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, |
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; |
Raises both LDL and HDL |
|
Trans |
Most margarines; vegetable shortening; partially |
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