THERAPEUTIC FOCUS
Dysplipidemia
Dyslipidemia is a broad category of diseases involving elevation of plasma cholesterol and/or triglyceride, and reduced high-density-lipoprotein bound cholesterol (HDL-C) which generally contribute to atherosclerosis. The most common forms of dyslipidemia include hypertriglyceridemia, mixed dyslipidemia, and hypercholesterolemia. Hypertriglyceridemia is characterized by elevation of serum triglycerides and very-low-desnisty-lipoprotein bound cholesterol (VLDL-C). Mixed dyslipidemia is characterized by elevation of serum triglycerides, total cholesterol, low-density-lipoprotein bound cholesterol (LDL-C), and VLDL-C. Hypercholesterolemia is characterized by elevated total cholesterol and LDL-C.
The majority of cases of dyslipidemia do not have a clear genetic basis, but are due to secondary causes including: sedentary lifestyle, excessive intake of dietary saturated fat and cholesterol, insulin resistance and excessive alcohol consumption.
Management and treatment of dyslipidemia involves changes in diet and lifestyle, and often includes pharmacotherapy when diet and lifestyle changes are ineffective in treating the disease.
The National Cholesterol Education Program (NCEP) in the Adult Treatment Program III (ATP III) guidelines provide the following classification of Risk Reduction Targets for treatment:
NCEP ATP III: Risk Reduction Targets
Classification of LDL-C, Triglycerides, and HDL-C (mg/dL)
| Primary: | LDL-C | |
| <100 | Optimal | |
| 100-129 | Near optimal | |
| 130-159 | Borderline high | |
| 160-189 | High | |
| ≥ 190 | Very high | |
| Secondary: | Triglycerides | |
| < 150 | Desirable | |
| 150-199 | Borderline high | |
| 200-499 | High | |
| ≥ 500 | Very high | |
| HDL-C | ||
| < 40 | Low | |
| ≥ 60 | High |
Very High Triglycerides (VHTG) and the Risk of Acute Pancreatitis
Acute pancreatitis is associated with significant mortality and morbidity. Although two-thirds of the cases present with minimal organ dysfunction, the remainder of cases are associated with intra and extrapancreatic necrosis, shock, multiple organ failure, and results in death in up to 20% of patients who present with severe symptoms. Approximately 80% of deaths in acute pancreatitis are associated with septic complications.
There are several causes for acute pancreatitis, including substantially elevated triglycerides (TG), alcoholism and biliary tract disease. Very high triglycerides (VHTG) (TG > 500 mg/dL) are a well-characterized risk factor for acute pancreatitis (AP). AP is an acute inflammatory process of the pancreas that may also involve peripancreatic tissues and/or remote organ system failure. Marked elevation of triglycerides is causally linked to acute pancreatitis and is found in 12% to 38% of patients with this disease. Even in AP attributable to etiologies other than elevated triglycerides, elevation in triglycerides contributes to more severe disease and increased mortality. Elevated triglycerides contribute to AP risk and severity by multiple mechanisms resulting in ischemia, apoptosis and necrosis. Sixty percent of patients with VHTG who have experienced AP will experience recurrence. Treatment of these patients to consistently lower their triglycerides effectively prevents recurrence. It is clear that even first events of AP may be prevented in patients who are at risk of AP due to persistent elevations in triglycerides, by the effective management of their triglycerides. According to National Cholesterol Education Program Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines, triglyceride reduction should be a primary target of therapy in patients with triglycerides > 500 mg/dL because of the increased risk of acute pancreatitis.
Triglycerides have both exogenous and endogenous sources. Triglycerides obtained from dietary sources are initially packaged in chylomicrons, while endogenous triglycerides synthesized by the liver are packaged in VLDL. These two lipoproteins are the predominant source of triglycerides in blood and interact with lipoprotein lipase and hepatic triglyceride lipase in peripheral tissue in order to clear the bloodstream of these particles and store triglycerides in muscle and adipose tissue. The development of hypertriglyceridemia is dependent on a balance between the synthesis and clearance of these lipoproteins.
The underlying bases by which elevations in triglycerides cause AP and worsen the disease condition are similar. AP can be induced in animal models by the infusion of triglycerides into the pancreatic vascular bed. It can also be induced when free fatty acids (FFA) are infused into the pancreatic vascular bed. Local application of a mixture of emulsified olive oil and pancreatic lipase produces massive necrosis in liver, kidney, pancreas, skeletal muscle, and perivascular sheath within 3 hours, with subsequent spread of necrosis. Similarly, in animal models of either acute edematous pancreatitis or acute necrotizing pancreatitis, the elevation of circulating triglycerides by the stimulation of hepatic triglyceride biosynthesis worsens the severity of AP as measured by extent of tissue damage. There are a number of hypotheses concerning the mechanism by which elevations in triglycerides contribute to acute pancreatitis. These hypotheses are not mutually exclusive and, therefore, all may contribute to disease risk and severity. Persistent elevations in circulating triglycerides in the dog, achieved by feeding a high fat diet, caused the cells of the pancreas to be predisposed to cell death under various stresses in contrast to cells from kidney or liver. Excess triglyceride from circulating triglyceride rich lipoprotein particles are hydrolyzed into FFA by high levels of pancreatic lipase which is released into the vascular bed of the pancreas. The very high concentration of FFA thus formed exceeds the binding capacity of plasma albumin. FFA then self-aggregates forming micellar structures with detergent properties. These FFA micelles will attack platelets, the vascular endothelium and, finally, pancreatic tissue resulting in ischemia, apoptosis and necrosis. The resultant ischemia creates an acidic environment, which further enhances FFA toxicity. Significantly elevated levels of chylomicrons, which follow saturation of LPL system contribute to plasma hyperviscosity resulting in ischemia and acidosis in pancreatic capillaries. Elevated triglycerides appear to predispose pancreatic cells to apoptosis and necrosis and, through FFA and chylomicrons to a lesser degree, function as the mediator of both ischemia and cellular damage resulting in AP.
Marked reduction of triglyceride levels in patients who had had at least one episode of acute pancreatitis effectively prevents further episodes. Dietary restriction of fat is a critical component of management of triglycerides. Additionally, increases in physical activity, cessation of smoking, reductions in alcohol consumption and weight loss all may contribute to management of elevated triglycerides. The use of TG-lowering drugs effectively prevents recurrence of AP in patients with hypertriglyceridemia-induced AP. In a 6-year prospective study of patients who had experienced hypertriglyceridemia-induced AP and were subsequently treated with an effective TG-lowering regimen, the only patient to experience a relapse was one who had discontinued treatment. The authors concluded that appropriate diet and drug treatment, including dose titration, of severe hypertriglyceridemia is very effective in preventing relapses of hypertriglyceridemia-induced AP, regardless of the underlying basis by which triglycerides are elevated.