The average TG level before plasmapheresis was 3532 mg/dl (range: 2524–4562 mg/dl; 39.9 mmol/l; range: 28.5–51.6 mmol/l). All patients made a full recovery, with a significant improvement in TG levels after plasmapheresis. The mean number of sessions was 1.3 (range 1–2), and mean TG level after plasmapheresis was 1051 mg/dl (range: 509–1771 mg/dl; 11.9 mmol/l; range: 5.8–20 mmol/l). After the first session, the average reduction of TG level was 2481 mg/dl (range 753–3750 mg/dl; 28 mmol/l; range: 8.5–42.4 mmol/l) or approximately 70%. None of the patients developed complications related to plasmapheresis.

Conclusions:

Plasmapheresis can be an effective and rapid treatment option in patients with severe HTG and complications. However, further research, including randomized controlled studies, is necessary.

Keywords

hypertriglyceridemia lipoprotein lipase pancreatitis plasmapheresis

Introduction

Severe hypertriglyceridemia (HTG) is a well known etiology of acute pancreatitis (AP) and is currently the third leading cause of AP after alcohol and gallstones in the United States.^1,2,3,4 Some studies suggest that up to 26% of patients with severe HTG experience at least one attack of AP in their lifetime, with younger populations noted to have a severe clinical course.^5,6 Additionally, it is a common cause of morbidity and mortality with a reported incidence of 40 per 100,000 persons in the Western population.⁷ Current management of HTG-associated AP (HTG-AP) includes resting the pancreas, adequate fluid resuscitation, as well as optimal pain control.⁸ Further management can include utilization of insulin as well as heparin drip.^9,10 Therapeutic plasmapheresis has been proposed and utilized as a possible treatment modality.^10–14 It is not clear if plasmapheresis offers benefits beyond those offered by other therapeutic modalities.

Pathophysiology

The pathophysiology of HTG-associated pancreatitis is key to understanding the basis of various treatment modalities as well as identifying high-risk patient populations. Environmental, as well as genetic factors play an important role in induction of HTG, and a number of genes that modulate triglyceride (TG) levels have been implicated.^15,16

Lipoprotein lipase (LPL) is a key enzyme that hydrolyzes TG in lipoproteins. LPL requires two other crucial apolipoproteins to function: apolipoprotein (apo) C-II, a cofactor of LPL, and apo A-V, a modulator of LPL function. Deficiency in LPL, apo C-II, or apo A-V leads to defective LPL-mediated TG hydrolysis.¹⁵

Most lipids are delivered to peripheral tissues such as muscle and fat through the activity of LPL. The function of LPL is a rate-limiting step for clearance of plasma TGs and is essential for generation of high density lipoprotein (HDL) particles.¹⁷ Additionally, LPL also hydrolyzes TGs in circulating TG-rich lipoproteins to allow peripheral sites such as adipose tissue and muscle access to preformed fatty acids. Furthermore, this lipid flux is also controlled by insulin, which increases LPL in fat and decreases LPL in muscle.¹⁸

Mutations in the LPL gene or its activator Apo C-II have been identified in AP-HTG.¹⁹ The incidence of LPL deficiency is about one:one million and the incidence of Apo C-II deficiency is even lower.¹⁹ Deregulation or deficiency of these key enzymes and substrates involved in TG metabolism has also been described in patients with recurrent HTG-induced AP.²⁰ This enzyme deficiency can also lead to two autosomal recessive disorders, Wolman disease and cholesteryl ester storage disease.²¹

The exact mechanism of HTG causing AP remains unclear and is a topic of controversial discussion.²² Theory proposed by Havel in 1969 suggests that excess TG is hydrolyzed by high levels of pancreatic lipase released in the vascular bed of the pancreas. This leads to free fatty acids (FFAs) being released in high concentrations.²³ As the concentration of FFAs increases, the free binding capacity of albumin diminishes.²⁰ These unbound FFAs self-aggregate into micellar structures with detergent properties, causing acinar-cell and pancreatic-capillary injury.²² This resultant ischemia creates an acidic environment, which further triggers FFA toxicity. Additionally, the elevated levels of chylomicrons also increase the viscosity of blood and further impair the blood flow in the pancreas, causing ischemia and acidosis within the pancreas.²²

Heparin and insulin infusions have been used for the treatment of HTG-AP. The underlying evidence for these treatment modalities comes mainly from case reports and observational series with no consensus existing currently in the field of endocrinology for standard therapy. The rationale for the use of insulin is linked with the synthesis of LPL from adipose and muscle cells.^{9,20,22,24–28} Infusion of unfractionated heparin releases LPL attached to the endothelial cells^{9,22,24,25,27,28} in addition to reducing the clotting susceptibility associated with hyperviscosity due to HTG.

Plasmapheresis can be used for rapid removal of plasma lipoproteins. Reduction of TGs is the primary goal in patients who have HTG-associated pancreatitis.²⁹ Correction of lipid levels is critical in patients who are at high risk of pancreatic necrosis and requiring intensive care.³⁰ Rapid correction may decrease overall morbidity in critically ill patients.

Subjects and methods

Approval from the Institutional Review Board of the University of Tennessee Health Science Center was obtained and a retrospective study was conducted at the Methodist University Hospital. Charts were reviewed of adults (age ≥ 18) from November 2007 to July 2016. A total of 15 patients using International Classification of Diseases, Ninth Revision (ICD-9) code for therapeutic plasmapheresis were selected. Twelve patients were excluded for various other indications for plasmapheresis such as thrombotic thrombocytopenic purpura, overdose and thrombocytosis, Guillain-Barre Syndrome and myasthenia gravis. Chart review was conducted to assess the indication for therapeutic plasmapheresis and three patients fulfilled the criterion for severe HTG-AP with treatment modality of plasmapheresis used to lower TG levels. Severe HTG was defined by TG levels > 1000 mg/dl (11.29 mmol/l).²²

Case 1

A 38-year-old African-American male with past medical history of pancreatitis secondary to HTG (compliant with gemfibrozil 600 mg twice daily), presented to the Emergency Department (ED) with nausea, emesis, and abdominal pain. Physical examination was consistent with diffuse abdominal tenderness. Laboratory values revealed lipase level of 4445 unit/l [normal fasting range: 73–393 unit/l; 74.1 (µmol/s·l), range: 1.2–6.6 (µmol/s·l)] and TG level of 4562 mg/dl (51.5 mmol/l; normal < 1.7 mmol/l) with bedside index for severity in acute pancreatitis (BISAP) score of 0 upon admission to the medical intensive care unit (MICU). No abdominal ultrasound or computed tomography (CT) was available for review during this hospital course. In the MICU, he was started on an insulin drip at 5 units/h as well as plasmapheresis. His next serum TG level obtained after one cycle of plasmapheresis was noted to be 812 mg/dl (9.2 mmol/l). Overnight, the patient’s abdominal pain had resolved and he was no longer having any episodes of emesis. He left the MICU against medical advice. His other pertinent information included no history of type 2 diabetes mellitus (T2DM). His total hospital stay was less than 2 days.

Case 2

A 36-year-old African-American male with a past medical history of hypertension and T2DM presented to the ED with nausea, emesis, and abdominal pain. Physical examination was consistent with diffuse abdominal tenderness but no guarding or rebound tenderness was present. Laboratory values revealed a lipase level of 11,250 unit/l [normal fasting range: 73–393 unit/l; 187.5 (µmol/s·l), range: 1.2–6.6 (µmol/s·l)] and TG level of 3704 mg/dl (41.8 mmol/l) with BISAP score of 2 upon admission to the MICU. CT imaging was consistent with necrotizing pancreatitis and the patient was treated for sepsis. He was also started on an insulin drip at 5 units/h. A repeat TG level 30 h after admission was noted to be 2524 mg/dl (28.5 mmol/l) and the patient was subsequently started on plasmapheresis. After the first session of plasmapheresis, his serum TGs decreased to 1771 mg/dl (20.0 mmol/l). The patient underwent a second cycle of apheresis, with reduction of his TG level to 172 mg/dl (1.9 mmol/l). It is worthy to note that reduction of TG levels cannot be attributed completely to initiation of plasmapheresis in this case, since significant reduction in TG was also noted following insulin therapy. The patient received intensive care treatment for 2 days, followed by a prolonged hospital stay of 14 days. At discharge, he was prescribed fenofibrate 145 mg daily and 40 mg of atorvastatin daily with a close follow up with his primary care doctor for liver-function monitoring.

Case 3

A 31-year-old white female with past medical history of polycystic ovarian syndrome, obesity and dyslipidemia compliant with rosuvastatin presented to the ED with a 1-day history of nausea, emesis, and abdominal pain. Physical examination was consistent with diffuse abdominal tenderness but no guarding or rebound tenderness was present. Laboratory values revealed lipase level of 1237 unit/l [normal fasting range: 73–393 unit/l; 20.6 (µmol/s·L), range: 1.2–6.6 (µmol/s·L)] and TG level of 3512 mg/dl (39.7 mmol/l) with BISAP score of 1 upon admission to the MICU. CT imaging was consistent with AP involving the entire pancreatic parenchyma. She was started on an insulin drip at 5 units/h, as well as received one cycle of plasmapheresis with reduction of TGs to 509 mg/dl (5.7 mmol/l). At the time of discharge, her TG level was 166 mg/dl (1.9 mmol/l). She spent a total of 6 days in the hospital, 5 of which were in the MICU. She was discharged on gemfibrozil.

Results

Characteristic profiles of the patients are included in Table 1. The mean age of the patients was 35, with an age range of 31–38. The mean BMI was 34.3 kg/m².² The mean TG level on admission was 3532 mg/dl (range: 2524–4562 mg/dl; 39.9 mmol/l, range: 28.5–51.1 mmol/l). All patients made a full recovery, with a significant improvement in TG levels after plasmapheresis. The mean number of sessions was 1.3 (range 1–2), and mean TG level after plasmapheresis was 1051 mg/dl (range: 509–1771 mg/dl; 11.9 mmol/l, range: 5.7–20.0 mmol/l). After the first session, the mean decrease in TG levels was 70% (2481 mg/dl, range: 753–3750 mg/dl; 28 mmol/l, range: 8.5–42.3 mmol/l) (Figure 1). None of the patients developed complications related to plasmapheresis, such as cardiac arrhythmias, hemorrhage or allergic reactions.³¹ No evidence of gallstones on imaging was noted and patients did not have any endoscopic intervention prior to admission to the hospital for AP. None of the patients required mechanical ventilation or vasopressor support secondary to hypotension and no mortality was noted. There were no readmissions to the hospital within 30 days of discharge. The mean length of hospital stay was 7.3 days in the hospital, with 3 days on average spent in the MICU.

Table 1.

Baseline characteristics of patients.

Case	Case 1	Case 2	Case 3
Gender	Male	Male	Female
Race	AA	AA	W
Age (years)	38	36	31
BMI (kg/m²)	29.7	33	40
HDL (mmol/l)	1.4	0.4	0.7
Cholesterol (mmol/l)	6.9	4.3	11.6
LDL (mmol/l)	3.5	2.0	1.5
Lipase on admission (µmol/s·l)	74.1	187.5	20.6
Lipase 24 h after admission (µmol/s·l)	39.9	32.6	19.7
Amylase on admission (µkat/l)	2.5	Not reported	2.31
TGA on admission (mmol/l)	51.5	41.8	39.7
TGA on day of apheresis (mmol/l)	51.5	28.5	39.7
TGA right after apheresis (mmol/l)	9.2	20.0	5.7
TGA around discharge (mmol/l)	9.2	1.9	1.9
Alcohol use	Yes	No	Occasional use
T2DM	No	Yes	No
BISAP score	0	2	0
TSH (mIU/ml)	3.67	0.517	1.16
No. of apheresis sessions	1	2	1
Complications of apheresis	None	None	None
MICU length of stay (LOS) in days	1	2	5
Total LOS (days)	2	14	6

AA, African-American; W, white; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TGA, Triglyceride; T2DM, type 2 diabetes mellitus; BISAP, bedside index for severity in acute pancreatitis; TSH, thyroid stimulating hormone; MICU, medical intensive care unit.

Figure 1:

Triglyceride levels at various time points during the course of hospitalization.

Implications for clinical care

HTG-AP typically occurs in individuals with an underlying genetic abnormality of lipid metabolism such as familial combined hyperlipidemia, familial HTG or other rare abnormalities.¹⁶ Severe HTG in a young patient in the absence of secondary causes should prompt clinical suspicion for genetic predisposition. Genetic testing and counseling to establish an early diagnosis should be considered to identify at-risk patients as well as their family members. Lipid screening for cardiovascular risk reduction should be regularly conducted and focus on lifestyle and dietary modification should be implemented.³² Younger patients are more likely to present with enzyme deficiencies leading to worse clinical outcome.³³ Additionally, patients with one or more secondary risk factors such as poorly controlled diabetes mellitus, heavy alcohol consumption, obesity, certain medications or pregnancy are also at an increased risk for developing HTG-AP.¹⁶ The Centers for Disease Control and Prevention (CDC) recommend that therapeutic intervention for class 1 obesity include lifestyle modifications, including diet and exercise.^34,35

Severe HTG is an uncommon condition that can lead to severe complications, such as AP. Standard treatment of AP includes diet, adequate replacement of electrolytes, and symptom control. However, a rapid decrease in TG levels is key to the successful management of HTG-induced pancreatitis.³⁶ Treatment for HTG-associated pancreatitis includes decreasing the TG levels using insulin, plasmapheresis, or a combination of both.²⁴ Treatment with insulin is essential and remains the standard of care.^37,38 Studies analyzing the effect of plasmapheresis for HTG-AP have been scarce with generally low sample sizes. However, several studies have showed that plasmapheresis is an effective tool for lowering TG levels.^36,37,39,40 In our sample, the mean decrease in TG level was approximately 70% after one session, thus showing that plasmapheresis is a useful tool for immediately decreasing TG to safe levels. Although there are no consensus endocrinology guidelines for management of HTG-AP, there are convincing data that reduction of serum TG levels to <500 mg/dl (5.6 mmol/l) can prevent development of AP.⁴¹ Combination of statin therapy, along with fenofibrate, has been shown to achieve considerable decrease in TG levels compared with monotherapy. The safety profile of combination versus monotherapy was comparable.⁴² In addition to pharmacological intervention, dietary modification and dietetics consultation should be strongly considered in maintaining goal TG levels.^16,43

Some studies have noted that patients with HTG-AP TG levels > 5000 mg/dl (56.5 mmol/l) who received plasmapheresis experienced shorter hospital course and decreased hospital readmissions than patients who did not receive plasmapheresis .⁴⁰ No evidence exists to support mortality reduction at this time.⁶ However, plasmapheresis usually requires a large tertiary treatment center, is more invasive and is generally more expensive compared with insulin therapy. On the contrary, insulin therapy is readily available and can be used safely in various settings and different levels of care, such as MICU or the ward floor.

Conclusion

Plasmapheresis is an effective and rapid treatment in patients with severe HTG who are at increased risk of developing complications. Plasmapheresis should be performed as early as possible, at 24-to-48 h intervals, until TG levels have been lowered to (ideally) <500 mg/dl (5.6 mmol/l). Randomized controlled studies are warranted to assess the efficacy of plasmapheresis as a treatment modality for HTG-associated pancreatitis.

Footnotes

Acknowledgements

Authors would like to thank Priya Abraham and Akshay Sharma for their thoughtful recommendations.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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