Hyperlipidemia is a common complication after solid organ transplantation and an important cause of patient death due to predisposing cardiovascular disease. The incidence of hyperlipidemia after heart transplantation can be as high as 93%, 66% for liver transplantation, 60% for kidney transplantation, and 52% for lung transplantation. Active intervention to control dyslipidemia is important to reduce the incidence of cardiovascular events and improve the quality of life and survival time of patients.
1. Etiology
Post-transplant hyperlipidemia is the result of a combination of factors, of which the application of immunosuppressive drugs is the most important causative factor. Cyclosporine, glucocorticoids and sirolimus all increase cholesterol and triglyceride levels. Mycophenolate, azathioprine and tacrolimus have relatively minor effects on lipids.
Long-term application of glucocorticoids significantly increased cholesterol and triglyceride levels. Hormones enhance insulin resistance and increase secretion of very low density lipoproteins by the liver. Cyclosporine inhibits cholesterol degradation by interfering with bile acid synthesis and inhibits uptake of LDL by downregulating hepatocyte LDL receptors. Cyclosporine also stimulates cholesterol synthesis, decreases lipoproteinase activity, and reduces the clearance of very low-density lipoproteins and celiacs. Cyclosporine can also cause hypercholesterolemia by impairing biliary phospholipid secretion. Sirolimus also has the effect of increasing cholesterol and triglyceride levels, but its mechanism of action is unclear.
2.Diagnosis
There is no unified international and domestic diagnostic criteria for hyperlipidemia. It was previously considered that a plasma total cholesterol concentration >5.17 mmol/L (200 mg/dl) could be diagnosed as hypercholesterolemia, and a plasma triglyceride concentration >2.3 mmol/L (200 mg/dl) could be diagnosed as hypertriglyceridemia. Currently, it is recommended to start drug therapy at LDL-C concentrations >130 mg/dL, with LDL-C concentrations <100 mg/dL as the treatment goal; for patients with hypertriglyceridemia, triglyceride levels >500 mg/dL should be started. If the risk of future cardiovascular disease is high medication should be started earlier and more stringent treatment goals should be adopted.
3.Harm of hyperlipidemia
Hyperlipidemia has a detrimental effect on both patient and graft survival. Elevated lipid levels, especially LDL cholesterol, significantly increase the risk of cardiovascular events. In addition, increased atherosclerosis in hyperlipidemic patients leads to reduced organ perfusion and deterioration of organ function.
Hyperlipidemia may also be involved in the chronic rejection of grafts. Studies have shown that hypercholesterolemia accelerates the development of proliferative vascular lesions similar to chronic rejection, and that LDL can upregulate the expression of HLA-II class antigens, which has a direct toxic effect on endothelial cells and induces macrophage formation of foam cells to accelerate atherosclerosis.
4.Treatment
In view of the risk of hyperlipidemia inducing atherosclerosis and cardiovascular events, organ transplant patients should regularly monitor lipid levels and treat hyperlipidemia with diet modification, exercise, control of obesity and diabetes, taking lipid-lowering drugs, and reducing or stopping glucocorticoids according to the situation.
(1) Lifestyle modification
Transplant patients should limit the intake of saturated fat and cholesterol, perform regular exercise, quit smoking, and control hypertension and diabetes. The benefit-risk ratio should be carefully evaluated when applying oral contraceptives, antidepressants, antiacne drugs, beta-blockers, thiazide diuretics and anti-infective drugs that may affect lipids.
(2) Adjustment of immunosuppressive regimen
Since immunosuppressive drugs play an important role in the development of hyperlipidemia after transplantation, active adjustment of immunosuppressive regimens plays an important role in controlling hyperlipidemia.
Glucocorticoids are an important component of many immunosuppressive regimens, and early discontinuation of hormones and no hormone regimens at all have gained widespread clinical use in recent years, and the vast majority of studies have achieved similar rejection prevention effects as applied hormone regimens, and the occurrence of hyperlipidemia is significantly due to the inclusion of hormone regimens. Therefore, the aggressive use of hormone-free or early discontinuation of hormonal regimens is a good choice for the prevention and treatment of hyperlipidemia in patients who are eligible.
With the widespread use of sirolimus and mycophenolate, patients with severe hyperlipidemia combined with risk factors for cardiovascular events may consider switching to a non-calmodulin inhibitor regimen to control hyperlipidemia, but the risk of rejection and the risk-benefit ratio of lipid-lowering therapy need to be strictly evaluated.
(3) Low-density lipoprotein cholesterol-lowering therapy
LDL cholesterol is the primary target of lipid-lowering therapy. In patients with cardiovascular disease, peripheral vascular disease, cerebrovascular disease, and diabetes, serum LDL cholesterol above 130 mg/dL should be initiated with a target of less than 100 mg/dL. statins, cholesterol absorption inhibitors, bile acid binding resins, and niacin are all effective in lowering LDL cholesterol.
Statins are recommended as first-line agents for hyperlipidemia in transplant patients, reducing cholesterol synthesis, causing increased cellular expression of LDL receptors, and accelerating LDL cholesterol clearance. Hepatic impairment and muscle damage are common side effects of this class of drugs. Creatine kinase and transaminases should be tested before dosing and should be rechecked after dosing or 4-6 weeks after dose adjustment. An elevation of transaminases more than 3 times the upper limit of normal should lead to dose reduction or discontinuation of the statin; creatine kinase more than 10 times the upper limit of normal should also be discontinued.
Ezetimibe is the only cholesterol absorption inhibitor available. Ezetimibe alone can reduce serum LDL cholesterol by approximately 18%, and in combination with a statin can further reduce it by 25%. Ezetimibe is commonly used in patients who are intolerant to statins and in patients who have had poor lipid-lowering results with statins alone. No serious adverse effects have been identified with ezetimibe, and data confirm its effectiveness in preventing cardiovascular events.
Cauleenimine disulfide, cauletipro and cauleverine are commonly used clinically as bile acid binding resins. These drugs have the benefit of being non-absorbable, but they are now being phased out of use in organ transplant recipients because of the large doses they require. In addition, these drugs increase triglyceride levels by increasing hepatic very low density lipoprotein synthesis, and bile acid binding resins are contraindicated in patients with triglycerides greater than 400 mg/dL.
Niacin is capable of lowering LDL cholesterol by 15-25%, lowering triglycerides by 20-50%, and raising HDL cholesterol by 20-30% at doses greater than 1000 mg/d. Niacin is very inexpensive, but its clinical use is not common due to side effects such as skin flushing, itching, and abnormal sensation. Niacin therapy can be applied to patients who cannot tolerate statins.
(4) Triglyceride-lowering therapy
Hypertriglyceridemia is also common in post-transplant patients, especially in patients with combined diabetes, significant weight gain and obesity. In most patients, triglyceride levels can be effectively lowered with lifestyle modification and glycemic control, but patients with significantly elevated triglycerides need to be treated with medication. Although niacin is effective in lowering triglyceride levels, fibrates and omega-3 fatty acid therapy are currently preferred due to side effects.
Betablockers can lower triglyceride levels by 20-50% and raise HDL cholesterol by 10-30%, and are well tolerated by most patients. Gemfibrozil and fenofibrate are the commonly used betablockers. Gemfibrozil reduces cardiovascular events by raising HDL cholesterol and lowering triglycerides without altering LDL cholesterol levels. Betablockers can also cause muscle damage, and special attention should be paid when combined with statins. In addition, fenofibrate can cause creatinine elevation, so fibrates are recommended only when triglyceride levels are greater than 500 mg/dL, and gemfibrozil is recommended in preference.
Omega-3 fatty acids can lower triglycerides and can be used as a treatment option for hypertriglyceridemia in patients with triglyceride levels greater than 500 mg/dL. However, the application of omega-3 fatty acids has side effects such as nausea, flatulence and diarrhea, which limit their application. In order to obtain significant triglyceride-lowering effects, high doses of fish oil need to be given. In patients with severely elevated triglycerides (>1000 mg/dL) who are at risk for pancreatitis, a short-term increase in fish oil intake can help to rapidly lower triglyceride levels.