Endocrinology Wyoming Medical Center Disclosure Holdings in Amarin Corporation Objectives Triglyceride rich lipoproteins TRLs Genetic causes of hypertriglyceridemia HTG Hypertriglyceridemia ID: 909538
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Slide1
Hypertriglyceridemia
Vishwanath Pattan, MD
Endocrinology
Wyoming Medical Center
Slide2Disclosure
Holdings in
Amarin Corporation
Slide3Objectives
Triglyceride rich lipoproteins (TRLs)
Genetic causes of hypertriglyceridemia (HTG)
Hypertriglyceridemia
induced
pancreatitis
Management of hypertriglyceridemia
Slide4What is the most common cause of pancreatitis in during pregnancy?
Alcohol and gall stones
Gall stones and smoking
Gall stones and medication induced pancreatitis
Hypertriglyceridemia
Hyperemesis gravidarum
7
Slide5What is the risk of developing acute pancreatitis when
triglyceride
level is <500 vs triglyceride level >2000 mg/dl?
2% and 5% respectively
<5% and 5-10% respectively
5% and 50% respectively
<5% and 10-20% respectively
5% and 70% respectively
7
Slide6All are therapeutic targets for management of hypertriglyceridemia except:
Apo-C III inhibitor
ANGLT3 inhibitors
Lipoprotein lipase-Adeno associated virus vecotor
Apo-C II inhibito
7
Slide755yo. Male nondiabetic patient presented with severe acute pancreatitis with triglyceride 5,640 mg/dl lipase 5 times the upper limit of normal.
What is the best treatment?
NPO, Therapeutic plasma exchange
NPO, Insulin and glucose infusion
NPO, Heparin
NPO, Insulin and heparin
NPO, Fenofibrate and insulin-glucose infusion
7
Slide8The highest risk of acute pancreatitis is with:
Elevated chylomicron
Elevated VLDL
Elevated LDL and VLDL
Decreased HDL and increased LDL
Decreased HDL and increased IDL
7
Slide9Triglyceride rich lipoproteins (TRLs
)
Slide10Fasting Plasma Lipoprotein sample of patient was subjected to electrophoresis and various subfractions were separated Which subfraction poses higest risk of acute pancreatitis when elevated?
a
b
c
d
Slide11The density and size distribution of the major classes of lipoprotein particles
Slide12Slide13Ultracentrifugation
Electrophoresis
Slide14Metabolic fate of chylomicrons
Slide15Metabolic fate of VLDL
Slide16Slide17Slide18Genetic causes of HTG
Slide19Most common cause of monogenic chylomicronemia is
Familial
LPL
Deficiency
Familial
ApoC-II
Deficiency
Familial GPIHBP1 deficiencyFamilial LMF1 deficiencyFamilial ApoA-V Deficiency
Slide20Slide21All are therpeutic targets for management of hypertriglyceridemia except
Apo-C III inhibitor
ANGPLT3 inhibitors
Lipoprotein lipase-Adeno associated virus vector
Apo C II inhibitor
Slide22Proteins involved in lipolysis of TRLs in which human mutations result in
severe
HTG
Plus
sign indicates enhancement or stimulation of LPL-mediated lipolysis,
whereas
a minus sign indicates inhibition
Slide23Slide24HTG within a family does not typically follow classical Mendelian patterns of
inheritance
HTG does not consistently show vertical transmission across generations in family
pedigrees
Although some cases do cluster in some families, they are usually not monogenic
Endocrine
Reviews, February 2015, 36(1):131–147
Slide25Slide26Primary Hypertriglyceridemias
Familial
LPL
Deficiency
Familial ApoC-II Deficiency
Familial GPIHBP1 Deficiency
Familial
ApoA-V Deficiency
Slide27Familial Hypertriglyceridemia (FHTG)
Is a
polygenic
hypertriglyceridemia
FHTG
is characterized by elevated fasting TGs without a clear secondary cause, average to below average LDL-C levels, low HDL-C levels, and a family history of
hypertriglyceridemia
ApoB levels are not elevated
Slide28Patients with very severe
HTG (TG 2000 mg/dL) are almost certain to have one or more genetic defects together with coexisting
secondary conditions
Endocrine
Reviews, February 2015, 36(1):131–147
Slide29Fasting Plasma sample of patient was centrifuged and various subfractions were separated
Which subfraction poses higest risk of acute pancreatitis when elevated?
a
b
c
d
e
Slide30Slide3155y male nondiabetic patient presented with severe acute pancreatitis with triglyceride 5,640mg/dL lipase 5 times the upper limit of normal. Best treatment is
NPO, Therapeutic plasma exchange
NPO, Insulin and glucose infusion
NPO, Heparin
NPO, Insulin and heparin
NPO, Fenofibrate and insulin-glucose infusion
Slide32Case presentation
53-year-old Asian Indian man originally from Fiji, was admitted on
7/1/2015
because of nausea, vomiting, abdominal pain and decreased appetite
HPI: Patient was apparently in his usual state of health until 2 years ago when he developed gradual onset progressive abdominal pain and underwent endoscopy at Chino Valley Medical Center on 1/22/2015 which showed multiple polyps, which on biopsy was consistent with carcinoid tumor
Slide33The patient underwent a repeat endoscopy and biopsy at City of Hope, on 2/19/2015, which showed multiple areas of the stomach involving the lesser curvature, body of stomach, which showed grade 1 neuroendocrine tumor with low proliferation index with Ki-67 less than 2%
He was offered options for surgery and monthly
Sandostatin
, and the patient preferred monthly
Sandostatin
injection which he started from 3/2015 and he has received a total of 4 injections and last dose was on 6/16/2015
Slide34Patient was admitted for severe abdominal pain on 3/21/2015 and was found to have acute pancreatitis confirmed on CT scan and with elevated lipase
Ultrasound on 3/22/16 did not show gallstones and due to
Hx
of alcohol use it was presumed to be either alcohol induced and /or passed gallstones(patient had elevated ALP301,AST 335, ALT109, Ca7.2, albumin 3.3)
Slide35Octreoscan
, on 3/27/2015, which was negative for any evidence of metastases
CT imaging, on 6/16/2015, showed near complete resolution of features of pancreatitis, which was previously seen
The
patient has been
drinking alcohol
for the last 30
yearsThe patient says that he takes at least scotch 1-2 drinks daily and usually 4 drinks per day
Slide36PAST MEDICAL
HISTORY:
Neuroendocrine
tumor involving the
stomach
Hypertension
Fatty
liver diseaseChronic alcoholismElevated liver enzyme, probably secondary to alcohol useHistory of acute pancreatitis
Slide37PAST SURGICAL HISTORY:
Gastric submucosal biopsy in 2/2015 and 1/2015.
FAMILY HISTORY:
No history of diabetes or thyroid problems in the family.
No history of cancers in the family.
No history of neuroendocrine tumor in the family.
Slide38SOCIAL HISTORY
The patient is married. He denies smoking but he drinks alcohol, one or two drinks daily for the last 30 years. No illicit drug use. No known drug allergies
Slide39HOME MEDICATIONS:
Hydrochlorothiazide 25 mg daily
Lisinopril 30 mg daily
Omega-3 fatty acid 1 g 3 times daily
Compazine 10 mg orally 3 times daily
Ecitalopram
10 mg daily
Ondansetron 8 mg every 8 hours as needed for nausea, vomitingOxycodone 5 mg tablet every 6 hours as needed for pain
Slide40PHYSICAL EXAMINATION
GENERAL: The patient is lying on bed, not in acute distress
SKIN: no
xanthelasma
, no eruptive xanthomas
VITAL SIGNS: HR80, BP127/95, RR18, T 98.2 F, saturating 96% on room air, body weight 76.8 kg, height 180 cm, BMI 23.7 kg/m2
HEENT: Pupils equal and reactive to light. Extraocular movements intact
NECK: Supple. No thyromegaly
Slide41PHYSICAL EXAMINATION…
HEART: S1, S2 regular. No murmurs, rubs, or gallops
LUNGS: Bilaterally clear to auscultation
ABDOMEN: tenderness in the epigastrium. No rebound. Bowel sounds present
NEUROLOGIC: The patient is awake, alert, and oriented x 3. No focal neurological deficits
EXTREMITIES: The patient has bilateral palpable pedal pulses. No pedal edema.
Slide42LABORATORY DATA
H
emoglobin
14.7, WBC count 3.6
, platelet
count
132
Sodium 137, potassium 4.6, chloride 102, bicarbonate is 18; BUN is 12, creatinine 0.77Glucose 162, calcium 7.7, phosphorus 2.8; Corrected calcium level of 7.94, HbA1c 6.9
Albumin 3.7, bilirubin is 1, alkaline phosphatase 169, AST 346, ALT 129Lipase
level
1195
Slide43Endo consult for elevated HbA1c 6.9 and new onset type 2 diabetes
Slide44New lab orders- Triglyceride level
Slide45Triglyceride 5016 mg/dL
Slide46ASSESSMENT AND PLAN
SEVERE HYPERTRIGLYCERIDEMIA PRECIPITATED BY ALCOHOL USE, COMPLICATED WITH ACUTE PANCREATITIS
NPO
IV fluids
Therapeutic plasma exchange was recommended to manage hypertriglyceridemia in this patient with acute pancreatitis
Our goal was to decrease triglyceride to <500mg/
dL
Slide47After 1 session of therapeutic plasma exchange triglyceride level improved from 5016
mg/
dL
to 1192 mg/Dl
After 2
nd
session of therapeutic plasma exchange plasma triglycerides decreased from 1192 mg/dL to 312 mg/dLPatient was pain free and started on clear liquids on day 3 and diet was advanced
Slide48Hypertriglyceridemia induced
pancreatitis
Slide49Hypertriglyceridemia is an important cause of pancreatitis that is often missed
The
risk of developing acute pancreatitis is approximately 5 percent with TG >1000 mg/dL and 10 to 20 percent with TG >2000
mg/dL
J
Clin Gastroenterol. 2014;48(3):195Alcohol increases serum triglyceride concentrations in a "dose-dependent" manner
Slide50In
women,
pregnancy-induced HTG
has been found to be responsible for up to
56 percent
of cases of acute pancreatitis occurring during pregnancy
Pancreas. 2017;46(4):504Persistent hyperchylomicronemia may lead to the formation of eruptive xanthomas over the extensor surfaces of the arms, legs, buttocks, and back; lipemia retinalis; and hepatosplenomegaly from fatty infiltration of the liver
Slide51Patients with
HTG induced pancreatitis
tend to have severe pancreatitis
as compared with patients with other causes of
pancreatitis
Lipids
Health Dis. 2017;16(1):124
Slide52In patients who develop Hypertriglyceridemia induced pancreatitis, the treatment includes conventional treatment of acute pancreatitis, and management of serum triglyceride levels with an
initial goal of <500 mg/dL
Maintenance of triglyceride levels below 500 mg/dL has been seen in multiple case series to
expedite clinical improvement
Slide53Therapeutic
plasma
exchange(TPE) is
the removal of plasma and replacement with a colloid solution (
eg
, albumin or plasma
)
TPE should be considered for hypertriglyceridemia-induced acute pancreatitis especially when serum triglyceride level >1000mg/dL plus lipase >3 times the upper limit of normal and signs of hypocalcemia, lactic acidosis, or signs of worsening inflammation or organ dysfunction
Slide54Severe or very severe HTG plus high lipase levels (>3 times the upper limit of normal) are associated with very high FFA levels and can further be complicated by systemic inflammation from both acute pancreatitis and direct activation of TLR2 and TLR4 by
FFA
Slide55Chylomicronemia
Chylomicronemia
— Commonly due to
partial LPL deficiency, where the type V phenotype
(in which chylomicrons are present in the supernatant, and the
infranatant
is cloudy due to VLDL particles) is brought out be one of the
exacerbating factors Type V phenotype shows Fasting triglyceride levels above the 99th percentileMarked hypertriglyceridemia (>1000 mg/dL
) may lead to chylomicronemia syndrome which can manifest with recent memory loss, abdominal pain and/or pancreatitis, dyspnea, eruptive xanthoma, flushing with alcohol, and lipemia retinalis
Slide56Chylomicronemia…
There is also a primary form of type V
hyperlipoproteinemia
in which there is no deficiency in LPL or its ligand
apo
C-II
The underlying defect in this disorder is uncertain but
apo E4, which is a ligand for the hepatic chylomicron and VLDL remnant receptor, may play a roleFasting chylomicronemia can be diagnosed by confirming the presence of chylomicrons and excess VLDL on agarose gel electrophoresis or ultracentrifugal analysisA simple technique is to refrigerate plasma overnight and examine the specimen for a creamy supernatant from chylomicrons and a turbid VLDL-rich
infranatant
Slide57Tube was set upright for four
hours
It
was not centrifuged
Slide58Chylomicronemia
…
In type I
hyperlipoproteinemia
, only chylomicrons accumulate and the
infranatant
is clear
They have complete absence of either lipoprotein lipase (LPL) activity (type Ia) or apo C-II (type Ib)
The only effective therapy has been a strict low-fat dietA gene therapy -LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec [Glybera]), has been approved for use in Europe
Slide59Chylomicronemia…
In clinical studies inhibitor
of APOC3 messenger RNA showed large reductions in triglyceride levels
Slide60Familial hypertriglyceridemia
Familial
hypertriglyceridemia (type IV
hyperlipoproteinemia
phenotype) is an autosomal dominant disorder associated with moderate elevations in the serum triglyceride concentration (200 to 500
mg/
dL
)It is often accompanied by insulin resistance, obesity, hyperglycemia, hypertension, and hyperuricemiaPatients with familial hypertriglyceridemia are heterozygous for inactivating mutations of the LPL gene and, typically have low serum HDL-C (
hypoalphalipoproteinemia)Familial hypertriglyceridemia is associated with increased coronary risk and is common in patients with premature CHD
Slide61Most common acquired causes
Diabetes
Alcohol
Pregnancy
D
rug- induced hypertriglyceridemia
D
iet-induced hypertriglyceridemia
Slide62Severe
Hypertriglyceridemia
(Type V)
Most
individuals with severe hypertriglyceridemia have type V hyperlipoproteinemia, signifying an increase in both chylomicrons and
VLDL-C
The
need to lower TG levels in these individuals is urgent to prevent acute pancreatitis and chylomicronemia syndrome
Slide63Borderline Hypertriglyceridemia
When
moderate hypertriglyceridemia (150-199
mg/dL
) in association with increased serum cholesterol
or low
HDL-C levels is the primary disorder, physical
activity, weight control, smoking cessation, and other lifestyle changes are first-line therapyThe approach to treatment of accompanying elevated LDL-C does not need to be modified
However, if the individual also has decreased HDL-C, the selection of secondary drug therapy may be affected
Slide64Slide65The criteria developed for
the Endocrine Society guidelines
focus on the ability to assess risk for premature CVD vs. risk for
pancreatitis
The
designations of mild and moderate hypertriglyceridemia correspond to the range of levels predominant in risk assessment for premature CVD, and this range includes the vast majority of subjects with
hypertriglyceridemia
Slide66In addition, these levels suggest different etiologies
Presence
of mild or moderate hypertriglyceridemia is commonly due to a dominant underlying cause in each patient, whereas severe or very severe hypertriglyceridemia is more likely due to several contributing
factors
Slide67Recommend
screening adults for hypertriglyceridemia as part of a lipid panel at least every 5
years
(1
/
⊕⊕oo)
Recommend basing the diagnosis of hypertriglyceridemia on fasting triglyceride levels and not on nonfasting triglyceride levels (1/ ⊕⊕⊕o)Recommend against the routine measurement of lipoprotein particle heterogeneity in patients with hypertriglyceridemia (1/ ⊕⊕oo)
Slide68Management of Hypertriglyceridemia
Slide69Endocrine
Society Clinical Practice
Guideline 2012
Strong recommendations use the phrase “we recommend” and the number 1, and weak recommendations use the phrase “we suggest” and the number
2
Cross-filled
circles indicate the quality of the evidence, such that
⊕ooo denotes very low-quality evidence; ⊕⊕oo, low quality; ⊕⊕⊕o, moderate quality; and ⊕⊕⊕⊕, high quality.
Slide70Endocrine Society Clinical Practice Guideline 2012
R
ecommend
lifestyle therapy, including dietary counseling to achieve appropriate diet composition, physical activity, and a program to achieve weight reduction in overweight and obese individuals as the initial treatment of mild-to-moderate hypertriglyceridemia
(1
/
⊕⊕OO)
For severe and very severe hypertriglyceridemia (1000 mg/dl), we recommend combining reduction of dietary fat and simple carbohydrate intake with drug treatment to reduce the risk of pancreatitis (1/ ⊕⊕⊕⊕)Recommend that the treatment goal for patients with moderate hypertriglyceridemia be a non-high-density lipoprotein (HDL) cholesterol level in agreement with NCEP ATP guidelines
(1/ ⊕⊕OO)
Slide71Management of hypertriglyceridemia
Recommend
that a
fibrate be used as a first-line
agent for reduction of triglycerides in patients
at risk for triglyceride-induced pancreatitis
(1/ ⊕⊕⊕O)Suggest that 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 triglyceride levels (2/ ⊕⊕OO)We recommend that
statins not be used as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk (1/ ⊕⊕OO)
Slide72Diet
The OmniHeart study compared the effects of healthful dietary patterns based on the DASH diet that lowered blood pressure and LDL
cholesterol
These
dietary patterns all emphasize fruits, vegetables, and low-fat dairy products; include whole grains, poultry, fish, and nuts; use unsaturated vegetable oils; and contain smaller amounts of red meat, sweets, and sugar-containing beverages than typical diets in the United States
Slide73Diet
Compared with a diet that emphasized carbohydrate, a similar diet that emphasized protein decreased triglyceride levels further, and this decrease was about twice the effect of a diet that emphasized unsaturated
fat
African-Americans have lower serum triglyceride levels than other racial or ethnic groups. The OmniHeart study, in which
50% of the population was African-American, found that diet modification had less effect on triglyceride levels in this ethnic group
than in a Caucasian population when matching baseline triglyceride levels
Slide74Exercise
The minimum exercise required to reduce a postprandial triglyceride increase has not been determined, but a period of
30 – 60 min of intermittent aerobic exercise or mild resistance
exercise has been shown to be effective in lowering plasma and VLDL
triglycerides
Slide75We do not recommend the use of heparin infusions or plasmapheresis
in the treatment of very severe hypertriglyceridemia with
pancreatitis
The
treatment of
underlying causes
including dietary fat restriction and use of long-term fibrate therapy should suffice
Slide76Fibrates
Fibrates decrease triglyceride levels by 30 –50% and sometimes increase HDL cholesterol
A
response to fibrates
is seen as early as
two weeks
into therapy with a
maximal effect in six to eight weeks Expert Rev Cardiovasc Ther. 2008;6(10):1319
Slide77Fish oil
Lovaza (4 g/day) reduced triglyceride levels by 45 percent but raised LDL-C levels by 31 percent
J
Cardiovasc Risk. 1997 Oct;4(5-6):
385-91
Another
commercial preparation, Vascepa, is more than 95 percent icosapent-ethyl, the ethyl ester of eicosapentaenoic acid Am J Cardiol. 2012;110(7):
984
Slide78Icosapent-ethyl (4 g/day) also reduced triglyceride levels by up to 45 percent, but did not significantly affect LDL-C levels
Am
J Cardiol. 2011 Sep;108(5):
682-90
The
majority of the
response with nicotinic acid is seen in six weeks and with fish oil in two weeks
Slide79AACE 2017 guidelines
Omega-3 Fish Oil
R63
. Prescription omega-3 oil, 2 to 4 g daily, should be used to treat severe hypertriglyceridemia (TG >500 mg/dL
).
(Grade A, BEL 1
)
Dietary supplements are not FDA-approved for treatment of hypertriglyceridemia and generally are not recommended for this purpose
Slide80Conclusions
Hypertriglyceridemia is an important cause of pancreatitis that is often
missed
Patients with HTG induced pancreatitis tend to have severe pancreatitis as compared with patients with other causes of
pancreatitis
Therapeutic Plasma Exhange should
be considered for hypertriglyceridemia-induced acute pancreatitis especially when serum triglyceride level >1000mg/dL plus lipase >3 times the upper limit of normal
and signs of hypocalcemia, lactic acidosis, or signs of worsening inflammation or organ dysfunction
Slide81At the present time, genetic testing for rare mutations rarely provides useful information to guide clinical therapy, but it is very relevant for understanding the pathophysiology of hypertriglyceridemic states
With greater understanding of genetic and environmental causes and their interaction, therapy can be intelligently targeted in the future
Slide82References
J
Clin Gastroenterol. 2014;48(3):
195
Endocrine Reviews, February 2015, 36(1):
131–147
Lipids
Health Dis. 2017;16(1):124Pancreas. 2008;37(1):13. Expert Rev Cardiovasc Ther. 2008;6(10):1319J Cardiovasc Risk. 1997 Oct;4(5-6):385-91Am J Cardiol. 2011 Sep;108(5):682-90Am J Cardiol. 2012;110(7):984
Endocrine Society Clinical Practice Guideline 2012AACE 2017 guidelines
Slide83Thank You