Hyperlipidemia refers to elevated plasma cholesterol or triglyceride levels or both. Cholesterol is a waxy substance that travels through the bloodstream on proteins called lipoproteins. At normal levels cholesterol has many important functions. It is one of the key components of cell membranes. Cholesterol is also an important precursor molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogen, and testosterone.
High cholesterol is characterized by increased levels of total cholesterol (<200 mg/dL) and low-density lipoprotein (LDL) (<100 mg/dL) particles and decreased levels of high-density lipoprotein (HDL) (>60 mg/dL) particles. The main cause of high cholesterol and LDL includes infection of the liver by gram-negative bacteria and unhealthy lifestyle habits such as diet with a fat intake greater than 40 percent of total calories, saturated fat intake greater than 10 percent of total calories; and cholesterol intake greater than 300 milligrams per day.1 Other lifestyle factors include obesity, smoking, heavy alcohol use, and lack of exercise.
High triglyceride levels (<150 mg/dL) can be an independent condition resulting from fatty liver disease with liver inflammation and infection by gram-positive bacteria. Fatty liver, or hepatic steatosis, is characterized by excess fat especially triglycerides built up in the liver cells with an increased production of VLDL particles and decreased clearance of VLDL from the blood. This results in high triglyceride levels and VLDL levels (>30 mg/dL) in the blood. High serum triglyceride levels can also result from high cholesterol when high cholesterol has catalyzed the onset of liver inflammation.
Although patients with hyperlipidemia are typically asymptomatic, high cholesterol levels, particularly high levels of LDL and VLDL can cause atherosclerosis and lead to the buildup of plaque in the arteries, narrowing or clogging of arteries, restricting blood flow and increasing the risk of heart attack and stroke.
Low-Density Lipoproteins (LDL)
LDL are particles in the blood are made up of a combination of 75% cholesterol with Apolipoprotein B-100 and a small number of phospholipids and triglycerides. LDL is known as “bad cholesterol” with its primary role to transport cholesterol from the liver to the cells. Most cholesterol in the blood is carried by LDL particles.
High-Density Lipoproteins (HDL)
HDL particles in the blood are made up of a combination of lipids including cholesterol, triglycerides and phospholipids and multiple proteins with Apolipoprotein A-I as the main protein component. HDL is known as “good cholesterol” because it carries cholesterol out of the bloodstream and from peripheral cells, such as macrophages, back to the liver for excretion. HDL particles play an important role in reverse cholesterol transport from peripheral tissues to the liver, which is one potential mechanism by which HDL may be anti-atherogenic. In addition, HDL particles have antioxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic properties, which may also contribute to their ability to inhibit atherosclerosis.2
Very Low-Density Lipoproteins (VLDL)
VLDL particles in the blood are made up of a combination of 50% triglycerides, 40% cholesterol and fatty acids and 10% proteins with apolipoprotein B-100 (ApoB-100) being the primary structural protein. The main function of VLDL is to transport triglycerides from the liver to various tissues in the body, providing them with a source of energy or storage.
Research shows that the combination of high VLDLs and high LDLs is more dangerous than high levels of either of those alone. As VLDLs circulate in the blood, VLDL particles will break down to release triglycerides and “remnant particles” to convert into LDLs which are then further processed. These “remnant particles” are made mostly of cholesterol. They’re small enough to get trapped inside the artery walls and promote atherosclerosis.
The Liver, Cholesterol, and LDL
The liver is central to the regulation of cholesterol levels in the body. The liver synthesizes not only the cholesterol, but also the HDL, LDL and VLDL. Cholesterol is both synthesized by the liver cells and taken in with food intake. The rate limiting enzyme in cholesterol synthesis is the HMG-CoA reductase which is under negative feedback regulation. When the sterol level is high, the liver cells will reduce the HMG-CoA reductase level and less cholesterol will be synthesized.6 LDL receptors in the liver can bind with the LDL and control the level of LDL in the blood as well. The amount of LDL receptors in the liver is also under the negative feedback control. When LDL is high in the blood, the LDL receptors will be decreased and less LDL will be released into the blood.6
Unhealthy eating habits and heavy alcohol use can cause liver injury and malfunctioning leading to the loss of the liver’s feedback control mechanism. Even though the level of LDL and cholesterol are high in the blood, the liver keeps synthesizing the cholesterol and maintaining high amounts of LDL receptors causing high cholesterol and VLDL levels in the blood.
Recent research has found that increased cholesterol and LDL levels can also be associated with lipopolysaccharides (LPS) from a gram-negative bacterial infection in the liver. Bacterial LPS induces increased synthesis of cholesterol and LDL leading to high cholesterol and LDL levels. Animal studies found that increased LDL levels help reduce peripheral nerve inflammation and brain inflammation and protects the neurological system from injury caused by the LPS.
Fatty Liver Disease, Triglycerides and VLDL
High triglycerides and VLDL levels are usually associated with fatty liver disease as well as liver inflammation and gram-positive bacterial infections. High triglyceride levels are early signs of fatty liver disease which drive increase VLDL particle release to the blood. Peptidoglycan (PGC) from the cell wall structure of gram-positive bacteria in the liver can induce increased levels of pro-inflammatory cytokines which trigger liver inflammation with increased synthesis and release of triglycerides and VLDL into the blood.
High levels of triglycerides in the blood may contribute to hardening of the arteries or thickening of the artery walls (arteriosclerosis) which increases the risk of stroke, heart attack and heart disease. Extremely high triglycerides can also cause acute pancreatitis, inflammation of the pancreas pancreatitis.
Although elevated LDL is well established as a major predictor of coronary heart disease risk and has been the primary target for lipid-lowering strategies, evidence suggests that an elevated triglyceride level is also an independent risk factor. In clinic, it has been found that even though statin drugs can help reduce LDL levels to lower the risk of cardiovascular diseases, the risk remains high in many cases despite optimal LDL reduction on statin monotherapy.14 It has been well recognized that in addition to the critical role that LDL plays in atherosclerosis, there is significant contribution from hypertriglyceridemia and VLDL. The risk is even higher in patients with combination of high triglyceride, VLDL, remnant particles, and insulin resistance when LDL have reached normal levels.
Complications
Hyperlipidemia is one of the most prevalent risk factors contributing to the evolution of atherosclerosis and consequent cardiovascular disease.1 Atherosclerosis frequently remains asymptomatic until plaque stenosis reaches 70- 80% of the vessel's diameter. The process begins when LDL and VLDL levels are increased in the blood, some of the Apolipoprotein B (ApoB) proteins can be retained in the artery wall and trigger artery wall inflammation damaging the blood vessels. High levels of triglycerides can also cause inflammation and injury to the artery. Such injury or damage permit the accumulation of lipids within the innermost endothelial layer. The trapped lipids are then engulfed by macrophages, leading to the establishment of "foam cells."1 This lipid build-up within the "foam cells" causes subsequent mitochondrial dysfunction, apoptosis, and, ultimately, necrosis of the underlying tissues.1 Smooth muscle cells encapsulate the pack of "foam cells" or debris, which produces a fibrotic plaque that inhibits the underlying lipids (debris) from being destroyed.
Complications from undertreated or untreated hyperlipidemia include all types of cardiovascular disease, which may prove fatal down the road.1 These include, but are not limited to, coronary artery disease, peripheral artery disease, cerebrovascular accidents, aneurysms, type II diabetes, high blood pressure, and even death.1
Statins and High Cholesterol
Statin medications are a class of drugs that are lipid-lowering. Unfortunately, statin medication complications include myopathy, renal injury, arthralgia, extremity pains, nausea, myalgia, elevated liver enzymes/hepatotoxicity, diarrhea, and rhabdomyolysis.1
Although statins are the most common medication prescribed for hyperlipidemia, not all patients can take it or will benefit from it. The most serious risk of these drugs is rhabdomyolysis with acute renal failure and even death. About 5-10% of individuals are unable to tolerate statins. For some, allergies can be the causative issue and, if taken, can lead to acute kidney failure. This type of patient may rely on diet and exercise as their only option to control their cholesterol levels. For others, rhabdomyolysis and chronic fatigue can be developed in combination with severe muscle aches as a side effect of statin medications. This is because statins lower the amount of coenzyme Q10 (CoQ10), which is important for muscle function. Simvastatin, for example, has been shown to decrease levels of CoQ10 by 40%.9 It’s important for individuals who have hyperlipidemia to exercise and maintain a healthy lifestyle, but statin medications can make this more difficult as they increase exercise-induced skeletal muscle injury. In a study done, the muscle pain prevented even moderate exertion during everyday activities in 38% of the patients with myalgia on statins.11
Patients who are on statins with no current side effects can develop long-term damage with high-dose and continued use. These include both liver and kidney damage. A large retrospective cohort study comparing long-term statin users with a matched group of nonusers found an association between statin treatment and an increased incidence of acute and chronic renal disease.10
