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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