Transcript Hypertriglyceridemic Pancreatitis

HYPERTRIGLYCERIDEMIA-INDUCED
PANCREATITIS
Richa Shukla, PGY5
Faculty Mentor: Dr. Suneal Agarwal
September 4, 2014
HPI
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Reason for consult: pancreatitis
31F G2P1, 24-weeks pregnant patient who presented
as an outside hospital transfer for management of
pancreatitis
Initially presented to a hospital in Odessa on
1/12/14 with complaints of 2-3 days of severe
epigastric pain. No clear etiology found and patient
was discharged after resolution of pain
Case Discussion (cont.)
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Patient returned to the OSH on 1/26/14 with ~2-3
days of worsening epigastric pain radiating to the
back
On admission, was found to be in diabetic ketoacidosis
and had laboratory evidence of pancreatitis with a
lipase of 2400.
Patient’s triglycerides were found to be >10,000
Was diagnosed with hypertriglyceridemic pancreatitis.
Case Discussion (cont.)
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Managed for both DKA and hypertriglyceridemic
pancreatitis with 2 days of plasmapharesis (1/27,
1/28), an insulin drip and aggressive IV fluid
resuscitation.
Lipase improved to 1000, triglycerides to 1800 and
DKA resolved
Transferred to the TCH Pavillion for Women on 1/28
for dyspnea, increased work of breathing and
pulmonary edema
Case Discussion (cont.)
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On admission reported persistent epigastric pain
requiring IV opiates, nausea/vomiting and dyspnea
Seen by Endocrinology and started on a subcutaneous
insulin regimen.
Pancreatitis was managed conservatively with bowel
rest and pain management.
Started on Omega-3-acid ethyl esters (Lovaza) on
1/31 and Gemfibrozil on 2/5
Case Discussion (cont.)
Past Medical History:
-?Type I v. Type IV v. Type V
hyperlipoproteinemia diagnosed at
age ~28
-Insulin-dependent Diabetes Mellitus
diagnosed at age ~23
-Recurrent pancreatitis
Past Surgical History:
-Cholecystectomy 2011
-complicated by abdominal wound
infection requiring abdominal wall
plasty
-Pancreatic debridement for necrotizing
pancreatitis 2011
Home Medications:
-Insulin Glargine 32 units SQ daily
-Insulin Novolog 8 units TID AC meals
-Previously on fibrates, self d/c’ed 1
year PTA
Social history
-Denies smoking, alcohol or drug use
-Currently unemployed
Family History:
-No known family members with
hypertriglyceridemia
Physical Exam
T 99.7, BP 126/84, HR 113, RR 22, O2 sat 96% 2L NC
Gen: NAD, AAOx4
HEENT: anicteric sclera, PERRL, EOMI, MMM, OP clear
CV: RRR no m/r/g
Chest: bilateral crackles in lower lung fields, no wheezes
Abd: soft, tender to palpation in epigastric region, NABS,
+gravid uterus
Ext: WWP, no clubbing or cyanosis, trace LE edema
Neuro: oriented x4, fatigued, conversational
Laboratory Results
Date
Prior to
admission
1/29
1/30
1/31
2/2
2/3
2/4
2/5
2/6
2/7
Lipase
2400
275
148
156
160
259
184
195
265
262
Amylase
N/A
87
N/A
N/A
82
118
105
97
125
132
834
883
629
562
646
606
411
494
502
Triglycerides >10000
Lovaza started
Gemfibrozil started
Severity of pancreatitis
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Not all results from her outside hospital admission
were available however notes from the OSH suggest
BISAP score of 2 on admission
Imaging Results
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Abdominal Ultrasound:
 Liver:
21.9 cm in length at the right midclavicular line.
Normal echogenicity. No mass. Main portal vein
diameter 1.3 cm. There is moderate degree of
periportal edema.
 Biliary tree: Common duct is 5 mm. No significant
intrahepatic biliary dilatation.
 Gallbladder: Removed.
 Pancreas: Partially visualized and unremarkable.
 Ascites: Small amount of perihepatic ascites.
 Spleen: 13.3 cm in length.
Imaging results
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Chest x-ray 1/29/14
 Bilateral
central perihilar and basilar opacities which are
nonspecific but may reflect a combination of edema and
atelectatic lung.
Case discussion
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Lipase and triglycerides stabilized on oral lipidlowering regimen
Patient placed on low fat diet
Weaned off narcotics
Pain, nausea, vomiting and dyspnea resolved
Clinical Questions
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What are the causes of acquired and inherited lipid
disorders? How do they cause pancreatitis?
How is hypertriglyceridemic pancreatitis managed?
Is there any relationship of hypertriglyceridemic
pancreatitis to pregnancy? If so, is there a specific
treatment in pregnant women?
Clinical Questions
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What are the causes of acquired and inherited lipid
disorders? How do they cause pancreatitis?
How is hypertriglyceridemic pancreatitis managed?
Is there any relationship of hypertriglyceridemic
pancreatitis to pregnancy? If so, is there a specific
treatment in pregnant women?
Hyperlipidemia
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Hyperlipidemia/dysplipidemia results from abnormal
levels (>90% percentile) of cholesterol OR
triglycerides in the blood
Inherited and acquired disorders of lipid metabolism
Acquired causes of hyperlipidemia include: obesity,
diabetes mellitus (especially DKA), nephrotic
syndrome, hypothyroidism, pregnancy, drugs
(clomiphene, mirtazapine, tamoxifen, HAART, estrogen,
beta-blockers, thiazide diuretics, steroids)
Fredrickson’s classification of inherited
lipid disorders
Present in
adulthood
Fredrickson DS, Lees RS. Editorial: A system of phenotyping hyperlipoproteinemia. Circulation 1965;31:321-27.
Hypertriglyceridemic Pancreatitis
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HTG: fasting serum triglyceride level of >150 mg/dL.
mild (150-199 mg/dL)
 moderate (200-999 mg/dL)
 severe (1000 to 1999 mg/dL)
 very severe (>2000 mg/dL)
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3rd most common cause of pancreatitis (~10% of all cases
of acute pancreatitis and up to 56% of pancreatitis cases
during pregnancy)
Risk of AP in patients with serum triglycerides >1000 and
>2000 mg/dL is ∼5% and 10% to 20%, respectively.
Speck et al. Arch Verin Wissenschaftl Heilkunde. 1865
Presentation of HTGP
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Similar to that of acute pancreatitis (AP) from other
causes: abdominal pain, nausea, and vomiting
Amylase may be falsely normal (due to high TG
levels), lipase may also be unaffected
Labs may also show pseudohyponatremia
Poorly controlled DM, alcoholism, obesity, pregnancy,
prior pancreatitis, and a personal or family history of
hyperlipidemia should suggest HTGP
Hypertriglyceridemia-induced
Pancreatitis
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Seen with secondary factors (ex. uncontrolled
diabetes, alcoholism, medications, pregnancy) in
patients with an underlying common genetic
abnormality of lipoprotein metabolism (Fredrickson’s
Type IIB and IV)
Less commonly, patients with rare genetic
abnormalities of lipoprotein metabolism (i.e.
Fredrickson’s Type I and V) will develop pancreatitis
without additional inciting factors.
Scherer J, Singh VP, Pitchumoni CS, Yadav D. Issues in hypertriglyceridemic pancreatitis: an update. J Clin
Gastroenterol. 2014 Mar;48(3):195-203.
Relationship between
primary and
secondary factors in
inducing severe HTG
and thus increasing
the risk of pancreatitis
Lactescent serum seen in HTG
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Chylomicrons: TG-rich
lipoprotein particles. Present
in circulation when TG > 900
mg/dl
Large enough to occlude
pancreatic capillaries,
leading to ischemia and
acinar structural alteration,
and also release of
pancreatic lipase
Photo adapted from Tsuang et al. Hypertriglyceridemic pancreatitis: presentation and management. Am J
Gastroenterology 2009 Apr;104(4):984-91
Mechanism of HTGP
Enhanced lipolysis from high pancreatic
lipase
Increased concentration of FFA
Formationof FFA micellar structures
Release of inflammatory mediators and free
radicals
Inflammation, edema, necrosis of pancreas
Kota et al. Indian J Endocrinol Metab. 2012 Jan-Feb; 16(1): 141–143.
Severity and outcomes in HTGP
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Unclear if the severity of pancreatitis is associated with
triglyceride levels
Lloret et al.
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Balachandra et al.
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129 patients with types IV and V HTG
20% developed pancreatitis with risk increasing with TG levels.
Of patients with severe and very severe HTG, 71.5% had severe AP
Small case series of 43 patients
showed that the severity of HTGP did not seem to correlate directly
with the triglyceride level
Pancreatic lipase activity, efficiency serum FFA clearance, and
severity of underlying pancreatic injury important in determining
overall outcomes
Lloret Linares et al. Pancreas. 2008;37(1):13.
Balachandra et al. Int J Clin Pract. 2006;60(2):156.
Clinical Questions
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What are the causes of acquired and inherited lipid
disorders? How do they cause pancreatitis?
How is hypertriglyceridemic pancreatitis managed?
Is there any relationship of hypertriglyceridemic
pancreatitis to pregnancy? If so, is there a specific
treatment in pregnant women?
Management of HTGP
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Conventional treatment of pancreatitis: aggressive
fluid resuscitation, analgesia, bowel rest
Insulin infusion
Heparin
Plasmapharesis
Lipid lowering agents – fibrates, omega-3 fatty acids
Insulin
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Decreases serum TG levels by enhancing lipoprotein
lipase activity
Inhibits hormone-sensitive lipase in adipocytes
HTGP often presents in poorly controlled diabetics
and thus should be used both to manage
hyperglycemia and HTG
Intravenous infusion of regular insulin in D5 at 0.1-0.3
units/kg/day to maintain blood glucose 150-200
mg/dl
Heparin
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Usually used in conjunction with insulin to enhance
lipoprotein lipase activity
One case report including 5 patients with HTGP with
TG levels > 1000 showed decrease in TG levels to <
500 within 3 days in all cases with use of heparin
and/or insulin
Use of heparin in management of HTGP is controversial
Berger et al. heparin and insulin treatment of acute pancreatitis caused by hypertriglyceridemia. Experience of 5
cases. Rev Med Chil. 2001;129(12):1373.
Plasmapharesis
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First described in 1978 by Betteridge et al.
Rapidly removes plasma TG and reduces risk of
recurrent pancreatitis. Also reduces inflammation by
removal of excess proteases and replacement of
protease inhibitors
Multiple studies showing success in reducing TG levels
Betteridge et al. Lancet 1978, Stefannuti et al Artif Organs. 2009 Dec, Lennertz et al. Ther Apher. 1999 Aug, Yeh et al J Clin Apher. 2003, Szczepiorkowski et al Journal
of Clinical Apharesis June 2010
Plasmapharesis
Reference
# of Patients
Plasma exchange
method
Significant
reduction in TG
level
Stefanutti et al.
17
Albumin
By 61%
Yeh et al.
18
FFP and albumin,
double membrane
filtration
By 66% (first
setting) and by 83%
(second setting)
Yeh et al.
17
FFP and albumin
Significant reduction
Chen et al.
94
FFP and albumin
No significant
reduction
Gubensek et al.
50
Albumin
Significant reduction
Kyriakidis et al.
10
FFP
By 62%
Table adapted from Ewald et al. Clin Res Cardiol Suppl. 2012 June; 7(Suppl 1): 31–35.
Plasmapharesis
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Severe HTG (TG > 1000 mg/dl) and lipase > 3 times
upper limit of normal result in very high FFA levels
which can result in high levels of systemic inflammation
Deng et al demonstrated positive correlation between
high TG levels and 24-h APACHE II score
Plasmapharesis is a useful and important tool in the
setting of severe HTG and significantly elevated
lipase levels
Deng et al. World J Gastroenterol. 2008 Jul
Other pharmacologic therapy
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Oral lipid lowering agents should be initiated when
tolerated by the patient as adjuvant therapy in HTGP
Fibrates lower TG levels by 40-60% and raise HDL
levels. Should be used as first line therapy for primary
HTG
Omega-3 fatty acids studied in a prospective, doubleblind, placebo-controlled trial proved capable of
lowering high TG (500 – 2,000 mg / dl) by 45 %
Tsuang et al. Hypertriglyceridemic pancreatitis: presentation and management. Am J Gastroenterology 2009
Apr;104(4):984-91
Clinical Questions



What are the causes of acquired and inherited lipid
disorders? How do they cause pancreatitis?
How is hypertriglyceridemic pancreatitis managed?
Is there any relationship of hypertriglyceridemic
pancreatitis to pregnancy? If so, is there a specific
treatment in pregnant women?
Pregnancy and HTGP
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Lipid profile changes in normal pregnancy: marked
elevations of total plasma cholesterol and triglyceride
levels, primarily through increased liver synthesis of
triglyceride and VLDL-C in response to elevated
estrogen levels
Pregnancy causes an increase in serum TG (peaks in
3rd trimester) but total serum TG rarely exceeds 300
mg/dl – a concentration that is not sufficient to cause
pancreatitis
Pregnancy and HTGP
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Responsible for ~56% of cases of AP occurring during
pregnancy with an estimated overall frequency of 1 in
6790 pregnancies over a 15-year period
Most causes of HTGP in pregnancy are attributable to
familial HTG however non-genetic, non-familial
pregnancy-induced HTGP has been reported
Several case reports describe gestational HTGP in
patients with underlying hyperchylomicronemia
Gursoy et al. Severe Hypertriglyceridemia-Induced Pancreatitis during Pregnancy. Journal of the National Medical
Association. VOL. 98, NO. 4, APRIL 2006
Management of HTGP in pregnancy
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Treatment generally does not differ in pregnancy
Case reports have shown success of apharesis in
management of HTGP in pregnancy
Initiation of fibrates and omega-3 fatty acids reduce
risk of recurrent pancreatitis
Dietary fat restriction also reduces chance of
recurrence of HTGP
Achard et al. Pancreatitis related to severe acute hypertriglyceridemia during pregnancy: treatment with lipoprotein
apheresis. Intensive Care Med. 1991;17(4):236.
Complications of HTGP in pregnancy
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Some reports suggest up to 20% increased mortality
in pregnancies complicated by pancreatitis
One of the most common reasons for maternal and
fetal mortality are acute pancreatitis itself
Very rarely, acute pancreatitis associated with
preeclampsia-eclampsia or HELLP syndrome
No guidelines exist about the need for early delivery
in patients with acute pancreatitis
Conclusion
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Both inherited and acquired causes of hyperlipidemia
HTGP usually multifactorial (underlying lipid disorder
exacerbated by secondary factor)
Pregnancy itself can cause hypertriglyceridemia
Several management strategies for HTGP including
plasmapharesis, insulin infusion and oral therapy.
Management is similar in pregnant patients
Important to recognize this disorder early in pregnant
patient to improve overall outcomes
THANK YOU!
References
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Sunil K. Kota, Siva K. Kota,Sruti Jammula, S. V. S. Krishna, and Kirtikumar D. Modi. Hypertriglyceridemia-induced recurrent acute
pancreatitis: a case-based review. Indian J Endocrinol Metab. 2012 Jan-Feb; 16(1): 141–143.
Srinivasa P Munigoti, Alan Rees. Hypertriglyceridaemia, LPL Deficiency and Pancreatitis. British Journal of Diabetes and Vascular
Disease. 2011;11(3):107-112.
Betteridge DJ, Bakowski M, Taylor KG, Reckless JP, de Silva SR, Galton DJ. Treatment of severe diabetic hypertriglyceridaemia by
plasma exchange. Lancet. 1978 Jun 24; 1(8078):1368.
Iskandar SB, Olive KE. Plasmapheresis as an adjuvant therapy for hypertriglyceridemia-induced pancreatitis. Am J Med Sci. 2004
Nov;328(5):290-4.
Stefanutti C, Di Giacomo S, Vivenzio A, Labbadia G, Mazza F, D'Alessandri G, Russi G, De Silvestro G, Marson P. Therapeutic plasma
exchange in patients with severe hypertriglyceridemia: a multicenter study. Artif Organs. 2009 Dec; 33(12):1096-102.
Lennertz A, Parhofer KG, Samtleben W, Bosch T. Therapeutic plasma exchange in patients with chylomicronemia syndrome complicated
by acute pancreatitis. Ther Apher. 1999 Aug; 3(3):227-33.
Yeh JH, Chen JH, Chiu HC. Plasmapheresis for hyperlipidemic pancreatitis. J Clin Apher. 2003; 18(4):181-5.
Yeh JH, Lee MF, Chiu HC. Plasmapheresis for severe lipemia: comparison of serum-lipid clearance rates for the plasma-exchange and
double-filtration variants. J Clin Apher. 2003; 18(1):32-6.
Gubensek J, Buturović-Ponikvar J, Marn-Pernat A, Kovac J, Knap B, Premru V, Ponikvar R. Treatment of hyperlipidemic acute pancreatitis
with plasma exchange: a single-center experience. Ther Apher Dial. 2009;13(4):314–317.
Chen JH, Yeh JH, Lai HW, Liao CS. Therapeutic plasma exchange in patients with hyperlipidemic pancreatitis. World J
Gastroenterol. 2004;10(15):2272–2274.
Ewald N, Kloer HU. Treatment options for severe hypertriglyceridemia (SHTG): the role of apheresis. Clin Res Cardiol Suppl. 2012
Jun;7(Suppl 1):31-5.
Deng LH, Xue P, Xia Q, Yang XN, Wan MH. Effect of admission hypertriglyceridemia on the episodes of severe acute pancreatitis. World
J Gastroenterol. 2008 Jul;14(28):4558-61.
Speck L. Fall von lipamia. Arch Verin Wissenschaftl Heilkunde. 1865: 1:232. Quoated in Thannhauser SJ, Ed. Lipidoses, disease of
intracellular lipid metabolism, 1958, 3rd ed. New York, Grune & Stratton, 307.
References
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Lloret Linares C, Pelletier AL, Czernichow S, Vergnaud AC, Bonnefont-Rousselot
D, Levy P, Ruszniewski P, Bruckert E. Acute pancreatitis in a cohort of 129
patients referred for severe hypertriglyceridemia. Pancreas. 2008;37(1):13.
Balachandra S, Virlos IT, King NK, Siriwardana HP, France MW, Siriwardena
AK. Hyperlipidaemia and outcome in acute pancreatitis. Int J Clin Pract.
2006;60(2):156.
Berger Z, Quera R, Poniachik J, Oksenberg D, Guerrero J. [heparin and insulin
treatment of acute pancreatitis caused by hypertriglyceridemia. Experience of
5 cases]. Rev Med Chil. 2001;129(12):1373.
Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A.
Hypertriglyceridemic pancreatitis: presentation and management. Am J
Gastroenterol. 2009 Apr;104(4):984-91. doi: 10.1038/ajg.2009.27. Epub
2009 Mar 17.
Achard JM, Westeel PF, Moriniere P, Lalau JD, de Cagny B, Fournier A.
Pancreatitis related to severe acute hypertriglyceridemia during pregnancy:
treatment with lipoprotein apheresis. Intensive Care Med. 1991;17(4):236.