Download Hypertriglyceridemia and acute pancreatitis – how fearful should we

Hypertriglyceridemia and Acute Pancreatitis –
How Fearful Should we be of Pushing the Limits?
Charlie Ramirez, PharmD
PGY2 Ambulatory Care Pharmacy Resident
South Texas Veterans Health Care System
Pharmacotherapy Grand Rounds
Pharmacotherapy Education and Research Center
The University of Texas Health Science Center at San Antonio
The University of Texas at Austin College of Pharmacy
September 13, 2013
OBJECTIVES:
1.
2.
3.
4.
Describe the pathophysiology and prevalence of hypertriglyceridemia (HTG)
Elaborate the potential causes, complications, and management of acute pancreatitis
Become familiar with the various classification schemes for HTG
Evaluate the management of HTG, including clinical guidelines, pharmacological
therapy, and supportive primary literature
5. Discuss the association between HTG and acute pancreatitis
6. Analyze primary literature surrounding the association between HTG and acute
pancreatitis
7. Determine a safe and effective threshold plasma triglyceride (TG) concentration above
which TG-targeted therapy should be aimed for preventing acute pancreatitis
I. INTRODUCTION
Pathophysiology 1
A. Lipids
i.
Lipoproteins
a) Definition:
• Macromolecular aggregates (large assemblies) of lipids and
proteins
• Soluble form of lipids that circulate in the blood
ii.
Lipoprotein Subtypes
Figure 1: Lipoprotein subtypes
Source: http://www.scientificpsychic.com/health/lipoproteins.gif
2
Table 1: Lipoprotein characteristics
Classification
Chylomicron
Composition
TG: 80-95%
Free cholesterol: 1-3%
Cholesterol esters: 2-4%
Phospholipids: 3-9%
Apoproteins: 1-2%
TG: 50-65%
Free cholesterol: 4-8%
Cholesterol esters: 16-22%
Phospholipids: 15-20%
Apoproteins: 6-10%
Primary Function
Transport dietary TGs to adipose
tissue and muscle for hydrolysis
by lipoprotein lipase
Intermediate density lipoprotein
(IDL)
Intermediate between VLDL and
LDL
Low density lipoprotein
(LDL)
TG: 4-8%
Free cholesterol: 6-8%
Cholesterol esters: 45-50%
Phospholipids: 18-24%
Apoproteins: 18-22%
TG: 2-7%
Free cholesterol: 3-5%
Cholesterol esters: 15-20%
Phospholipids: 26-32%
Apoproteins: 45-55%
Transport endogenous
cholesterol for either conversion
to LDL or receptor-mediated
endocytosis by liver
Transport endogenous
cholesterol for receptormediated endocytosis by either
the liver or extrahepatic tissues
Very low-density lipoprotein
(VLDL)
High density lipoprotein
(HDL)
Transport endogenous TGs to
adipose tissue and muscle for
hydrolysis by lipoprotein lipase
Removal of cholesterol from
extrahepatic tissues via transfer
of cholesterol esters to IDL and
LDL
B. Triglyceride (TG)
i.
Definition:
a) (Triacylglycerol): an ester of glycerol with three fatty acids
b) Cellular storage form of fatty acids
ii.
Uptake and Transport:
a) Plasma TGs are primarily produced by the intestines and liver
b) Dietary TGs enter the circulation within chylomicrons
c) TGs assembled from de novo synthesized fatty acids and from lipids
returning to the liver are secreted in VLDL
Hypertriglyceridemia
A. Prevalence2
i.
National Health and Nutrition Examination Survey
a) 1.7% (3.4 million Americans)
• 33% of the nearly 6,000 participants (1999 – 2004; 37% men,
30% women) had serum TG ≥ 150 mg/dL
o Mild hypertriglyceridemia (150 – 200 mg/dL): 14%
o TG 200 – 500 mg/dL: 16%
o TG > 500 mg/dL: 2%
ii.
Kaiser Permanente
b) 1.5%
3
B. Risk factors
i.
Obesity/overweight
ii.
Physical inactivity
iii.
Cigarette smoking
iv.
Excess alcohol intake
v.
High carbohydrate diet (> 60% energy intake)
vi.
Several diseases (e.g., type 2 diabetes mellitus, hypothyroidism, chronic renal
failure, nephrotic syndrome)
vii.
Certain drugs (e.g., corticosteroids, estrogens, retinoids, higher doses of betaadrenergic blocking agents)
viii.
Genetic disorders (e.g., familial combined hyperlipidemia, familial
hypertriglyceridemia, familial dysbetalipoproteinemia)
C. Causes3
i.
Familial disorders
Table 2: Familial Disorders
Lipid Phenotype
Plasma lipid
Elevated
Phenolevels
Lipoproteins
type
(mg/dL)
Isolated Hypercholesterolemia
Familial
Hetero:
LDL
IIa
hypercholesterolemia
TC 275-500
Familial defective apo
B100
Polygenic
hypercholesterolemia
Familial
hypertriglyceridemia
Homo:
TC > 500
Hetero:
TC 275-500
TC 250-300
LDL
IIa
LDL
IIa
Isolated Hypertriglyceridemia
TG = 250-750 VLDL
IV
Familial lipoprotein
lipase deficiency
TG > 750
Chylomicrons
I, V
Familial apo CII
deficiency
TG > 750
Chylomicrons
I, V
Clinical Signs
Usually develop
xanthomas in adulthood
and vascular disease at
30-50 years
Usually develop
xanthomas and vascular
disease in childhood
Usually asymptomatic
until vascular disease
develops; no xanthomas
Asymptomatic; may be
associated with increased
risk of vascular disease
May be asymptomatic;
may be associated with
pancreatitis, abdominal
pain,
hepatosplenomegaly
May be asymptomatic;
may be associated with
pancreatitis, abdominal
pain,
hepatosplenomegaly
4
Table 2: Familial Disorders (Cont’d)
Hypertriglyceridemia and Hypercholesterolemia
Combined
TG = 250-750 VLDL, LDL
IIb
Usually asymptomatic
hyperlipidemia
Total
until vascular disease
cholesterol =
develops; familiar form
250 -500
may also present as
isolated high TG or an
isolated high LDL
cholesterol
Dysbetalipoproteinemia TG = 250-500 VLDL, IDL
III
Usually asymptomatic
Total
LDL normal
until vascular disease
cholesterol =
develops; may have
250 -500
palmar or tuboeruptive
xanthomas
a) Patients with types I, IV, and V hyperlipidemia (in which HTG is an
association) are predisposed to developing pancreatitis
• Majority of adults 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
• Type IV almost always requires a secondary factor to increase
TG levels substantially
b) Type I hyperlipidemia: fasting chylomicronemia4
• Almost always presents in infancy and early childhood
• Characteristics:
o Eruptive xanthomas, lipemia retinalis,
hepatosplenomegaly, and, although not invariably,
acute pancreatitis
• Factors that reduce VLDL clearance can raise TG concentrations
because of the competition with chylomicrons for a common
saturable removal mechanism
o Genetic hypertriglyceridemia:
 Rare genetic syndromes:
• LPL deficiency (familial type I), apo CII
deficiency, apo AV homozygosity,
GPIHBP1
 Other genetic syndromes:
• Heterozygous apo AV, heterozygous LPL
deficiency, familial
hypertriglyceridemia, FCHL,
dysbetalipoproteinemia (familial type
III)
 Typically younger patients presenting with the
chylomicronemia syndrome and an increased
risk for pancreatitis
5
•
•
•
ii.
Type V phenotype
o Complex interaction between genetic (less severe
disorders of TG metabolism) and environmental factors
o Fasting chylomicronemia and increased VLDL
o TG concentrations exceed 1000 mg/dL and, when
exacerbated by weight gain, certain medications, or
metabolic perturbations, can lead to the
chylomicronemia syndrome and increased risk of
pancreatitis
Though no single threshold of TG concentration above which
pancreatitis may occur, increased risk is defined arbitrarily by
levels exceeding 1000 mg/dL
Chait and Brunzell studied 123 patients referred to their lipid
clinic for elevated TG (> 2,000 mg/dL)5
o All patients had a genetic basis for their HTG
o 110 out of 123 had an associated secondary factor
contributing to their elevated TG levels
o Identifying presence of secondary factors is important
when managing a patient with severe HTG
Obesity4
a) Evidence from epidemiological and controlled clinical trials suggests a
marked relationship between TG levels and body weight status and
body fat distribution
Table 3: Association between BMI and Hypertriglyceridemic State
6
D. Complications
i.
Vascular disease4, 6
Figure 2: Atherogenicity of TG-Rich Lipoproteins
a) Remnant hypothesis:
• Conversion of TGs to remnants produces particles that enter the
arterial wall and deposit cholesterol
b) Lipolytic toxin hypothesis:
• During lipolysis of TGs, inflammatory lipids are released that
alter the endothelial biology
• Such inflammatory lipids increase expression of adhesion
molecules and cytokines that promote coagulation
ii.
Acute pancreatitis3
a) Etiology
• Prevalence: < 1% in the United States
• Approximately six per 100,000 populations will develop chronic
pancreatitis
Table 4: Causes of Acute Pancreatitis
Common Causes
Gallstones (including microlithiasis)*
Alcohol (acute and chronic alcoholism)*
Hypertriglyceridemia
Endoscopic retrograde cholangiopancreatography (ERCP), especially after biliary manometry
Trauma (especially blunt abdominal trauma)
Postoperative (abdominal and non-abdominal operations)
Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid,
anti-HIV medications)
Sphincter of Oddi dysfunction
7
Table 4: Causes of Acute Pancreatitis (Cont’d)
Uncommon Causes
Vascular causes and vasculitis (ischemic-hypoperfusion states after cardiac surgery)
Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP)
Cancer of the pancreas/hereditary pancreatitis
Hypercalcemia
Periampullary diverticulum
Pancreas divisum
Cystic fibrosis
Renal failure
Rare Causes
Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites)
Autoimmune (e.g., Sjorgen’s syndrome)
Causes to Consider in Patients with Recurrent Bouts of
Acute Pancreatitis without an Obvious Etiology
Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis, sludge drugs
Hypertriglyceridemia
Pancreas divisum
Pancreatic cancer
Sphincter of Oddi dysfunction
Cystic fibrosis
*Most common causes in the United States
b) Pathophysiology
• Premature activation of trypsinogen to trypsin within the
pancreas, leading to activation of other digestive enzymes and
autodigestion of the gland
• Activated enzymes released into the pancreas and surrounding
tissues produce damage and necrosis of the pancreatic tissue,
surrounding fat, vascular endothelium, and adjacent structures
• Release of cytokines by acinar cells injures those cells and
enhances the inflammatory response
8
Figure 3: Acute Pancreatitis: Pathophysiology
Source: http://pathwiki.pbworks.com/f/acute%20pancreatitis.jpg
c) Clinical Features
Table 5: Clinical Features of Acute Pancreatitis
Symptoms
- Steady, mid-epigastric pain radiating to the
upper quadrants of the back that is frequently
increased in the supine position (95% of
patients)
- “Knife-like,” “boring”
- Nausea, vomiting (85% of patients)
Physical Exam
- Low-grade fever, tachycardia, hypotension
- Erythematous skin nodules due to
subcutaneous fat necrosis
- Basilar rales, pleural effusion (often on left)
- Abdominal tenderness and rigidity,
diminished bowel sounds, palpable upper
abdominal mass
- Cullen’s sign: blue discoloration in the
periumbilical area due to hemoperitoneum
- Turner’s sign: blue-red-purple or greenbrown discoloration of the flanks due to tissue
catabolism of hemoglobin
9
d) Laboratory findings
• Serum amylase:
o > 3 x ULN
o Typically return to normal in 48-72 hours
• Serum lipase:
o > 3 x ULN
o Increases in parallel with serum amylase level
• Hypocalcemia (25% of patients)
• Hyperglycemia
• Hypoalbuminemia
• Leukocytosis: 15,000-20,000/µL
• Hypertriglyceridemia (15-20% of patients)
• Transient elevations: serum bilirubin, alkaline phosphatase,
aspartame aminotransferase
• Hypoxemia (25% of patients)
e) Imaging
• Abdominal radiographs: abnormal in 30-50% of patients (not
specific for pancreatitis)
• Abdominal computerized tomography (CT) scan
f)
Diagnosis
• Should be made within 48 hours
• Characteristics of abdominal pain + elevations of amylase,
lipase, or both to at least 3 X ULN
g) Treatment
Figure 4: Treatment Algorithm: Acute Pancreatitis
10
h) Complications
Table 6: Complications of Acute Pancreatitis
Systemic
Shock, GI bleeding, common duct obstruction, ileus, splenic infarction or rupture, DIC,
subcutaneous fat necrosis, ARDS, pleural effusion, acute renal failure, sudden blindness
Local
- Pancreatic necrosis:
• Necrosis may become secondarily infected in 40-60% of patients
• Typically 1-2 weeks after the onset of pancreatitis
• Most frequent organisms: gram-negative bacteria of alimentary origin
- Pancreatic pseudocysts:
• Occurs in 15% of patients
• Typically develops over 1-4 weeks
• Abdominal pain is the usual complaint +/- upper abdominal mass
• Can be detected by abdominal ultrasound or CT scan
- Pancreatic abscess:
• Ill-defined liquid collection of pus that evolves over 4-6 weeks
- Pancreatic ascites and pleural effusions:
• Disruption of the main pancreatic duct
i)
Risk factors that adversely affect survival
• Associated with organ failure and/or local complications such as
necrosis
• Clinical manifestations
o Obesity (BMI > 30)
o Hemoconcentration (hematocrit > 44%)
o Age > 70
• Organ failure
o Shock
o Pulmonary insufficiency (oxygen partial pressure [PO2] <
60)
o Renal failure (CR > 2.0 mg/dL)
o GI bleeding
• ≥ 3 Ransom criteria (not fully utilizable until 48h)
• Apache II score > 8
11
II. CLASSIFICATION OF HYPERTRIGLYCERIDEMIA7
National Cholesterol Education Program Adult Treatment Panel III (ATP III)
Normal TGs
< 150 mg/dL
Borderline-high TGs
150 – 199 mg/dL
High TGs
200 – 499 mg/dL
Very high TGs
≥ 500 mg/dL
The Endocrine Society Clinical Practice Guideline
Normal
< 150 mg/dL
Mild hypertriglyceridemia
150 – 199 mg/dL
Moderate hypertriglyceridemia
200 – 999 mg/dL
Severe hypertriglyceridemia*
1000 – 1999 mg/dL
Very severe hypertriglyceridemia
≥ 2000 mg/dL
*Severe hypertriglyceridemia, although not causative of pancreatitis, indicates risk for
development of severe hypertriglyceridemia
III. MANAGEMENT OF HYPERTRIGLYCERIDEMIA
General principle: accurate measurement of TG requires fasting for 9-12 hours prior to the test
A. VA/DoD Lipid Guidelines8
TG >200-499 mg/dL
•
•
•
•
Lifestyle management
Weight loss
Alcohol cessation
Secondary causes
•
•
•
•
•
•
*MNT (Medical nutrition therapy)
B. ATPIII Guidelines9
TG 150-199 mg/dL
TG ≥500 mg/dL
Very low fat diet
Low concentrated
carbohydrate diet
Alcohol cessation
Secondary causes
Consider drugs, if no
response to above
Consider referral
TG 200-499 mg/dL
First-line therapy:
• Life habit changes:
o Body weight
• Weight reduction
control
• Increased physical activity
o Regular physical
Second-line therapy (drugs to
activity
achieve non-HDL goal):
o Smoking cessation • Statins (LDL, VLDL)
• Restriction of alcohol use
• Fibrates (VLDL-TG, VLDL)
(when consumed in excess) • Nicotinic acid (LDL, VLDL)
• Avoid high carbohydrate
intakes (> 60% of calories)
TG > 1000 mg/dL
•
•
•
•
Strict MNT (avoidance of
alcohol, fat, and restrict
calories)
Secondary causes
Drug therapy, if no
response to above
Consider referral
TG ≥ 500 mg/dL
TG lowering to prevent
pancreatitis:
• Very low-fat diet when TG
> 1000 mg/dL (< 15% of
total calories as fat)
• Institute weight
reduction/physical activity
• Fish oils (replace some
long-change TGs in diet)
• TG-lowering drugs
(fibrate or nicotinic acid)
12
C. The Endocrine Society Clinical Practice Guideline7
TG 150-999 mg/dL
TG ≥ 1000 mg/dL
Lifestyle therapy:
Combination of reduction of dietary
fat/simple carbohydrate intake with drug
• Dietary counseling
treatment
• Decreased carbohydrate intake, increased
• Recommend fibrate be used as first-line
fat (monounsaturated/poly-unsaturated)
agent for reduction of TG in patients at
intake
risk for TG-induced pancreatitis
• Increased physical activity
• Recommend three drug classes (fibrates,
• 30 – 60 minutes of intermittent aerobic
niacin, n-3 fatty acids) alone or in
exercise or mild resistance exercise
combination with statins be considered as
• Weight reduction
treatment options in patients with
moderate to severe TG levels
Evidence 8
Table 7: Summary of Evidence for TG-Lowering Modalities
Recommendation
Source of Evidence
QE
Elevated TG should receive intensive
NCEP ATP-III, 2002
II-3
MNT, exercise, and screening for
Stone & Blum, 2002
underlying causes
Consider drug therapy to prevent
Cleeman, 1998
III
pancreatitis
NCEP ATP-III, 2002
Stone & Blum, 2002
Use of fibrates, niacin, and fish oil to
Farmer et al., 2001
I
lower hypertriglyceridemia
Harris, 1997
QE = quality of evidence
R = Recommendation
Overall Quality
Fair
R
B
Poor
I
Fair
B
Pharmacologic Therapy 8
A. Fibrates
i.
MOA:
- Bind to PPARs (peroxisome
proliferator-activated
receptors), which help
regulate lipid metabolism
- Increase expression of
lipoprotein lipase 
decreased triacylglycerides
13
ii.
Drugs:
iii.
Potential Adverse Effects:
a) GI symptoms (nausea [2.3%], abdominal pain [4.6%], vomiting,
diarrhea [2.3%]), rash, hepatitis, gallstones, myopathy [3.4%], and
rhabdomyolysis [3%])
Precautions/Contraindications/Comments:
a) Gallbladder disease
b) Monitor LFTs throughout therapy; contraindicated in hepatic disease
c) Reduce dose in modest renal insufficiency; contraindicated in severe
renal dysfunction
d) Risk of myopathy/rhabdomyolysis increases when combined with
statins
e) Monitor INR; may need to adjust warfarin dosage to prevent bleeding
complications
iv.
Agent
Gemfibrozil
Fenofibrate
Dose
1200 mg/day (divided BID before meals)
160-200 mg/day
B. Nicotinic acid
i.
MOA:
- Inhibit lipolysis in adipose
tissue, the primary producer of
circulating free fatty acids
(precursor to triacylglycerol
synthesis)
- Lowering of VLDL synthesis
ii.
Drugs:
iii.
Potential Adverse Effects:
a) Flushing [88%], blurred vision, GI distress [2-9%], itching, headache,
hepatotoxicity, hyperglycemia, hyperuricemia
Agent
Niacin ER
Niacin IR
Dose
500 mg – 2 g daily at bedtime
1.5 – 3 g/day (divided TID)
Start IR 50-100 mg BID – TID
Increase dose by 300 mg/day per week
14
iv.
Precautions/Contraindications/Comments:
a) Hepatic disease; persistent elevation of LFTs
b) Monitor LFTs at baseline; 6-12 weeks after start or dosage change; monitor
every 6-12 months thereafter
c) Active peptic ulcer disease (PUD); avoid in patients with a documented
history of PUD
d) Arterial bleeding
e) May cause glucose intolerance; caution in DM
f) Decreases urinary secretion of uric acid, caution with gout
g) Take with food to avoid flushing or GI upset
h) ASA 30 minutes prior to dose may minimize flushing
C. Fish oil
i.
MOA: Lower fasting and postprandial TG levels in a dose-dependent fashion
ii.
Drugs:
Agent
Dose
Omega-3 fatty acid
2-4 g daily or in divided doses
Lovaza (omega-3 ethyl ester) 4 g daily or in divided doses
iii.
iv.
Potential Adverse Effects
a) GI (nausea [3%], eructation [4%], and taste perversion or fishy taste [4%])
b) LDL-C elevation (especially in those with very high TG and no concomitant
statin)
c) ALT elevation
Precautions/Contraindications/Comments:
a) Drug to drug interaction with anticoagulants
b) ALT should be checked at baseline and 6-12 weeks after initiation of fish oils
and periodically thereafter
c) Lipid panel, including TG and LDL-C should be checked within 6-12 weeks of
initiation of treatment
Efficacy 8
A. As monotherapy, fibrates offer the most TG reduction, followed by immediate-release
niacin, omega-3 methyl esters, extended-release niacin, statins, and ezetimibe4
i.
Non-Statins
Drug
Fibrates
Niacin
Fish oil
Expected % Reduction in TG
-20 to -50
-20 to -35
-20 to -30
15
ii.
10mg
20mg
40mg
80mg
Statins10
Rosuvastatin
19.8%
23.7%
26.1%
-
Statin
Atorvastatin
Simvastatin
20%
11.9%
22.6%
17.6%
26.8%
14.8%
28.2%
18.2%
Pravastatin
8.2%
7.7%
13.2%
-
B. Fibrates have more commonly been shown to provide greater benefit in subgroups with
increased TG levels4
Table 8: Summary of Evidence for Fibrate Therapy
Trial Name
Population
Duration
(years)
5
Intervention
(n)
Placebo (2030)
Gemfibrozil
(2051)
Baseline
TG
176.7
175.3
FollowUp TG
177.7
114.8
6.2
Placebo (1542)
Benzafibrate
(1548)
Placebo (4900)
Fenofibrate
(4895)
145
145
149.6
124.4
153.3
154.2
165.7
130.2
Helsinki Heart
Study
Primary
Benzafibrate
Infarction
Prevention Study
Fenofibrate
Intervention and
Event Lowering
in Diabetes
Study
Veterans Affairs
HDL Intervention
Trial
Stable CHD
Stable CHD
5.1
Placebo (1267)
Gemfibrozil
(1264)
160
161
166
115
Diabetes
Atherosclerosis
Intervention
Study
Stable CHD
3
Placebo (211)
Fenofibrate
(207)
214.4
229.5
Not
reported
Action to Control
Cardiovascular
Risk in Diabetes
Primary
Prevention
4.7
Placebo +
simva (2753)
Fenofibrate +
simva (2765)
162
164
152
120
High Risk
5
Primary Endpoint
Fatal/non-fatal MI
and cardiac death:
Yes
NNT 71
Fatal/non-fatal MI
or sudden death:
No
First occurrence of
either non-fatal MI
or death from
coronary heart
disease: No
Non-fatal MI and
death from
coronary heart
disease: Yes
NNT 23
Change in mean
lumen diameter: No
Composite of the
first event of death
from CHD, non-fatal
MI, ischemic stroke,
hospitalization, ACS,
or symptom-driven
coronary or
cerebral
revascularization:
No
Note: Benefit was shown in the subgroup with elevated TG levels (> 204 mg/dL) and low HDL
(<34 mg/dL)
16
C. In patients with HTG, statin therapy may be beneficial in the setting of an LDL-C level
that merits treatment4,8
i.
If further TG lowering is required, addition of niacin or fish oils may be
considered for additional lowering (although there are no clinical endpoint trials
examining the combination of statins plus fish oils)
D. Discourage the use of statin-fibrate combination for synergistic TG lowering10
i.
Health outcomes
a) The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial lacked
evidence to support a greater benefit in health outcomes with combination
therapy versus a statin alone11
ii.
Pharmacokinetics
a) Gemfibrozil has been found to significantly increase the AUC and Cmax of
lovastatin, simvastatin, pravastatin and rosuvastatin
b) Fenofibrate has been noted to cause a “small increase” in AUC and Cmax
when combined with pravastatin and rosuvastatin, though data is only
available for these two statins
iii.
Adverse Effects
a) Risk for muscle toxicity with combination therapy is greater than that for
either statins or fibrates alone
b) One systematic review reported (out of 1,674 patients) two patients (0.12%)
experiencing myopathy (myalgia with creatinine kinase > 10 time the upper
limit of normal) and 33 patients (1.9%) developing other muscle-related
symptoms, including myalgias, myositis, muscle weakness, or
musculoskeletal pain
E. Discourage the use of ezetimibe-fibrate combination for synergistic TG lowering8
i.
Aside from LDL lowering, there is no evidence to support a reduction in
cardiovascular events with ezetimibe when used alone for primary or secondary
prevention of coronary heart disease
ii.
Ezetimibe should not be used in combination with statins or fenofibrates due to
increases in transaminases
IV. ASSOCIATION BETWEEN HYPERTRIGLYCERIDEMIA AND ACUTE PANCREATITIS
A. The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a
systematic review and meta-analysis12
i.
Eligibility criteria:
a) Randomized and observational studies
b) Patients enrolled with untreated hypertriglyceridemia and a reported
relative association measure between fasting serum TG levels and the
outcomes of interest
ii.
Exclusion criteria:
a) Uncontrolled studies
b) Studies of non-fasting hypertriglyceridemia
iii.
Outcomes of interest:
a) All-cause mortality
b) Cardiovascular death and events
c) Pancreatitis
17
iv.
Results:
a) Total number of included studies: 35
b) Hypertriglyceridemia was significantly associated with cardiovascular death,
cardiovascular events, myocardial infarction, and pancreatitis; with odds
ratios (95% confidence interval) of 1.8 (1.31 – 2.49), 1.37 (1.23 – 1.53), 1.31
(1.15 – 1.49), and 3.96 (1.27 – 12.34), respectively
B. Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia13
i.
Objective: to assess, retrospectively, the prevalence and predictive factors of
acute pancreatitis (AP) in a population of patients referred for very high TGs
ii.
Inclusion criteria:
a) Patients referred, between 2000 and 2005, by their general practitioner or
general hospital for very high TG (≥ 1000mg/dL)
• 119 with type IV phenotype; 10 with type V phenotype
iii.
Characteristics
iv.
v.
Outcome definition (AP):
a) Typical abdominal pain
b) Serum lipase > 3 times the upper limit of normal
c) Evidence of pancreatitis on computed tomographic scan according to
Balthazar’s classification
Results:
a) 129 patients referred for investigation of severe HTG
b) 14 patients with AP were carefully excluded for other potential etiologies,
mainly gallstones and alcohol intake
• Mean maximal TG level: 7003 mg/dL
• Six patients had biological markers of chronic alcoholism
o All had TG > 4000 mg/dL at the time of AP
• No evidence of gallstones, per abdominal imaging
c) 26 patients experienced at least one episode of AP
• No differences noted from patients without AP for sex,
percentage of smokers or alcohol users, mean BMI, or diabetes
mellitus
o Mean maximal TG level significantly higher in patients
with AP (4470 versus 2450 mg/dL, P < 0.0001)
• Maximum TG levels:
o > 3000 mg/dL: 85%
o > 5000 mg/dL: 65%
d) Conclusion: AP occurs at a higher TG level than previously thought
18
V. PRIMARY LITERATURE: ACUTE PANCREATITIS
Sandhu S, Al-Sarraf A, Taraboanta C, Frohlich J, Francis GA. Incidence of pancreatitis, secondary
causes, and treatment of patients referred to a specialty lipid clinic with severe
hypertriglyceridemia: a retrospective cohort study. Lipids Health Dis. 2011;10:157.14
Objective
Determine the frequency of physical signs and symptoms of high TGs, including
pancreatitis, among patients with severe hypertriglyceridemia
Inclusion
Patients with severe hypertriglyceridemia (TG > 1772 mg/dL) referred to a
Criteria
specialty lipid disorders clinic between 1986 to 2007 (n = 95)
Methods
Retrospective chart review
Statistical
- Cohort’s characteristics: mean and standard deviation for continuous variables
Analysis
- Means compared using paired Student t tests
Outcomes
1. Frequency of classical signs and symptoms associated with severe
hypertriglyceridemia
2. Most common secondary factors contributing to TG > 1772 mg/dL
3. Differences in treatment for severe hypertriglyceridemia between referring
physicians and lipid clinic specialists
4. Changes in the lipid profile of patients with severe hypertriglyceridemia
followed at a specialty clinic
Results
History of Pancreatitis (n = 15)
TG Levels
- Time of non-acute presentation (mean): 3377 mg/dL
- Lowest level associated with prior pancreatitis: 1815 mg/dL
Cohort of 91 patients with TG levels between 886-1771 mg/dL:
- 3 patients with a history of pancreatitis
- All levels at the time of acute pancreatitis > 1771 mg/dL
Risk Factors
- 75 patients (78.9%) had high fat (>35%) and carbohydrate intake (>55% total
calories)
- 42 patients (49.4%) had no regular exercise
- 11 patients (11.6%) consumed > 14 alcoholic drinks/week
- 8 patients (8.4%) consumed 7-14 drinks/week
- Of the 15 (17.1%) of patients with hypothyroidism, 5 were inadequately
controlled
- 24 patients (25.3%) had smoked cigarettes within the past year
- 16 patients (16.9%) were on beta-blockers, 6 (6.4%) were on estrogen therapy,
4 (4.3%) were on anti-retroviral therapy, and 3 (3.2%) were on a thiazide diuretic
- BMI (kg/m2):
- > 30: 45 (47.4%)
- 25-30: additional 29.5%
- Dysglycemia:
- 30 patients (31.6%) had a prior diagnosis of diabetes mellitus (DM)
- 23 had poor control (FBS 179 ± 79 mg/dL)
19
Medication Use
Upon Arrival
Discussion
Clinic
Treatment
n (%)
54 (56.8)
1 (1.1)
8 (8.4)
0
0
9 (9.5)
1 (1.1)
Latest Visit
n (%)
n (%)
Fibrate
17 (17.9)
31 (36.9)
Statin
16 (16.8)
6 (7.1)
Monotherapy Fish oil
1 (1.1)
3 (3.6)
Niacin
1 (1.1)
2 (2.4)
Resin
1 (1.1)
1 (1.2)
Fibrate/statin
4 (4.2)
11 (13.1)
Fibrate/
1 (1.1)
1 (1.20
Combination
niacin/ fish oil
Fibrate/ fish
1 (1.1)
16 (16.8)
4 (4.8)
oil
Other
0
2 (2.2)
17 (20.02)
Frequency of Clinical Findings
n/N
%
> 30 kg/m2
45/95
47.4
Body Mass Index 25 – 30 kg/m2
28/95
29.5
< 25 kg/m2
22/95
23.2
Eruptive xanthomas
8/95
8.5
Dermatological
Palmar xanthomas
3/95
3.2
Ophthamalogical Corneal arcus
24/95
25.3
Lipemia retinalis
2/95
2.1
Gastrointestinal Abdominal
3/95
3.2
tenderness
Hepatomegaly
6/95
6.3
- Acute pancreatitis, as a consequence of HTG, occurs rarely unless TG > 1772
mg/dL
- Most common risk factors predisposing to HTG: high fat and carbohydrate diet,
physical inactivity, and obesity
- Most common co-morbidities: uncontrolled DM and hypothyroidism
Miller A, Lees RS, McCluskey MA, Warshaw AL. The natural history and surgical significance of
hyperlipemic abdominal crisis. Ann Surg. 1979;190: 401-8.15
Methods
- 35 patients with proven Type V hyperlipoproteinemia investigated and treated
at the Arteriosclerosis Center, Massachusetts Institute of Technology, between
the years 1969-1978
- Diagnosis of acute pancreatitis:
- Clinical characteristics ±
- Laboratory features (elevation of serum amylase or depression of calcium)
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Results
- 19 patients: multiple episodes of abdominal pain ± attacks of pancreatitis
A) Pancreatitis as the initial manifestation
B) Multiple episodes of abdominal pain of varying severity preceding one or
more attacks of acute pancreatitis
C) Multiple episodes of abdominal pain (similar to those in group B), without
progression to acute pancreatitis
Highest mean pre-treatment TG plasma TGs (mg/dL):
A) 2030
B) 6127
C) 6017
Patient
19
23
25
29
35
Cholesterol (mg/dL)
1071
1420
486
548
764
Triglycerides (mg/dL)
8400
7100
6790
10800
11371
Milder episodes of abdominal discomfort (not requiring urgent medical
attention) were associated with TGs in the range of 2000-5000 mg/dL
- 16 patients: no history of abdominal pain or pancreatitis
Discussion
- Clinical manifestations of Type V hyperlipoproteinemia are directly related to
the patients’ plasma lipid concentrations
- Patients presenting with severe abdominal pain or pancreatitis all had TGs >
6000 mg/dL
- Lesser attacks were associated with plasma TGs between 2000-5000 mg/dL
- Although it was not possible to identify a threshold plasma TG concentration
above which pain inevitably occurred, it was possible to specify a concentration
below which pain did not occur, approximately 2000 mg/dL
Fortson MR, Freedman SN, Webster PD 3rd. Clinical assessment of hyper-lipidemic pancreatitis.
Am J Gastroenterol.16
Objectives
Three questions:
1. What is the clinical syndrome of pancreatitis secondary to hyperlipidemia?
2. What is the role of alcohol, diabetes, or other known causes of HTG in such
patients?
3. Does the course of pancreatitis secondary to HTG differ from that of other
etiologies?
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Methods
Results
Discussion
- Retrospective chart review (n = 70)
- Inclusion criteria:
Patients discharged between 1982 and 1994 with a diagnosis of pancreatitis and
HTG with:
- Clinical presentation consistent with acute pancreatitis
- Elevated amylase and lipase or evidence of pancreatitis by ultrasound, CT
imaging, or surgery
- Serum TG levels or lipemic serum documented shortly after admission
Participating hospitals: Medical College of Georgia Hospital (MCGH), the
Veterans Affairs Medical Center (VAMC), The University Hospital (UV), and St.
Joseph’s Hospital (SJH), Augusta, Georgia
Group A
Group B
- All 70 patients
- 18 patients who received their entire
- Data only from the first hospital
treatment at the MCGH
admission
Frequency of HLP as an Etiology of Pancreatitis
Cases
HLP/100 Patients with
Pancreatitis (%)
MCGH
33
3.8
VAMC
14
1.4
University Hospital
18
1.3
St. Joseph Hospital
5
3.5
Total Cases
70
Admission Findings (%)
Abdominal pain
100
Nausea/vomiting
91
Lipemic serum
45
Shock/critical
21
MICU admission
32
Overweight
80
Obese
68
Laboratory Data
Median
Range
Mean ± SD
TGs (mg/dL)
3300
600 – 17,770
4587 ± 3616
Serum amylase*
309
17 – 3,250
600 ± 698
Serum lipase**
100
12 – 4,980
386 ± 1113
* > 2 x ULN: 54%
> 5 x ULN: 31%
** > 2 x ULN: 67%
> 5 x ULN: 27%
- The frequency of hyperlipidemia as an etiological factor in patients with
pancreatitis ranged from 1.3 to 3.5%
- No patients with hyperlipidemic pancreatitis had admission TG levels lower
than 1000 mg/dL
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VI. CONCLUSIONS
A. Hypertriglyceridemia poses a potential, yet controversial, risk for contributing to the
development of acute pancreatitis
B. Supportive primary literature consists primarily of retrospective analyses
i.
Majority of subjects evaluated possessed genetic pre-dispositions for HTG
C. Acute pancreatitis, as a consequence of HTG, occurs rarely unless TG > 1772 mg/dL
i.
When retrospectively evaluating patients discharged with a diagnosis of
pancreatitis and HTG, the frequency of hyperlipidemia as an etiological factor
ranged from 1.3 to 3.5%
ii.
Most common risk factors predisposing to HTG: high fat and carbohydrate diet,
physical inactivity, and obesity
D. Most common co-morbidities associated with acute pancreatitis: uncontrolled DM and
hypothyroidism
VII. RECOMMENDATIONS
A. Given supportive literature, recommend TG-targeted therapy when TGs ≥ 1000mg/dL
for prevention of acute pancreatitis
B. Given lack of head-to-head evidence, recommend fibrates as first-line therapy for
reduction of TG, when no indication for statin therapy is present
i.
Recommend statin monotherapy in the setting of an LDL-C level that merits
treatment or when statin indication is present
a) If additional TG lowering is required, recommend addition of niacin or fish
oils
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