Transcript Muchanisms of TG Synthesis, Development of Hypertriglyceridemia

This lecture was conducted during the Nephrology Unit Grand
Ground by Registrar under Nephrology Division under the
supervision and administration of Prof. Jamal Al Wakeel, Head of
Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al
Suwaida, Chairman of Department of Medicine. Nephrology
Division is not responsible for the content of the presentation for
it is intended for learning and /or education purpose only.
HYPERTRIGLYCERIDEMIA
AND PLASMAPHERESIS
Presented by:
Dr. Habib Ur Rahman
Registrar
June 2008
RECENT TRIALS
Mechanism of TG.Synthesis
Causes
► Hypertriglyceridemia
has many causes,
including familial and genetic syndromes,
metabolic disease, and drugs.
► Genetic causes:
► Abnormalities of the enzyme pathway for
chylomicron metabolism are the bestcharacterized genetic causes of hTG.
However, less clearly defined inheritable
disorders are more frequent causes of
elevated TGs.
Table 2. Fredrickson Dyslipidemia Classification
Type
Elevated
Lipoprotein
Total Cholesterol
Level
Triglyceride
Level
Relative
Frequency
I
CM*
Normal
++
<1%
IIa
LDL
++
Normal
10%
LDL/VLDL
++
+
40%
III
IDL
+
+
<1%
IV
VLDL
Normal to+
++
45%
+
++
5%
(FHC)
IIb
(FCH)
(FHT)
V
CM
VLDL
*
CM, chylomicron; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; IDL, intermediate density
lipoprotein; FHC, familial hypercholesterolemia; FCH, familial combined hyperlipidemia; FHT, familial
hypertriglyceridemia.
Metabolic causes
 Diabetes:
 Uncontrolled diabetes mellitus,
►Patients
with type 1 diabetes mellitus
►with uncontrolled type 2 diabetes mellitus and
hyperinsulinemia
 Obesity:
 Hypothyroidism:
 Nephrotic syndrome:
Other causes of hTG
► Alcohol:
 Excessive alcohol intake is frequent cause of hTG.
► High-carbohydrate
intake)
► Acute pancreatitis
diets (>60% of caloric
 may cause substantial elevations in TGs by unknown
mechanisms. However, much more frequently, severe
hTG causes acute pancreatitis. In patients presenting
with acute pancreatitis and TGs greater than 1000
mg/dL, not assuming that the TGs are the cause of
the pancreatitis is prudent. Other causes, such as
common bile duct obstruction and alcoholism, must
be considered as possible etiologies
► Pregnancy
Table 3. Medications That Elevate Triglyceride
Atypical anti-psychotics
Beta blockers
Bile acid binding resins
Estrogen (in higher dose oral contraceptives and
unopposed oral estrogen)
Glucocorticoids
Immunosuppressants
Isotretinoin
Protease inhibitors
Tamoxifen
Thiazides
Hypertriglyceridemia
Fung, M. A. et al. CMAJ 2002;167:1261-1266
Copyright ©2002 Canadian Medical Association or its licensors
Fung, M. A. et al. CMAJ 2002;167:1261-1266
Copyright ©2002 Canadian Medical Association or its licensors
Obesity
Classification of Triglyceride Levels
Classification
Normal
Triglyceride Level (mg/dL)
<150 (1.7 m mol/L)
Borderline high
150 to 199 (1.7-2.26 m mol/L)
High
200 to 499 (2.26-5.65 m mol/L)
Very high
>500 (5.65 m mol/L)
Table 6. Basic Laboratory Evaluation for Confirmed
Hypertriglyceridemia
Serum urea nitrogen
Creatinine
Fasting glucose and lipid profile.
Fasting insulin level (if metabolic syndrome is suspected)
Liver function
Serum electrolyte
Urinalysis
SERUM AMYLASE
Treatment Categories, LDL-C
Goals and Cut points
Risk Category
CHD or
CHD risk equivalent
2 Risk Factors
10-yr risk 10–20%
10-yr risk <10%
<2 Risk Factors
LDL-C Goal
Consider Drug
Therapy
<100 mg/dL
130 mg/dL*
<130 mg/dL
<130 mg/dL
<160 mg/dL
130 mg/dL
160 mg/dL
190 mg/dL
* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Table 3. Initial Management of Hypertriglyceridemia
Intervention
Description
Comments
Counsel patients about
therapeutic lifestyle changes
Body weight control, regular
physical activity, tobacco-use
cessation, avoidance of highcarbohydrate foods, diet low in
saturated fat and sugar
Patients with triglyceride levels
above 1,000 mg per dL (11.30
mmol per L) should immediately
start a very low-fat diet
Screen for metabolic syndrome
Constellation of increased
abdominal circumference and low
HDL-C levels, high triglyceride
and blood sugar levels, and
elevated blood pressure
Diagnosis and management
remain controversial
Search for secondary causes
Nephrotic syndrome, diabetes,
chronic renal failure,
hypothyroidism, various
medications
Optimizing glycemic control may
improve hypertriglyceridemia
Search for acquired causes
Overweight and obesity,
excessive alcohol intake, high
carbohydrate intake, tobacco use
-
Determine cardiac risk profile
Determine cardiac risk factors,
and stratify the patient's 10-year
risk of coronary heart disease
using Framingham risk
calculators
-
Physicians should stratify the patient's risk to determine a lipid treatment goal. High-risk patients
Fung, M. A. et al. CMAJ 2002;167:1261-1266
Copyright ©2002 Canadian Medical Association or its licensors
Management of Hypertriglyceridemia
Fig. 2: Mechanism of niacin action
Fung, M. A. et al. CMAJ 2002;167:1261-1266
Copyright ©2002 Canadian Medical Association or its licensors
PLASMAPHERESIS
PLASMAPHARESIS
Plasmapheresis: Basic
Principles
Membrane vs. Centrifugation
► In
the US, most TPE is performed by
centrifugation.  One machine can do
all apheresis procedures.
► Double filtration method: first
membrane separates plasma from
cellular portion and second membrane
separates globulin from albumin.
► LDL apheresis: using membrane coated
with antibody to LDL, only LDL
cholesterol can be removed.
Continuous vs. Intermittent
► Continuous:
COBE Spectra, Fenwall CS3000
► Intermittent:
Haemonetics
Blood Components Separated by Centrifugat
Platelets
Plasma
Lymphocytes
Monocytes
Granulocytes
Neocytes
Erythrocytes
Plasma Exchange
TPE: Available techniques
techniques...
• Cascade or secondary filtration: Separated
blood is perfused through a plasma filter (1)
to remove certain plasma elements. The
second column (2) (cascade) absorbs the
element and the plasma is returned to the
patient.
1
2
PATIENT
Plasma removal is affected by:
• Qb
• Hct
• Pore Size
• TMP
=Plasma effluent
Qb 100-150
Hct 25-45%
Pore Size
TMP <50 mmHg
Rationale of Plasma Exchange
► The
existence of a known pathogenic
substance in the plasma.
 IgG, IgM, phytanic acid, cytokines (?)
► The possibility of removing this substance
more rapidly than it can be renewed in
the body.
Efficiency of removal is greatest early in the
procedure and diminishes progressively during the
► 1.0
Small vs. Large Volume
Exchange
plasma volume exchange: minimizes
time required for each procedure but may
need more frequent procedures.
► 2.0 – 3.0 plasma volume exchange: greater
initial diminution of pathologic substance
but requiring considerably more time to
perform the procedure.
Mechanical Removal of Antibodies
► When
antibody is rapidly and massively
decreased by TPE, antibody synthesis
increases rapidly.
► This rebound response complicates
treatment of autoimmune diseases.
► It is usually combined with immune
suppressive therapy.
Replacement Fluid
► Fresh
frozen plasma – TTP, liver failure,
coagulopathy with inhibitors, patients with
coagulopathy, immediate post surgery.
► Cryopoor plasma – TTP
► 5% albumin – Most cases.
Plasmapheresis
►
►
►
►
►
►
►
and plasma exchange may be considered medically
necessary for any of the conditions listed below:
Myasthenia gravis in crisis or as part of preoperative
preparation
Hyperviscosity syndromes associated with multiple
myeloma, Waldenström's macroglobulinemia, or other
conditions
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Idiopathic thrombocytopenic purpura in emergency
situations
Guillain-Barré syndrome in severely ill patients who are
diagnosed with grades 3-5 disease (see grading below)
Plasmapheresis
►
Chronic inflammatory demyelinating polyneuropathy
meeting all of the following three criteria:
 Associated with life-threatening symptoms or severe disability;
 Diagnosed by slowing of nerve conduction velocity on EMG/NCS
and elevated spinal fluid protein on lumbar puncture; and
 Failed to respond to previous treatment with prednisone and
intravenous immunoglobulins (IVIg)
IgA or IgG paraproteinemia polyneuropathy
► HELLP syndrome of pregnancy
► Post-transfusion purpura
► Progressive renal failure due to anti-basement membrane
antibodies (i.e., Goodpasture's syndrome
► Acute fulminant CNS demyelination associated with
multiple sclerosis or other idiopathic inflammatory
demyelinating diseases, such as transverse myelitis, which
may proceed to severe cognitive dysfunction, hemiplegia,
paraplegia or quadriplegia
►
Plasmapheresis
Cryoglobulinemia
Chronic myelogenous leukemia
► Chronic demyelinating gammopathy
► Leukapheresis in the treatment of leukemia
► Life-threatening rheumatoid vasculitis
► Pure red cell aplasia unresponsive to steroid and
immunosuppressive therapy
► Plasma perfusion of charcoal filter for treatment of pruritus
of cholestatic liver disease
► Prior to solid organ transplant, treatment of patients at
high risk of antibody-mediated rejection, including highly
sensitized patients, and those receiving an ABO
incompatible organ
► Following solid-organ transplant, for the treatment of
antibody-mediated rejection
►
►
Plasmapharesis
► is
considered investigational for all
other applications, including but not
limited to:








Rheumatoid arthritis
Scleroderma (systemic sclerosis)
Systemic lupus erythematosus
Polymyositis and dermatomyositis
Inclusion body myositis
Pemphigus
Guillain-Barré syndrome, grades 1-2
Multiple sclerosis in the absence of acute
fulminant onset
Plasmapharesis
 Amyotrophic lateral sclerosis
 Paraneoplastic syndromes including LambertEaton myasthenic syndrome
 Paraproteinemic polyneuropathy, including
monoclonal gammopathy of undetermined
significance (MGUS)
 Chronic fatigue syndrome
 Regional enteritis (Crohn's disease)
 Rapidly progressive glomerulonephritides,
excluding those related to anti-basement
membrane immunoglobulins (i.e., Goodpasture’s
syndrome -- covered above)
 Asthma
 Stiff man syndrome
 Acute pancreatitis related to hyperlipidemia
PLASMAPHARESIS IN 10 CASES
Kyriakidis AV, Raitsiou B, Sakagianni A, Harisopoulou V, Pyrgioti M, Panagopoulou A,
Vasilakis N, Lambropoulos S.
Intensive Care Unit, General Hospital Sismanogleion, Athens, Greece. [email protected]
PLASMAPHARESIS IN 10 CASES
►
►
►
Kyriakidis AV, Raitsiou B, Sakagianni A, Harisopoulou V, Pyrgioti M,
Panagopoulou A, Vasilakis N, Lambropoulos S.
 Intensive Care Unit, General Hospital Sismanogleion, Athens, Greece.
[email protected]
severe hyperlipidemic pancreatitis when triglyceride levels
exceed 11.3 mmol/l.
10 patients were evaluated the therapeutic guidelines for
severe hyperlipidemic pancreatitis.
►
►
►
►
►
►
►
RESULTS:
Standard treatment was essential for all the patients
but plasmapheresis was the procedure that lowered the
triglyceride and lipid levels in all cases.
It improved abdominal pain, clinical state, and signs and
symptoms of the disease.
Two patients underwent surgery due to infection of the necrotic
segments and one of them died.
Follow-up lasted 4-54 months with no recurrences of
pancreatitis.
Management of acute severe
hyperlipidemic pancreatitis.
► CONCLUSION:
 Hyperlipidemic pancreatitis should initially be
treated conservatively study shows that standard
treatment is essential,
. Plasmapheresis is a method that has lately
been used successfully for hyperlipidemic
pancreatitis. It seems that all therapeutic
measures should be applied as early as
possible, within the first 48 h.
► PMID:
16940728 [PubMed - indexed for MEDLINE]
Plasmapheresis in the management of acute severe hyperlipidemic
pancreatitis: report of 5 cases. 2006 S. Karger AG, Basel
► Plasma
exchange lowered the lipid
level and TGLs in all 5 cases.
 It also improved abdominal pain,
 Complications of treatment were not
encountered,
 none of the patients died and
 only 1 patient underwent surgery.
 Follow-up of the patients lasted 4-28 months,
and recurrence of pancreatitis was not noted.
First case of acute pancreatitis induced by hypertriglyceridemia in
.
the setting
of an uncontrolled cytophagic histiocytic panniculitis successfully
treated by plasmapheresis
► One
patient was treated with one plasmapheresis
that allowed a dramatic (89%) decrease in the
triglycerides level.
► The acute pancreatitis resolved and the patient
was discharged from the intensive care unit at day
5 with lipids and pancreatic enzyme levels within
normal range.
PMID: 14569604 [PubMed - indexed for MEDLINE]
Plasmapheresis as an adjuvant therapy for
hypertriglyceridemia-induced pancreatitis.
►
Iskandar SB, Olive KE.
 Department of Internal Medicine, James H. Quillen College of Medicine,
East Tennessee State University, Johnson City, TN 37614, USA.
Hypertriglyceridemia is an uncommon cause of
pancreatitis.
► A serum triglyceride level of more then 1000 to 2000
mg/dL(13.1 to 26.2 m mole/L) is an identifiable risk
factor.
► Interestingly, serum pancreatic enzyme levels may be
normal or only minimally elevated in such cases.
► The reduction of triglyceride level to below 1000
mg/dL (13.1 m mole/L) effectively prevents further
episodes of pancreatitis.
►
Plasmapheresis as an adjuvant therapy for
hypertriglyceridemia-induced pancreatitis.
Iskandar SB, Olive KE.
Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee
State University, Johnson City, TN 37614, USA.
► The
mainstay of treatment for the
hypertriglyceridemia associated with
pancreatitis includes
 dietary restriction of fat and administration of
lipid-lowering agents.
► It
is thought that within 24 to 48 hours of the
onset of pancreatitis, in the majority of
patients, triglyceride levels fall rapidly as a
result of fasting status, as the absorption of
chylomicrons to the blood is cut off.
► Experiences with plasmapheresis are limited.
Hypertriglyceridemia: apheretic treatment. treated 15 cases of
hypertriglyceridemia complicating the course of patients receiving
Cyclosporin A after bone marrow transplantation
► Giannini
G, Valbonesi M, Morelli F, Carlier P,
De Luigi MC, Dejana AM, Ruzzenenti MR.
► Patients with extremely high triglyceride levels and
associated lipemia are at high risk for acute
pancreatitis.
 Two factors can increase triglyceride-rich lipoproteins;
one is overproduction and other is a defect in clearance.
► Either mechanism can cause hypertriglyceridemia and both
may exist simultaneously.
► Causes can be either primary or secondary.
►
► Plasmapheresis
is efficacious for severe
Hypertriglyceridemia in patients who have not
responded to previous therapies..
PMID:
16288440 [PubMed - indexed for MEDLINE]
RANSON CRITERIA
►
Initial 24 hrs
1.Age >55 years
2.Glucose >than 200
mgm/dl
3.WBC > 16,000
cells/mic L
4.LDH >350 IU/liter
5.AST >250IU/liter
►
Subsequent 48 hrs
1.Art o2tension <60mmHg
2.Bun Increase >8mg/dl
3.Ca < 8mg/dl
4.Base deficit
>4meq/liter
5.Estimated fluid
sequestration >6liters
6.Fall n Hct >10%
Mortality prediction (as per
Ranson criteria)

A. < 3 signs = 1%

B. Three to Four signs=11%

C. Five to six signs=33%

D. >Six signs= 100%
IMRIE,S CRITERIA
► During
first 24 hours
1.Age>55 yrs
2.WBC >15x 10 9/l
3.Blood glucose
>10mmol/l
4.Plasma
Urea>16mmol/l
5.Pao2<8Kpa
6.Pl ca<2.0mmo/l
7.Pl albumin<32g/l
8.LDH>600 u/l(n=250)
9.AST or ALT >100 u/l
GLASGOW CRITERIA
► Any
time during
First 48hrs after
admission;
WBC >15000 Cu/mm
Blood
glucose>10mmol/l
BUN >16mmol/L
Art po2,< 60mmHg
Ser ca. <2.0 ml/l
Ser Albumin<32gm/l
Ser LDH
>600u/L(n=250)
AST Or ALT >200u/l
APACHEII-variables
1.
2.
3.
4.
5.
6.
Temp
Mean Art Pressure
Heart Rate
Resp rate
Oxygenation(Pao2)
Arterial Ph
1.
2.
3.
4.
5.
6.
Serum sodium
SerumPottasium
Serum creatinine
Haematocrit
WCC
Glasgow coma scale
Apache II score(Sum of A+B+C)
►
A=+4 to 0 points
 TEMP>41=4,<29=4
 Mean Art Pr>160=4
<49=4
 Heart & Resp rate
OXYGENATION
ART PH
Ser Na,K,Creat,
 HCT,WBC
 GLASGOW COMA Score
► B=Age
<44=0 pts
 >75=6points
► C=Chronic
points
Health
 H/o organ insufficiency
Liver,CVS,Resp,Renal,
,Immunocompromised
►
APACHE SCORE42=90% Mort
FUTURE DIRECTIVES
1.This modality of treatment needs further
exploration
2.Large prospective clinical trials are needed
to confirm it,s beneficial role in treatment of
Hyperlipidemia.
3.In future it will be adjunctive therapy or
may be the sole therapy to acute
pancreatitis.
References
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Harrison,s principles of internal medicine.
E. medicine
Digestion
CMAJ
PUBMED
Journal of american family physicians
AMERICAN JOURNAL OF GASTROENTEROLOGY
Journal american college of physicians
Comperehensive clinical nephrology
Massry and Glassok,s text book of nephrology
American association of family physician