Dyslipidemia-Hyperlipidemia, Artherosceloris, Fatty liver

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.

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
 â
 steatohepatitis + cirrhosis
â
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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