Lecture 4.1 (unfinished) Flashcards
1) Define edema
2) How may it present?
1) The accumulation of fluid in tissues resulting from net movement of water into extravascular spaces
2) May be swollen feet, might be flash pulmonary edema
Define the following terms:
1) Hyperemia
2) Congestion
3) Hemostasis
4) Thrombosis
5) Embolism
6) Effusion
1) Too much arterial blood
2) Too much venous blood
3) The process of blood clotting
4) Bad clot
5) A bad clot that moved
6) Extravascular fluid collected in body tissues
1) Define infarction
2) What may tissues related to this look like? Why?
1) Ischemia that has lasted long enough to cause cell death
2) Congested tissues sometimes take on a cyanotic appearance due to deoxygenated blood
What are the two opposing forces of fluid balance?
1) Hydrostatic pressure
2) Oncotic pressure (colloid osmotic pressure)
In fluid balance, which force wins? By how much? Explain
1) Hydrostatic “wins”
-But only a little bit
2) Lymphatics clean up the extra fluid
Fluid balance: What opposes hydrostatic pressure?
Plasma colloid osmotic pressure (i.e. activity around solutes, incl. water’s interaction) that pull fluid in to the venous system
List conditions with venous return issues causing edema
** Too much pressure:**
1) ** Congestive heart failure:** pump isn’t working so fluid is backing up in venous system, some starts to leak out
2) ** Constrictive pericarditis:** same as above
3) ** Ascites (liver cirrhosis): impeding flow in liver = backing up in venous system, = ^ pressure
4) ** Venous obstruction or compression : impeding flow
5) ** Thrombosis: impeding flow
6) ** External pressure (mass/cancer) : impeding flow
7) Lower extremity inactivity – dependency
List conditions of oncotic pressure causing edema
1) Solute is gone: fluid leaks out, hydrostatic force wins too much
2) Protein-losing glomerulopathies (nephrotic syndrome): not enough albumin
3) Liver cirrhosis: (albumin!)
4) Malnutrition
5) Protein-losing gastroenteropathy: solute is gone
List conditions of lymphatic obstruction causing edema
Drain is broken
1) Inflammatory dz
2) Neoplasm: cancer in lymph. system
3) Post surgical: drain is missing
4) Postirradiation: impede flow
List conditions involving sodium retention-related edema
Water follows salt
1) **Too much salt – too little kidney function: ** water follows salt, volume is super high & leaking out
2) Increased Na+ uptake
3) Renal hypoperfusion: if kidneys think they’re being starved of oxygen, they keep salt
4) Increased renin-angiotensin-aldosterone secretion: causes kidneys to ask for more salt
What should you think abt when you hear “sodium”?
Blood volume
List types of inflammation that can cause edema
1) Acute inflammation
2) Chronic inflammation
What happens when the kidneys are “thirsty”?
Renin, Angiotensin, Aldosterone:
The pathway whereby hypoperfused kidneys attempt to increase renal blood supply
Renin, Angiotensin, Aldosterone system:
Step 1: Renin, once secreted, activates ______________ and turns into ______________
(_________________ is a plasma protein that is already, always present in plasma)
1) angiotensinogen and turns into angiotensin I
(Angiotensinogen)
Renin, Angiotensin, Aldosterone system Step 2:
Angiotensin I activated in the lungs via pulmonary circulation and turned into angiotensin II by angiotensin-converting enzyme (ACE) which is abundant in pulmonary capillaries
Step 3 RAAs:
Angiotensin II stimulates aldosterone release from the adrenal cortex
Angiotensin II is also a potent vasoconstrictor, increasing BP
[Stimulates thirst (increase fluid intake) and vasopressin (which increases H2O retention from kidneys]
Step 4
What ends the renin angiontensin aldosterone system?
1) Aldosterone increases Na+ reabsorption which results in H2O retention rise in blood volume and rise in arterial blood pressure
2) A rise in those factors alleviate renin triggers
What do ACE inhibitors do?
Stop the conversion of angiotensin I to II
What do the kidneys do for BP?
Regulate salt Renin-angiotensin-aldosterone
BP regulation: Myocardium
1) What does it release?
2) What do these do & when?
1) Release natriuretic peptides
2) Inhibit Na+ reabsorption when volume expansion is sensed
1) What does HF cause?
2) What does renal failure cause?
1)Decreased flow to kidneys
2) Increased fluid on the heart
1) What is a contributing factor to the HF-renal failure cycle?
2) What is this?
Another contributing factor is change in oncotic force:
2) an issue with albumin
1) Define hemorrhage – extravasation of blood
Hematoma – blood mass, may be trivial or life-threatening depending on location
Hemorrhage – extravasation of blood
Hematoma – blood mass, may be trivial or life-threatening depending on location
1) What are Petechia (3mm) / Purpura?
2)
Petechia (3mm) / Purpura – small hemorrhages into skin, mucous membranes, serosal surfaces
Caused by low platelets! defective platelet function!
1) What is ecchymoses?
2) Where does it occur?
3) What is the mechanism?
1) Bruises
2) Under sub-q
3) RBCs are degraded by macrophages
Hemoglobin goes from blue bilirubin (blue-green) hemosiderin (golden brown)
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Massive hemorrhage – blood loss, hypovolemic shock, exsanguination, death
Hematoma – compression of tissues/compartments
Compartment syndrome, (worst-case scenario for a hematoma)
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Intracerebral hemorrhage – stroke, death
Chronic hemorrhage – slow blood loss iron deficiency anemia
1) What is the first thing that happens when you damage a vessel? Why does this happen?
2) What is the second thing?
1) Arteriolar vasoconstriction: Stop the flow! Local response (endothelin) won’t last long
2) Primary hemostasis: platelet plug
Step 2: Primary hemostasis: Describe the process of platelet plug formation
1) When the endothelium is broken > von Willebrand factor (vWF) is released
2) This promotes platelet activation shape change!
3) Platelets release granules that recruit more platelets
4) This leads to platelet aggregation primary hemostatic plug
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Secondary hemostasis: fibrin clot
Tissue factor is exposed from basement membrane clotting cascade
Thrombin turns fibrinogen into a fibrin clot
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Clot stabilization and resorption
Fibrin makes a solid, permanent scaffolding that stops further clotting
Counterregulatory mechanisms come into play to limit too much clotting
Tissue plasminogen activator tPA
Plasmin breaks down fibrin
Resorption and repair – mediated by interactions with endothelial cells
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Clinical Testing
A sign that clotting has been going on occurs when breakdown products of fibrinogen appear in the blood
“fibrin-split products”
One of these products, called D-dimer, is measurable
This is what the “D-dimer” blood test is looking for
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PT/INR addresses extrinsic pathway
PTT addresses the intrinsic pathway
*Note there are several “feedback loops” that amplify the sequence
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Heparin-Like Molecule
Activates antithrombin!
Binds to thrombin
No more turning fibrinogen into a fibrin clot!
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In their passive state are anticoagulant in the factors they emit
After endothelial injury, they become procoagulant – for a time
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Then they revert to anticoagulant to keep a balance
They become anticoagulant by releasing tissue factor VIIa complexes that block VII activity
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Thrombomodulin and endothelial protein C receptor
Together, these bind thrombin and protein C in a complex on the endothelial surface
This robs thrombin of the ability to “feedback” and activate coagulation factors and platelets – also keeps thrombin from forming clot
Instead, thrombin activates Protein C
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Protein C and its cofactor protein S are anticoagulants that disrupt the clotting pathway
(Inhibits Va and VIIIa which are secondarily Vitamin K dependent)
What would deficiency of protein C and protein S do?
Make you clot [taking away the anticoagulant will make you clot]
Clotting inhibition:
tPA made by endothelium
Becomes active when bound to fibrin
Given as medicine to break up clot
Comes with a risk of bleeding
Clotting inhibition: list some other endothelial anticoagulant products
Prostacyclin (PGI2), nitric oxide, (both inhibit platelets) adenosine diphosphatase (degrades ADP: this affects clotting because ADP promotes platelet aggregation)
Warfarin (anticoagulant)
Acts by inhibiting vitamin K and depletes its reserves in the body
The Liver uses vitamin K to synthesize factors II, VII, IX, and X
This inhibits the extrinsic pathway and its effect is measured by PT/INR
It is a notoriously unstable steady state and is often “tinkered with” in clinic
Reversed, as you can imagine, by giving vitamin K
Heparin (IV when solo; anticoagulant)
Made by the liver
Activates antithrombin
Inhibits thrombin
Also given as medicine to prevent clotting
It can be quickly reversed by giving Protamine Sulfate, which is soluble in the blood – binds to heparin
Xa inhibitors: Novel Oral Anticoagulants (anticoagulant)
Act directly on Xa clotting factor
Some reversal agents have been developed
Aspirin (antiplatelet)
Binds irreversibly to platelets and inactivates them
P2Y12 inhibitors (antiplatelet)
Block the receptor for ADP on platelets
This inhibits the ability of ADP to activate platelets and promote clot
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Why “bridge to Warfarin” by giving Heparin?
Because warfarin inhibits production of Protein C and S, causing a temporary procoagulant state, before the clotting cascade is fully blocked
What can go wrong?
Factor V Leiden Mutation
Protein C and S deficiency
Antithrombin III deficiency
Von Willebrand’s disease
How do we intervene on other pathology with medicines that act on hemostasis?
Blood Clots and Cardiovascular Disease
Anticoagulate with heparin or NOAC now called (DOAC)
Use ASA or P2Y12 inhibitors for antiplatelet therapy
Lyse clot with tPA
Q) What makes you clot?
A) Virchow’s Triad; which is what? Explain?
1) Endothelial injury is most important
2) Abnormal blood flow?
Turbulent flow irritates endothelium and leads to. . .
. . . Endothelial injury
3) Hypercoagulability: (Well yeah)
List conditions that cause Hypercoagulability
Factor V Leiden mutation
Anti-thrombin III deficiency
Protein C and S deficiency
Immobility!
Cancer!
Surgery!
Tissue injury!
Prosthetic valves
Anti-phospholipid antibody syndrome
Smoking
Atrial fibrillation!
Pregnancy and postpartum
Oral contraceptives (esp. if smoking over 35)
Arterial or cardiac thrombi
Think endothelial injury or turbulent flow
“Mural thrombi” – those occurring in aortic lumen and heart chambers
Thrombi on heart valves are called “vegetations”
Venous thrombi – think stasis
When deep these are called DVT
When superficial they are called superficial thrombophlebitis
Venous thrombi – almost invariably occlusive
1) Thrombus growth: where do they attach and grow toward?
2) ___________ thrombi grow retrograde and __________ extend with blood flow
3) ______________ portion is poorly attached and prone to fragmentation > embolus
1) Attach to underlying vascular surface and grow toward the heart
2) Arterial thrombi grow retrograde and venous extend with blood flow
3) Propagating portion
1) Define embolism
2) ________%
3) What are the two main types?
4) What makes the pathology vary?
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Systemic thromboemboli refers to what emboli?
Emboli in circulation
80% of arterial thrombi arise from what?
2) Give examples
1) intracardiac mural thrombi
2) Left ventricular wall infarcts
Dilated left atria secondary to mitral valve defects
Aortic aneurysm
Atherosclerotic plaque
Arteriolar embolization often causes tissue infarction
Major sites for venous emboli are lower extremities
Fate of the thrombus:
List 2 fates that are “risks” and what happens to them
1) Risk: Propagation
It enlarges through addition of platelets and fibrin
2) Risk: Embolization
It may move elsewhere in part or whole
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1) Risk: Propagation
2) Risk: Embolization
3)Dissolution
4)
Dissolution
Fibrinolytic factors may lead to its shrinkage
Heparin will prevent spread
Organization and recanalization
Old thrombi become organized by new endothelial cells, smooth muscle, and fibroblasts
Capillary channels are formed
The original lumen is restored (at least in part)
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What are the two different colors of infarcts? What causes each?
1) White Infarct (anemic): Arterial occlusion or Solid tissues
2) Red infarct (hemorrhagic): Venous occlusion
List and explain 3 factors that affect the outcome of an infarct
1) Anatomy of the vascular supply: Is there an alternative path?
2) Rate of occlusion: Did this develop abruptly?
Is there time to divert to collateral blood supply?
3) Tissue vulnerability for hypoxia
Ex: Is this the brain or skeletal muscle?
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Factor V Leiden
Autosomal dominant with incomplete penetrance
Exacerbated by environmental factors
Low incidence in Black and Asian and higher among Whites
Physical exam
DVT
Possible PE
Factor V accelerates clotting
Inheritance Risk
One parent carries mutant allele
50% risk of child getting it
10% penetrance
5% lifetime risk
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Heparin induced thrombocytopenia (HIT)
Up to 5% of patients who get heparin
Autoantibodies bind to complexes of heparin and platelet membrane protein and endothelial surfaces
This results in platelet activation, aggregation, and consumption also causes endothelial injury
This leads to a PROTHROMBOTIC state!
For this reason: PT/INR PTT always required for baseline before starting heparin
Disseminated Intravascular Coagulation (DIC)
1) When does it occur?
2) What is it?
3) What is activated at the same time? What does this lead to?
It occurs in some severe sepsis / shock, obstetric complications, advanced malignancy
This is wide-spread clotting in the microcirculation all over the body
At the same time, fibrinolytic mechanisms are activated
Leads to profuse bleeding
Define shock & what causes it
Is it reversible? Explain
Either by decreased cardiac output or decreased circulating blood volume – tissues are not being perfused
Either something’s wrong with the pump or something’s wrong with the pipes
Bad news
Initially, cellular injury is. . . Reversible
Until it passes the point of no return
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Septic Shock and Hypotension:
1) How/ when would endothelial activation through normal pathways occur?
2) What does this lead to?
3)
1) In response to microbial infection; MC = Gram positive, then negative, then virus and fungi
Cytokines release endothelial tight junctions and vessels leak
Activated endothelium upregulates nitrous oxide and other vasoactive mediators
Smooth muscle relaxes
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Sepsis alters the expression of clotting factors, and it favors coagulation
Cytokines (TNF and IL-1) increase tissue factor production
TNF Initiates clotting cascade
Inhibits tissue factor pathway inhibitor, thrombomodulin, and protein C hypercoagulable
Also, dampens fibrinolysis!
Vascular leakage diminishes the “washout” of activated coagulation factors
One of the ways that clotting is regulated in normal physiology
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Cytokines (TNF and IL-1) upregulate stress hormones
glucagon, growth hormone, cortisol this drives gluconeogenesis
At the same time inflammatory cytokines suppress insulin release and promote insulin resistance in the liver
Leads to hyperglycemia
(added complication Hyperglycemia decreases neutrophil function)
So, the ability to fight infection is diminished
After this phase, if enough time passes, there can be a respondent adrenal insufficiency and deficit of glucocorticoids
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Leads to hyperglycemia
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As the cells continue bearing the brunt of shock (inadequate perfusion) they become increasingly hypoxic, and lactic acid is produced, leading to lactic acidosis
Blood pH drops
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Septic Shock and organ dysfunction
Systemic hypotension, interstitial edema and small vessel thrombosis all decrease oxygen and nutrients to tissues
Mitochondria start to take damage due to oxidative stress
Myocardial contractility starts to diminish
Reducing cardiac output
Increased vascular permeability leads to ARDS
Finally, kidneys, liver, lungs, heart are all catastrophically effected, leading to death
* Note well: severe shock by other means still leads to poor perfusion which can cause most of this to occur
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Depends on precipitating result
The primary threat to life is the underlying initiating event, though cardiac, cerebral, and pulmonary changes aggravate the situation
Prognosis varies with origin and duration
Organized into 3 concentric layers (more apparent in larger arteries
Intima
Media
Adventitia
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Clog the pipe
Weaken the pipe
Born with bad pipes
Main forms of vascular disease:
1) List examples of conditions that “clog the pipe”? (type 1)
2) List examples of conditions that “weaken the pipe”? (type 2)
3) List examples of conditions that are “born with bad pipes)
1)
2)
3) Congenital anomalies
1) What can be described as small dilations in cerebral vessels (often in circle of Willis)
Fatal if ruptured
Berry aneurysms
abnormal connections between arteries and veins that bypass capillaries
May be benign, may cause abnormal shunting of blood into venous system
Done intentionally for dialysis
Fibromuscular dysplasia
irregular thickening of walls of medium to large sized arteries as a result of medial and intimal hyperplasia – results in luminal stenosis (clogged pipe)
Seen in young women
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List the 2 main types of atherosclerosis and where they can occur
1) Generalized: All arteries
2) Localized: Cerebral, Coronary, Aortic
Describe how atherosclerosis can cause an aneurysm
Soft lipid core covered by firm fibrous cap
Protrudes into lumen, obstructing flow (stenosis)
Weakens underlying media (arterial wall)
Plaque ruptures in vessel, thrombus forms
Vessel wall expands – aneurysm and rupture
List and describe the 4 types of aneurysms
1) True, saccular: wall focally bulges
2) True, fusiform: circumferentially bulges
3) False: wall is ruptured, collection of blood bounded by extravascular tissues
4) Dissection: blood has entered wall of vessel and separated layers
Tunica intima from media
List the clinical consequences of AAA
1) Obstruction of branch vessel
2) Iliac, renal, mesenteric
3) Compression of adjacent structure
4) Abdominal mass
5) Rupture into peritoneal cavity – usually fatal
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Atherosclerotic aneurysms occur most frequently in the abdominal aorta and common illiac
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Left: Aortic aneurysm that ruptured (arrow)
Right: Opened view with probe in rupture tract; wall of aneurysm is thin, lumen filled with thrombus
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Aortic
Sudden onset of excruciating pain
Type A aortic dissection more common and more dangerous
Most common cause of death is rupture into pericardial, pleural, peritoneal spaces
Marfan syndrome
An autosomal dominant genetic disorder that affects the skeletal system, cardiovascular system, and eyes
Individuals are tall and thin, with long arms and legs, and thin fingers
Caused by a loss-of-function mutation in the fibrillin 1 (FBN1) gene
Major component of microfibrils in ECM; scaffold for elastin
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Peripheral resistance is mostly controlled by arterioles
Neural and humoral factors
Vasoconstrictors
Vasodilators
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Autoregulation comes from self protective response where vasoconstriction occurs from high blood flow to prevent hyperperfusion
pH and hypoxia fine tune arterial tone to adjust perfusion of tissues
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What are the 4 main types of vasculitis?
1) Giant-cell (Temporal) arteritis
2) Polyarteritis nodosa
3) Kawasaki disease
4) Thrombangiitis obliterans (Buerger disease)
1) What is the Most common form of vasculitis?
2) Who does it typically occur in?
3) What are the typical Sx?
4) What is involved?
Over 50-60 years of age
Pain and tenderness
3) One-sided HA
4) Involves temporal artery
Can involve ophthalmic artery and lead to blindness
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Granulomatous inflammation with giant cells, lymphocytes, intimal fibrosis
Possibly T-cell mediated autoimmune response to vessel wall antigen
a) giant cells near fragmented internal elastic membrane
Formed by fusion of epithelial cells and macrophages
b) focal destruction of internal elastic membrane
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1) What is Kawasaki disease the leading cause of?
2)
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Kawasaki disease
Enlarged cervical lymph nodes, cheilitis, strawberry tongue, etc
How is Kawasaki disease diagnosed?
Fever for 5 days + four of the following without other explanation:
-Bilateral conjunctivitis
-Oral mucous membrane changes
-Peripheral extremity changes
-Erythema of palms/soles, desquamation
-Polymorphous rash
-Cervical LAD at least 1 greater than 1.5 cm
Kawasaki disease:
1) Etiology?
2)
Cause unknown
Potential autoimmune component
Appx 20% correlation with upper respiratory illness
Now seen in SARS Covid 2 with “Kawasaki Like” illness
Multisystem inflammatory syndrome
Thrombangitis Obliterans (Buerger Disease)
Affects medium-sized and small arteries, mainly of the extremities (especially tibial and radial arteries)
Acute and chronic inflammation of the vessel wall, with luminal thrombosis
Almost exclusively in heavy smokers, usually before 35
Cessation can be curative
Thrombus typically contains microabscesses (arrow)
Buerger Disease
Superficial nodular phlebitis
Cold sensitivity in the hands
Pain in instep of foot
Severe pain, even at rest
Chronic ulceration of toes, feet, or fingers, which may be followed by gangrene
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Kaposi Sarcoma
Most frequently associated with AIDs
Forms of KS, similar viral pathogenesis
Classic (European)
Endemic (African)
Transplant-associated (immunosuppression)
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Familial Hypercholesterolemia list all types discussed
Lipoproteins
Particles with protein and phospholipid coats that transport cholesterol and other lipids in blood
Low density lipoproteins (LDLs), 45% cholesterol
High density lipoproteins (HDLs), 20% cholesterol
Familial Hypercholesterolemia Disease Etiology and Incidence:
FH occurs among all races
FH accounts for somewhat less than 5% of patients with hypercholesterolemia
Familial hypercholesterolemia (FH) is a disorder of cholesterol and lipid metabolism caused by mutations in the low-density lipoprotein receptor (LDLR) gene
97 Pathogenesis
LDL receptor is expressed in the liver and adrenal cortex
Hepatic LDL receptors clear half of intermediate-density lipoproteins and up to 80% of LDL from circulation by endocytosis
Mutations occur through combination of large insertions, deletions and recombination involving Alu repeats
Mutations in the LDLR gene disrupt production of LDL receptor and cause accumulation of plasma LDL
Phenotype and Natural History
In heterozygotes, hypercholesterolemia usually manifests at birth and is the only finding in the first decade of life
In heterozygotes of all ages, the plasma cholesterol concentration is twice as high in unaffected individuals
In heterozygotes, arcus corneae and tendon xanthomas begin to appear by the end of the second decade
The development of coronary artery disease among heterozygotes depends on gender and age (e.g., at age 50, 50% of males have CAD and only 20% of females)
Homozygous FH presents in the first decade of life with arcus corneae and tendon xanthomas. Plasma cholesterol concentration is twice that of heterozygotes and without aggressive treatment homozygotes will usually die by age 30.
Familial Hypercholesterolemia
Aggressive normalization of LDL cholesterol concentration is required to reduce the risk of CAD
Rigorous adherence to a low-fat, high-carbohydrate diet usually produces only a 10-20% reduction in LDL cholesterol, which is usually insufficient
Therefore, heterozygous patients receive bile acid sequestrants
They block bile acid in your stomach from being absorbed in your blood
Also they will be given statin drugs that inhibit hepatic cholesterol synthesis
Also LDL apheresis
Where LDL is filtered from the blood using a machine
Inheritance Risk
Because FH is an autosomal dominant disorder, each child of an affected heterozygous parent has a 50% chance of inheriting the mutant LDLR allele
