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.
Hyperlipidemia, more commonly known as high cholesterol, is a condition in which there are high levels of lipids in the blood. This is characterized by increased levels of low-density lipoprotein (LDL) particles and decreased levels of high-density lipoprotein (HDL) particles. The main cause of secondary hyperlipidemia includes unhealthy lifestyle habits in which a major risk factor is mainly poor diet i.e. 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 such as obesity, smoking, heavy alcohol use, and lack of exercise can also lead to hyperlipidemia.
High triglyceride levels can be an independent condition resulting from fatty liver disease with liver inflammation. High serum triglyceride levels can also result from high cholesterol when high cholesterol has catalyzed the onset of liver inflammation.
Low-Density Lipoproteins
There are two types of lipoproteins that carry cholesterol to and from the cells. LDL and very low-density lipoprotein (VLDL) are both known as “bad cholesterol” because LDL carries cholesterol from the liver to the cells and VLDL contains the highest amount of triglycerides. LDL carries the majority of the cholesterol that is in the circulation and is one of the most prevalent risk factors contributing to the evolution of atherosclerosis and consequent vascular disease. LDL receptors in the liver play a major role in determining plasma LDL levels (a low number of receptors is associated with high plasma LDL levels while a high number of hepatic LDL receptors is associated with low plasma LDL levels).2
High-Density Lipoproteins
HDL is known as “good cholesterol” because it carries cholesterol out of the bloodstream and back to the liver. 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.2 The pathway by which excess cholesterol from peripheral cells, such as macrophages, in the vessel wall is transported to the liver for excretion is through HDL. In addition, HDL particles have anti-oxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic properties, which may also contribute to their ability to inhibit atherosclerosis.2
HDL particles are enriched in cholesterol and phospholipids. Phospholipids and most likely cholesterol are added to ApoA-I, the main protein constituent of HDL, by the ATP-binding cassette (ABCA1) transporter. ApoA-I is secreted from the liver and intestine in a relatively lipid-poor state.2
The Liver and Cholesterol
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. The HMG-CoA reductase in the hepatocytes is under negative feedback regulations. 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 the 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, heavy alcohol use, or certain medications such as statins can cause liver injury and malfunctioning. This can lead to the loss of the liver’s feedback control mechanism. Regardless of the high level of LDL and cholesterol in the blood, the liver keeps synthesizing the cholesterol and maintaining high amounts of LDL receptors causing high cholesterol in the blood.
A poorly functioning or deficient liver also can’t synthesize the proper amount of HDL particles. This leads to a decrease in the number of ApoA-I, the main protein constituent of HDL, and the resulting less cholesterol which has been absorbed from food intake being brought back to the liver to be excreted. This causes an imbalance between LDL and HDL levels which can contribute to hyperlipidemia as well as atherosclerosis.
Fatty Liver Disease and Cholesterol
Hypercholesterolemia is also a main cause of nonalcoholic fatty liver disease (NAFLD) as well as atherosclerosis. High cholesterol also can turn fatty liver disease (steatosis) into a more serious condition, nonalcoholic steatohepatitis (NASH) which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. Increased cholesterol synthesis or cholesterol overload can also cause free cholesterol accumulation in the liver. The presence of the increased levels of cholesterol in liver can significantly increase the risk factor of the “second hit” and amplify the impact of the “second hit” triggering the onset of liver inflammation and speed up the irreversible progression of NASH. The accumulation of free cholesterol in the liver can also cause liver injury because of the activation of Kupffer cells (KCs) and Satellite cells (HSCs) which promotes inflammation and fibrogenesis. In addition, free cholesterol accumulation in liver mitochondria induces mitochondrial dysfunction, which results in increasing production of reactive oxygen species (ROS), and triggers the unfolded protein response in the endoplasmic reticulum (ER) causing ER stress and apoptosis.11,12
Patients who have hyperlipidemia with high cholesterol may or may not have high triglycerides levels in their blood. When patients with cholesterol also has an fatty accumulation in the liver (first hit of fatty liver disease) got the “second hit” and riggers the onset of liver inflammation being triggered, the triglycerides levels in the blood will start rising. High triglycerides 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.
Diet and Cholesterol
Small, dense LDL particles are particularly atherogenic while large buoyant LDL cholesterol is not known to be atherogenic.7 Levels of small, dense LDL particles are closely correlated with dietary carbohydrate intake. Fructose also increases levels of small, dense LDL particles more than glucose does. Dietary saturated fat increases levels of both HDL cholesterol and large buoyant LDL cholesterol.7
An abundance of small dense LDL particles are seen in association with hypertriglyceridemia, low HDL levels, obesity, type 2 diabetes and infectious and inflammatory states.2 Small dense LDL particles have a decreased affinity for the LDL receptor resulting in a prolonged retention time in the circulation.2 Additionally, they more easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall.
Complications
Hyperlipidemia, in particular elevated LDL (hypercholesterolemia), is one of the most prevalent risk factors contributing to the evolution of atherosclerosis and consequent vascular disease.1 Atherosclerosis frequently remains asymptomatic until plaque stenosis reaches 70 to 80% of the vessel's diameter. Atherosclerosis originates after underlying endothelial damage occurs, which appears to stem from the loss of nitric oxide within the endothelium.1 This process leads to increased inflammation directly around the site of dysfunction, permitting the accumulation of lipids within the innermost layer of the endothelial wall. The lipids are then engulfed by macrophages, leading to the establishment of "foam cells."1 This cholesterol 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 vascular 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
Western medicine typically prescribes Statin medications which 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
Statins and High Cholesterol
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 result of 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
