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. Describe the pathophysiology and prevalence of hypertriglyceridemia (HTG) 2. Elaborate the potential causes, complications, and management of acute pancreatitis 3. Become familiar with the various classification schemes for HTG 4. 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 Pathophysiology1

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 Composition Primary Function Chylomicron TG: 80-95%

Free cholesterol: 1-3% Cholesterol esters: 2-4% Phospholipids: 3-9% Apoproteins: 1-2%

Transport dietary TGs to adipose tissue and muscle for hydrolysis by lipoprotein lipase

Very low-density lipoprotein (VLDL)

TG: 50-65% Free cholesterol: 4-8% Cholesterol esters: 16-22% Phospholipids: 15-20% Apoproteins: 6-10%

Transport endogenous TGs to adipose tissue and muscle for hydrolysis by lipoprotein lipase

Intermediate density lipoprotein (IDL)

Intermediate between VLDL and LDL

Transport endogenous cholesterol for either conversion to LDL or receptor-mediated endocytosis by liver

Low density lipoprotein (LDL)


Transport endogenous cholesterol for receptor-mediated endocytosis by either the liver or extrahepatic tissues

High density lipoprotein (HDL)


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 beta-adrenergic 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

levels (mg/dL)

Elevated Lipoproteins

Pheno- type

Clinical Signs

Isolated Hypercholesterolemia Familial hypercholesterolemia

Hetero: TC 275-500

LDL IIa Usually develop xanthomas in adulthood and vascular disease at 30-50 years

Familial defective apo B100

Homo: TC > 500 Hetero: TC 275-500

LDL IIa Usually develop xanthomas and vascular disease in childhood

Polygenic hypercholesterolemia

TC 250-300 LDL IIa Usually asymptomatic until vascular disease develops; no xanthomas

Isolated Hypertriglyceridemia Familial hypertriglyceridemia

TG = 250-750 VLDL IV Asymptomatic; may be associated with increased risk of vascular disease

Familial lipoprotein lipase deficiency

TG > 750 Chylomicrons I, V May be asymptomatic; may be associated with pancreatitis, abdominal pain, hepatosplenomegaly

Familial apo CII deficiency

TG > 750 Chylomicrons I, V May be asymptomatic; may be associated with pancreatitis, abdominal pain, hepatosplenomegaly

4

Table 2: Familial Disorders (Cont’d) Hypertriglyceridemia and Hypercholesterolemia

Combined hyperlipidemia

TG = 250-750 Total cholesterol = 250 -500

VLDL, LDL IIb Usually asymptomatic until vascular disease develops; familiar form may also present as isolated high TG or an isolated high LDL cholesterol

Dysbetalipoproteinemia TG = 250-500 Total cholesterol = 250 -500

VLDL, IDL LDL normal

III Usually asymptomatic until vascular disease develops; may have 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

• 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

ii. 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 Physical Exam

- 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)

- 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 green-brown 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 TG ≥500 mg/dL TG > 1000 mg/dL • Lifestyle management • Weight loss • Alcohol cessation • Secondary causes

• Very low fat diet • Low concentrated

carbohydrate diet • Alcohol cessation • Secondary causes • Consider drugs, if no

response to above • Consider referral

• Strict MNT (avoidance of alcohol, fat, and restrict calories)

• Secondary causes • Drug therapy, if no

response to above • Consider referral

*MNT (Medical nutrition therapy)

B. ATPIII Guidelines9 TG 150-199 mg/dL TG 200-499 mg/dL TG ≥ 500 mg/dL

• Life habit changes: o Body weight

control o Regular physical

activity o Smoking cessation

• Restriction of alcohol use (when consumed in excess)

• Avoid high carbohydrate intakes (> 60% of calories)

First-line therapy: • Weight reduction • Increased physical activity Second-line therapy (drugs to achieve non-HDL goal): • Statins (LDL, VLDL) • Fibrates (VLDL-TG, VLDL) • Nicotinic acid (LDL, VLDL)

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:

• Dietary counseling • Decreased carbohydrate intake, increased

fat (monounsaturated/poly-unsaturated) intake

• Increased physical activity • 30 – 60 minutes of intermittent aerobic

exercise or mild resistance exercise • Weight reduction

Combination of reduction of dietary fat/simple carbohydrate intake with drug treatment • Recommend fibrate be used as first-line

agent for reduction of TG in patients at risk for TG-induced pancreatitis

• Recommend three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins be considered as treatment options in patients with moderate to severe TG levels

Evidence8

Table 7: Summary of Evidence for TG-Lowering Modalities Recommendation Source of Evidence QE Overall Quality R

Elevated TG should receive intensive MNT, exercise, and screening for underlying causes

NCEP ATP-III, 2002 Stone & Blum, 2002

II-3 Fair B

Consider drug therapy to prevent pancreatitis

Cleeman, 1998 NCEP ATP-III, 2002 Stone & Blum, 2002

III Poor I

Use of fibrates, niacin, and fish oil to lower hypertriglyceridemia

Farmer et al., 2001 Harris, 1997

I Fair B

QE = quality of evidence R = Recommendation Pharmacologic Therapy8

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: Agent Dose Gemfibrozil 1200 mg/day (divided BID before meals) Fenofibrate 160-200 mg/day

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%])

iv. 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

B. Nicotinic acid i. MOA:

ii. Drugs:

Agent Dose Niacin ER 500 mg – 2 g daily at bedtime Niacin IR 1.5 – 3 g/day (divided TID)

Start IR 50-100 mg BID – TID Increase dose by 300 mg/day per week

iii. Potential Adverse Effects:

a) Flushing [88%], blurred vision, GI distress [2-9%], itching, headache, hepatotoxicity, hyperglycemia, hyperuricemia

- Inhibit lipolysis in adipose tissue, the primary producer of circulating free fatty acids (precursor to triacylglycerol synthesis) - Lowering of VLDL synthesis

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. 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

iv. 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 Efficacy8

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 Expected % Reduction in TG Fibrates -20 to -50 Niacin -20 to -35 Fish oil -20 to -30

15

ii. Statins10

Statin Rosuvastatin Atorvastatin Simvastatin Pravastatin

10mg 19.8% 20% 11.9% 8.2% 20mg 23.7% 22.6% 17.6% 7.7% 40mg 26.1% 26.8% 14.8% 13.2% 80mg - 28.2% 18.2% -

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) Intervention

(n) Baseline

TG Follow-Up TG

Primary Endpoint

Helsinki Heart Study

Primary 5 Placebo (2030) Gemfibrozil (2051)

176.7 175.3

177.7 114.8

Fatal/non-fatal MI and cardiac death: Yes NNT 71

Benzafibrate Infarction Prevention Study

Stable CHD 6.2 Placebo (1542) Benzafibrate (1548)

145 145

149.6 124.4

Fatal/non-fatal MI or sudden death: No

Fenofibrate Intervention and Event Lowering in Diabetes Study

High Risk 5 Placebo (4900) Fenofibrate (4895)

153.3 154.2

165.7 130.2

First occurrence of either non-fatal MI or death from coronary heart disease: No

Veterans Affairs HDL Intervention Trial

Stable CHD 5.1 Placebo (1267) Gemfibrozil (1264)

160 161

166 115

Non-fatal MI and death from coronary heart disease: Yes NNT 23

Diabetes Atherosclerosis Intervention Study

Stable CHD 3 Placebo (211) Fenofibrate (207)

214.4 229.5

Not reported

Change in mean lumen diameter: No

Action to Control Cardiovascular Risk in Diabetes

Primary Prevention

4.7 Placebo + simva (2753) Fenofibrate + simva (2765)

162 164

152 120

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. 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 v. 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 Criteria

Patients with severe hypertriglyceridemia (TG > 1772 mg/dL) referred to a specialty lipid disorders clinic between 1986 to 2007 (n = 95)

Methods Retrospective chart review Statistical Analysis

- Cohort’s characteristics: mean and standard deviation for continuous variables - 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 Clinic

Treatment Latest Visit

n (%) n (%) n (%) Monotherapy

Fibrate 17 (17.9) 54 (56.8) 31 (36.9) Statin 16 (16.8) 1 (1.1) 6 (7.1) Fish oil 1 (1.1) 8 (8.4) 3 (3.6) Niacin 1 (1.1) 0 2 (2.4) Resin 1 (1.1) 0 1 (1.2)

Combination

Fibrate/statin 4 (4.2) 9 (9.5) 11 (13.1) Fibrate/ niacin/ fish oil

1 (1.1) 1 (1.1) 1 (1.20

Fibrate/ fish oil

1 (1.1) 16 (16.8) 4 (4.8)

Other 0 2 (2.2) 17 (20.02) Frequency of Clinical Findings

n/N % Body Mass Index

> 30 kg/m2 45/95 47.4 25 – 30 kg/m2 28/95 29.5 < 25 kg/m2 22/95 23.2

Dermatological

Eruptive xanthomas 8/95 8.5 Palmar xanthomas 3/95 3.2

Ophthamalogical Corneal arcus 24/95 25.3 Lipemia retinalis 2/95 2.1

Gastrointestinal Abdominal tenderness

3/95 3.2

Hepatomegaly 6/95 6.3 Discussion - 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)

20

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 Cholesterol (mg/dL) Triglycerides (mg/dL) 19 1071 8400 23 1420 7100 25 486 6790 29 548 10800 35 764 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?

21

Methods - 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 - Data only from the first hospital admission

- 18 patients who received their entire treatment at the MCGH

Results 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 Nausea/vomiting Lipemic serum Shock/critical MICU admission Overweight Obese

100 91 45 21 32 80 68

Laboratory Data Mean ± SD Median Range TGs (mg/dL) 4587 ± 3616 3300 600 – 17,770 Serum amylase* 600 ± 698 309 17 – 3,250 Serum lipase** 386 ± 1113 100 12 – 4,980 * > 2 x ULN: 54% > 5 x ULN: 31% ** > 2 x ULN: 67% > 5 x ULN: 27%

Discussion - 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

22

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

23

References:

1. Talbert RL. Chapter 28. Dyslipidemia. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7974214. Accessed September 4, 2013

2. Lederle F, Bloomfield H. Drug treatment of asymptomatic hypertriglyceridemia to prevent pancreatitis: where is the evidence? Annals of Internal Medicine. 2012; 157(9); 662-665.

3. Fauci A, Braunwald E, Kasper D, et al. Harrison’s Manual of Medicine. 17th ed. New York: McGraw-Hill; 2009.

4. Miller M, Stone N, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011; 123: 2292-2333.

5. Yadav D, Pitchumoni C. Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol. 2003; 26(1): 54-62.

6. Goldberg I, Eckel R, McPherson R. Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol. 2011; 31:1716-1725

7. Berglund M, Brunzell J, Goldberg A, et al. Evaluation and treatment of hypertriglyceridemia: an endocrine society clinical practice guidelines. J Clin Endocrinol Metab. September 2012, 97: 2969–2989.

8. The Management of Dyslipidemia- Working Group. VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia.

9. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Pro- gram (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143-421.

10. Jones P, Davidson M, Stein E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses. Am J Cardiol. 2003; 92(2):152-60.

11. Statin-Fibrate Report: Focus on Safety. VHA Pharmacy Benefits Management-Strategic Healthcare Group and The Medical Advisory Panel.

12. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1563-1574.

13. Murad M, Hazem A, Coto-Yglesias F, et al. The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis. BMC Endocrine Disorders 2012, 12:2.

14. Linares C, Pelletier A, Czernichow S, et al. Pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Pancreas 2008; 37:13Y18

15. 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.

16. Miller A, Lees RS, McCluskey MA, Warshaw AL. The natural history and surgical significance of hyperlipemic abdominal crisis. Ann Surg. 1979; 190: 401-8.

17. Fortson MR, Freedman SN, Webster PD 3rd. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol. 1995; 90:2134-9.

24

hypertriglyceridemia and acute pancreatitis – how fearful should we

Documents