Dyslipidemia
Objective
At the end of this lecture, student will be able to
– Describe different types of dyslipidemia
– Explain the treatment for the various diseases Hyperlipidemia, Artherosceloris, Fatty liver
The story of lipids
• Chylomicrons transport fats from the intestinal mucosa to the liver
• In the liver, the chylomicrons release triglycerides and some cholesterol and become low-density lipoproteins (LDL)
• LDL then carries fat and cholesterol to the body’s cells.
• High-density lipoproteins (HDL) carry fat and cholesterol back to the liver for excretion
• When LDL cholesterol level gets high, atheroma formation in the walls of arteries occurs, which causes atherosclerosis.
• HDL cholesterol is able to go and remove cholesterol from the atheroma.
Dyslipidemia
Dyslipidemia encompasses various disorders characterized by abnormal levels of lipids (fats) in the bloodstream. These disorders can be classified based on the specific lipid affected or the underlying cause. Here are the different types of dyslipidemia:
- Hypercholesterolemia: This type of dyslipidemia involves elevated levels of LDL cholesterol, often referred to as “bad” cholesterol. High LDL cholesterol is a significant risk factor for atherosclerosis and cardiovascular disease.
- Hypertriglyceridemia: Hypertriglyceridemia is characterized by elevated levels of triglycerides in the blood. Triglycerides are a type of fat found in the bloodstream and stored in fat cells. High triglyceride levels are associated with an increased risk of heart disease and pancreatitis.
- Low HDL Cholesterol: HDL cholesterol, often termed “good” cholesterol, helps remove LDL cholesterol from the bloodstream. Low levels of HDL cholesterol are linked to an increased risk of heart disease and are often seen in individuals with dyslipidemia.
- Mixed Dyslipidemia: This type of dyslipidemia involves abnormalities in multiple lipid parameters, such as elevated LDL cholesterol, triglycerides, and/or low HDL cholesterol. Mixed dyslipidemia is common in individuals with metabolic syndrome and diabetes.
- Familial Hypercholesterolemia (FH): FH is a genetic disorder characterized by very high levels of LDL cholesterol from birth. It is caused by mutations in genes responsible for LDL receptor function, leading to impaired clearance of LDL cholesterol from the bloodstream. FH significantly increases the risk of premature atherosclerosis and cardiovascular events.
- Secondary Dyslipidemia: Secondary dyslipidemia is caused by underlying medical conditions, such as diabetes, hypothyroidism, obesity, chronic kidney disease, and certain medications like corticosteroids and antiretroviral drugs. Treating the underlying condition is essential for managing secondary dyslipidemia.
- Remnant Dyslipidemia: Also known as type III hyperlipoproteinemia, remnant dyslipidemia is characterized by elevated levels of remnant lipoproteins, which are intermediate-density lipoproteins (IDL) and very-low-density lipoproteins (VLDL). Remnant dyslipidemia is associated with an increased risk of cardiovascular disease.
Atherosclerosis
• Atherosclerosis is a narrowing of the arteries caused by a buildup of plaque.
• Plaque is made of cholesterol, fatty substances, cellular waste products, calcium and fibrin (clotting material).
• This narrows the opening, reducing blood flow and the supply of oxygen to cells.
• Where plaque occurs, two things can happen.
– One is that a piece of plaque may break off and be carried by the bloodstream until it gets stuck.
– The other is that a blood clot (thrombus) may form on the plaque’s surface. If either of these things happen, the artery can be blocked and blood flow cut off.
• Atherosclerosis can occur in an artery located anywhere in your body, including your heart, legs, and kidneys
It can cause various diseases these include:
• Coronary heart disease (plaque in arteries in or leading to the heart),
• Angina (chest pain from reduced blood flow in arteries supplying the heart muscle),
• Carotid artery disease (plaque in neck arteries that supply blood to the brain),
• Peripheral artery disease (PAD; plaque in arteries of extremities, especially the legs) and
• Chronic kidney disease.
• If the blocked artery supplies the heart or brain, a heart attack or stroke occurs. If an artery supplying oxygen to the extremities (often the legs) is blocked, gangrene can result. Gangrene is tissue death.
• Atherosclerosis is a slow, progressive disease. Some hardening of the arteries is normal as you age.
Cause
• Many scientists believe plaque begins when an artery’s inner lining (endothelium) becomes damaged. Three possible causes of damage are:
• Elevated levels of cholesterol and triglycerides in the blood
• High blood pressure
• Cigarette smoking
Treatment
• Cholesterol medications. Aggressively lowering the low-density lipoprotein (LDL) cholesterol, the “bad” cholesterol, can slow, stop or even reverse the buildup of fatty deposits in the arteries. Boosting the high-density lipoprotein (HDL) cholesterol, the “good” cholesterol, may help, too.
• A range of cholesterol medications, including drugs known as statins and fibrates. In addition to lowering cholesterol, statins have additional effects that help stabilize the lining of the heart arteries and prevent atherosclerosis.
• Anti-platelet medications. anti-platelet medications, such as aspirin, reduce the likelihood that platelets will clump in narrowed arteries, form a blood clot and cause further blockage.
• Beta blocker medications. These medications are commonly used for coronary artery disease. They lower the heart rate and blood pressure, reducing the demand on the heart and often relieve symptoms of chest pain. Beta blockers reduce the risk of heart attacks and some heart rhythm problems.
• Angiotensin-converting enzyme (ACE) inhibitors. These medications may help slow the progression of atherosclerosis by lowering blood pressure and producing other beneficial effects on the heart arteries. ACE inhibitors can also reduce the risk of recurrent heart attacks.
• Calcium channel blockers. These medications lower blood pressure and are sometimes used to treat angina.
• Water pills (diuretics). High blood pressure is a major risk factor for atherosclerosis. Diuretics lower blood pressure.
• Other medications. The doctor may suggest certain medications to control specific risk factors for atherosclerosis, such as diabetes.
• Sometimes specific medications to treat symptoms of atherosclerosis, such as leg pain during exercise, are prescribed.
Dietary sources of Cholesterol
| Type of Fat | Main Source | Effect on Cholesterol levels |
| Monounsaturated | Olives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocados | Lowers LDL, Raises HDL |
| Polyunsaturated | Corn, soybean, safflower and cottonseed oil; fish | Lowers LDL, Raises HDL |
| Saturated | Whole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil , egg yolks, chicken skin | Raises both LDL and HDL |
| Trans | Most margarines; vegetable shortening; partially hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods |
Raises LDL |
Hyperlipidemia
• Hyperlipidemia refers to heightened levels of ‘bad’ cholesterol, or LDL, in the blood.
• Cholesterol becomes a problem when too much bad cholesterol, or low-density lipoprotein (LDL), is produced or ingested through unhealthy foods.
• Lipoproteins transport cholesterol through the blood to the cells.
• HDL is good because it carries extra cholesterol back to the liver where it can be eliminated.
• LDL is bad because it enables excess cholesterol to build up in the blood.
• Triglycerides are a type of fat in the blood. These are different from cholesterol, but because of their strong association with heart disease, triglycerides are also measured.
• A person with hyperlipidemia may have high levels of both LDL and triglycerides.
Causes
• Genetic factors: known as primary hyperlipidemia.
• Familial hyperlipidemia stems from a genetic disorder.
• A mutated gene is passed down from a parent and causes a missing/ malfunctioning LDL receptor. The LDL builds to dangerous amounts in the blood.
• When the body cannot use or remove excess fat, it builds up in the blood. Over time, this damages the arteries and internal organs and contributes to the development of heart disease.
• Poor diet and other factors: known as secondary hyperlipidemia.
Other causes include:
• excessive alcohol consumption
• obesity
• medications-hormones or steroids
• diabetes
• kidney disease
• hypothyroidism
• Pregnancy
• Nephrotic syndrome
• Anorexia nervosa
• Diabetes mellitus
• Obstructive liver disease
• Acute hepatitis
• Systemic lupus erythematousus
• AIDS (protease inhibitors)
Symptoms
• A person with hyperlipidemia usually has no signs or symptoms. In familial hyperlipidemia, there may be yellowish fatty growths around the eyes or the joints.
• It is detected during a routine blood test, or following a cardiovascular event, such as a heart attack or stroke.
• Excessive fat in the blood accumulates over time, forming plaques on the walls of the arteries and blood vessels.
• This narrows the openings, producing unstable blood flow through the vessels. The heart has to work harder to pump the blood through the constricted areas.
Hyperlipidemia- Treatment
• A person with hyperlipidemia usually has no signs or symptoms. In familial/inherited, hyperlipidemia, there may be yellowish fatty growths around the eyes or the joints.
• It is detected during a routine blood test, or following a cardiovascular event, such as a heart attack or stroke.
• Excessive fat in the blood accumulates over time, forming plaques on the walls of the arteries and blood vessels.
• This narrows the openings, producing unstable blood flow through the vessels. The heart has to work harder to pump the blood through the constricted areas.
• Self-management to reduce the level of LDL in blood
• Most commonly prescribed medicines are statins, such as simvastatin, lovastatin, atorvastatin, rosuvastatin.
• There are also new medications called PCSK9 inhibitors being studied
• Occasionally, statins are not tolerated, side effects of muscle pain, and people stop taking them.
• However, it is worth balancing the risk of a cardiovascular event against the risk of side effects before stopping the medication
• Hyperlipidemia can lead to serious cardiovascular disease, but it can be prevented and treated through appropriate use medications and maintenance of a heart-healthy lifestyle.
Checking lipids
• Non-fasting lipid panel
• measures HDL and total cholesterol
• Fasting lipid panel
• Measures HDL, total cholesterol and triglycerides
• LDL cholesterol is calculated:
– LDL cholesterol = total cholesterol – (HDL + triglycerides/5)
Goals for Lipids
• LDL
– <100 →Optimal
– 100-129→ Near optimal
– 130-159→ Borderline
– 160-189→High
– ≥190 → Very High
• Total Cholesterol
– < 200 → Desirable
– 200-239→ Borderline
– ≥240→ High
• HDL
– <40 → Low
– ≥60 → High
• Serum Triglycerides
– < 150 → normal
– 150-199→ Borderline
– 200-499→ High
– ≥ 500 → Very High
LDL Goals
• 0-1 Risk Factors:
• LDL goal is 160
• If LDL ≥ 160: Initiate TLC (therapeutic lifestyle changes)
• If LDL ≥ 190: Initiate pharmaceutical treatment
• 2+ Risk Factors
• LDL goal is 130
• If LDL ≥ 130: Initiate TLC
• If LDL ≥ 160: Initiate pharmaceutical treatment
• Coronary Heart Disease
• LDL goal is 100 (or 70)
• If LDL ≥ 100: Initiate TLC and pharmaceutical treatment
Treatment for hyperlipidemia
• Lifestyle modification
– Low-cholesterol diet
– Exercise
Fatty liver
Fatty liver- Terminology
• ALD:
Alcoholic Liver Disease
Significant alcohol consumption*
> 21 drinks/week for males
> 14 drinks/weeks for females
• NAFLD: Non-Alcoholic Fatty Liver Disease steatosis without hepatocyte injury
• NASH: Non-Alcoholic Steatohepatitis steatosis with inflammation, hepatocyte injury with or without fibrosis
Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between.
Alcoholic liver disease
– Fatty liver disease means presence of extra fat in liver
– Cause is Heavy drinking. Over time, too much alcohol leads to a buildup of fat inside the liver cells. This makes it harder for the liver to work
• Some people don’t have any symptoms. But if the liver becomes enlarged, pain or discomfort on the upper right side of the stomach may develop.
• It usually gets better when you stop drinking alcohol.
• Fatty liver disease usually comes first. It can then get worse and becomes alcoholic hepatitis. Over time, it may turn into alcoholic cirrhosis.
• Alcoholic hepatitis. This is swelling in the liver that can cause fever, nausea, vomiting, abdominal pain, and jaundice (yellowish skin and eyes).
• Alcoholic cirrhosis. This is a buildup of scar tissue in your liver. It can cause the same symptoms as alcoholic hepatitis plus:
• High blood pressure in the liver
• Bleeding in your body
• Confusion and changes in behavior
• Enlarged spleen
• Liver failure, which can be fatal
Non-alcoholic liver disease
• NAFLD is characterized by increased accumulation of fat, especially triglycerides, in the liver cells.
• It is normal for the liver to contain some fat and by itself, this causes no symptoms.
• In some patients, the excess fat can cause inflammation called steatohepatitis (steato=fat+hepa=liver +itis=inflammation)
– although there is no relationship between the amount of fat present and the potential for inflammation.
• Steatohepatitis can lead to cirrhosis (fibrosis, scarring and hardening of the liver). There is also an association with liver cancer (hepatocellular carcinoma).
Causes of fatty liver
• Diet: Consumption of excess calories in the diet (the excess caloric intake overwhelms the liver’s ability to metabolize fat in a normal fashion, which results in fat accumulation in the liver).
• Diseases: Fatty liver is also associated with type II diabetes, obesity, and high triglyceride levels in the blood, celiac disease, and Wilson’s disease (abnormality of copper metabolism).
• Medical conditions: Rapid weight loss and malnutrition.
• Medications: Medications such as tamoxifen (Soltamox), amiodarone injection (Nestorone), amiodarone oral (Cordarone, Pacerone), and methotrexate (Rheumatrex Dose Pack, Trexall) are associated with NAFLD.
• There is an association between insulin resistance and the development of NAFLD. In this situation, although the body makes adequate insulin, the ability of cells to adequately use that insulin to metabolize glucose is abnormal. The relative excess of glucose is then stored as fat and can accumulate in the liver
Natural History of
FLD
fatty liver
â
steatohepatitis
â
steatohepatitis + fibrosis
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steatohepatitis + cirrhosis
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cryptogenic cirrhosis
NAFLD: risk factors
• Middle age
• Female gender
• Over-weight or obese
• Viral hepatitis
• Iron overload
• Medications
• Rapid weight loss
• Starvation/refeeding syndrome
• Reye’s syndrome
• Auto-immune disease
• Malnutrition
• Abetalipoproteinemia
• Overgrowth of bacteria in small intestines
• TPN
• Acute fatty liver of pregnancy
• Hereditary
• It is not known why some people accumulate fat in the liver. NAFLD and NASH are both linked to the following:
• Overweight or obesity
• Insulin resistance, in which your cells don’t take up sugar in response to the hormone insulin
• High blood sugar (hyperglycemia), type 2 diabetes
• High levels of fats, particularly triglycerides, in the blood
• These combined health problems appear to promote the deposit of fat in the liver. For some people, this excess fat acts as a toxin to liver cells, causing liver inflammation and nonalcoholic steatohepatitis, which may lead to a buildup of scar tissue (fibrosis) in the liver.
• A wide range of diseases and conditions can increase your risk of nonalcoholic fatty liver disease, including:
• High cholesterol
• High levels of triglycerides in the blood
• Metabolic syndrome
• Obesity, particularly when fat is concentrated in the abdomen
• Polycystic ovary syndrome
• Sleep apnea
• Type 2 diabetes
• Underactive thyroid (hypothyroidism)
• Underactive pituitary gland (hypopituitarism)
Nonalcoholic steatohepatitis is more likely in these groups:
• Older people
• People with diabetes
• People with body fat concentrated in the abdomen
Risk factor: Medications
• Amiodarone
• Methotrexate
• Tamoxifen
• Corticosteroids
• Diltiazem
• Valproic acid
• Highly active antiretroviral therapy
NAFLD: complications
• The main complication of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis is cirrhosis, which is late-stage scarring (fibrosis) in the liver.
• Cirrhosis occurs in response to liver injury, such as the inflammation in nonalcoholic steatohepatitis.
• As the liver tries to halt inflammation, it produces areas of scarring (fibrosis).
• With continued inflammation, fibrosis spreads to take up more and more liver tissue.
• If the process isn’t interrupted, cirrhosis can lead to:
• Fluid buildup in the abdomen (ascites)
• Swelling of veins in your esophagus (esophageal varices), which can rupture and bleed
• Confusion, drowsiness and slurred speech (hepatic encephalopathy)
• Liver cancer
• End-stage liver failure, which means the liver has stopped functioning
• About 20 percent of people with nonalcoholic steatohepatitis will progress to cirrhosis.
Treatment
Lifestyle Interventions
Weight loss by lower caloric intake and increased physical activity.3-5% weight loss reduces the amount of fat in the liver
Choose a healthy plant based diet
Exercise most days of the week
• Alcohol consumption:
– Quit drinking. Only way to keep the damage from getting worse
• No medications are approved to treat NAFLD.
– For complications due to NASH, such as cirrhosis or liver failure, liver transplant may be required.
Insulin sensitizing agents
• Metformin*
– reduction in IR and enzymes,
– no improvement in histology
• Thiazolidinediones
– Rosiglitazone**: improved enzymes and steatosis, but not inflammation
– Pioglitazone:***+weight gain, but improvement in hepatocellular injury
*Uygun, et al Aliment Pharm Ther 2004
*Nair, et al Aliment Pharm Ther 2004
**Ratziu, et al Gastroenterology 2008
***Sanyal, et al NE J Med 2010
Other medicines for NASH
• Ursodeoxycholic acid*
– no histologic benefit
• Omega-3 fatty acids**
– Effective in treating hypertriglyceridemia in pts with NAFLD
– Evidence for treatment of NASH inconclusive to date
– Large multi-center trial on-going now
Statins
• CVD common cause of death for NAFLD and NASH
• Stratify risks and treat accordingly
• Several studies show NAFLD and NASH pts are not at increased risk of liver injury over general population*
• No RCTs with histological end points using statins to treat NASH
Summary
• A reversible condition wherein large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis
• Fatty liver (FL) is commonly associated with alcohol or metabolic syndrome
• Defects in fatty acid metabolism are responsible for pathogenesis of FLD
• Severe fatty liver is sometimes accompanied by inflammation, a situation referred to as steatohepatitis
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