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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 ► ► ► ► ► ► ► ► ► ► ► 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