Arterial disease

So these three words look the same: Arteriosclerosis, Atherosclerosis, and Arteriolosclerosis.

Arteriosclerosis is a general umbrella term describing diseases where the wall of the artery
becomes thicker, harder, and less elastic than normal.
You can figure that out right from the name: “arterio” which is Greek for artery, and sclerosis
which is Greek for “hardening”.
Now the word arteriolosclerosis is any sort of hardening of small arteries in arterioles.
This is also pretty easy to remember since the “olo” in the middle of the word indicates small
arterioles.
And then finally, atherosclerosis is the hardening of any artery (even though it’s usually
medium- to large-sized arteries) which is caused by the buildup of plaque.
These plaques are called atheromatous plaques and happen in the innermost wall of the blood
vessel called the tunica intima or endothelium. Okay now that we’ve differentiated been all three
of those words, let’s first take a look at atherosclerosis.
So the blood vessel endothelium is made up of a single layer of cells and does two jobs: First,it
protects the rest of the blood vessel wall from the blood, like a coat of varnish on your wood
furniture and then, secondly, it secretes proteins on its surface to prevent the blood from clotting,
because blood just inherently likes to clot whenever it gets the chance.
Now, Your endothelium can become damaged in lots of different ways. Low density
lipoproteins, chemicals from smoking cigarettes, and high blood pressure all wreak havoc on the
endothelium because these irritants break down the endothelium.
The damaged endothelium allow low-density lipoproteins to enter the endothelial wall.
The white blood cells called monocyte follow the low-density lipoproteins and break them down
through oxidation.
Okay, so you might think macrophages eating the embedded low-density lipoproteins is a good
thing, but if there is a lot of low-density lipoprotein, then the macrophage will eat so
much cholesterol that it can die. It basically eats itself to death.
After it dies, it deposits itself under the damaged endothelium. So now we have a
dead macrophage filled with low density lipoprotein stuck in the damaged endothelium as well.
These dead macrophages are called foam cells and that’s because some guy a while back looked
at these things in a microscope and thought they looked like foam on the beach, hence the name.
Also, when the macrophage dies, it releases cytokines, which calls over more monocytes which
come over and eat low-density lipoprotein, inevitably dying while doing so, and thus this vicious
cycle of gross overeating and massive fatalities has begun.
As more and more of these foam cells build up, they form a lesion we call a fatty-streak.
Now the fatty streak is thrombogenic meaning that blood can clot on it.
Platelets begin to gather at the damaged endothelium and release platelet-derived growth factor,
which in turn encourages the growth of smooth muscle cells.
Now normally smooth muscle cells are supposed to stay within the middle layer of the blood
vessel, the tunica media.
The release of platelet-derived growth factor draws the media smooth muscle cells to the tunica
intima where they multiply.
The growing smooth muscle secretes collagen, proteoglycans, and elastin fibrous cells that help
form a wall around the fatty streak, preventing blood clotting.We call this extracellular
matrix wall a fibrous cap, and together both the fatty streak and the surrounding fibrous cap is
called plaque.
The presence of fatty streaks cause the underlying smooth muscle in the blood vessel wall to also
start depositing calcium into the plaque, creating crystals.
Normally calcium is deposited into the vessel wall by low-density-lipoproteins and is then
removed by high-density lipoproteins.
The accumulation of plaque in the vessel messes up the ability of high-density lipoproteins to
remove calcium from the vessel, so a buildup of calcium occurs in the vessel wall and it
crystallizes.
Now remember calcium makes stuff hard, which is why your bones are full of calcium, right? So
this deposit of calcium into the plaque is what stiffens the walls of the arteries.
Now remember the word that describes the immune system getting involved with something is
called inflammation, so atherosclerosis is an inflammatory disease.
Now as another aside, the protein called C-reactive protein increases in the blood during an
infection or when inflammation is occurring somewhere in the body.
While an elevated C-reactive protein isn’t specific enough to diagnose atherosclerosis, it can act
as a red flag that atherosclerosis might be occurring, especially if someone
has atherosclerosis symptoms or other risk factors.
From time-to-time that fibrous cap can crack and expose the underlying thrombogenic foam cells
to blood.
And, this can happen randomly, and when it does, within moments you can see a blood clot start
form within the already partially occluded artery, quickly leading to even less blood being able to
flow by.
After about 70% of a blood vessel is occluded from the plaque and the new overlying blood clot,
cell injury and death begin in the areas that were relying on the blood flow.
If blood flow is reduced in the coronary arteries, angina and myocardial infarctions can occur.
Seriously occluded internal carotid and middle cerebral arteries lead to strokes and cerebral
atrophy, an occluded superior mesenteric artery affects the small intestine, and an
occluded popliteal artery can cause peripheral vascular ischemia, like gangrene or claudication,
which is frequent leg cramping during exercise.
Now, the building up of plaque also weakens the artery walls, which means it can lead
to aneurysms which explains why atherosclerosis is a main cause of abdominal aortic aneurysms.
But the complications of atherosclerosis don’t stop there! If we move on to the kidneys, plaque
build up in the renal arteries reduces blood flow to the kidney, and tricks the kidney into
thinking blood pressure is low.
The kidneys then activate the renin-angiotensin-aldosterone system which unnecessarily increase
blood volume in the body, causing hypertension.
Occasionally, some of the plaque can also break off from the main plaque deposit and become
an embolism, floating around in the blood stream until it gets stuck in a smaller blood vessel or
another artery with significant atherosclerotic plaque build up.
And you can totally see this in a tissue biopsy, as the affected blood vessel will
have cholesterol clefts, these big white entities in the middle of the blood vessel.
So, moral of the story, atherosclerosis isn’t great. There are a few things you can do to prevent it
though.
Maintaining a normal blood pressure, not smoking, and avoiding excessive sugary and fatty
foods and drinks all reduce your risk of the disease.
There are other risk factors that may be out of your control though. You’re more likely to
get atherosclerosis as you get older. Males and postmenopausal females are also more prone to
the disease, but premenopausal females are less at risk because higher levels of estrogen have a
protective effect against atherosclerosis. No big surprise here, but people who have a family
history with atherosclerosis are also more at risk. Ok, that’s enough atherosclerosis for one day.
Another type of arteriosclerosis is called Monckeberg Sclerosis or Medial Calcific Sclerosis.
And this is caused by the formation of calcium crystals in the muscular layer of the blood vessel
wall, leading to hardening of the blood vessel, but it this does not affect the diameter of the
lumen.
Since blood flow isn’t impaired, it doesn’t really cause any signs and symptoms, so it’s usually
detected during a diagnostic procedure for something else like mammograms, since
mammographies are used to look for calcification as a sign of breast cancer.
So the last arteriosclerosis category we’ll talk about is arteriolosclerosis.
Arteriolosclerosis is a category of blood vessel hardening diseases that affect small blood vessels
and is caused by high-blood pressure and diabetes.
Hyaline arteriolosclerosis is one type of arteriolosclerosis where instead of a buildup of plaque
on the walls of the arteries, the high-pressured blood flowing through the blood vessels causes
proteins floating around in the blood to leak into the blood vessel walls.
Overtime these you’ll see these walls begin to build up a lot of these proteins, making the blood
vessels stiffer.
When you look at a blood vessel through a microscope, you’ll see a pink hyaline material that is
making the blood vessel very thick.
Thick walls means that the lumen of the vessels start to get narrower. And this basically
reduces blood flow to the organs that are supplied blood through these vessels, and the organs
get starved of oxygen.
And, this is usually seen in the kidneys where not enough blood is supplying the small glomeruli
blood vessels and the glomerulus itself, causing the glomerulus to scar (which summed up nicely
by the term arteriolonephrosclerosis).
If we don’t do something to stop it, we’ll see scarring occur to enough glomeruli that a person
develops chronic renal failure.
People with diabetes can have hyaline arteriolosclerosis through a different mechanism.
Chronic exposure to high blood sugar can directly damage the endothelium, likely by
altering carbohydrate and fat metabolism, which in turn damages the basement membrane of the
blood vessels.
Another type of arteriolosclerosis is called hyperplastic arteriolosclerosis, which is also happens
due to thickening of the blood vessel walls, and occurs when a person has extreme hypertension.
The blood vessels compensate for this high blood pressure by adding additional layers of smooth
muscle and basement membrane, to the blood vessel wall, making the blood vessel stronger.
The downside is this extra muscle is that it decreases the space in the lumen for blood to pass
through.
If you look at these hyperplastic blood vessels under a microscope, you can see the rings
of smooth muscle with a small lumen. Which kind of looks like an onion.
Just like in hyaline arteriolosclerosis, hyperplastic arteriolosclerosis can then cause ischemia in
the organs it supplies.
Also just like hyaline arteriolosclerosis, hyperplastic arteriolosclerosis typically affects the
arteriole walls of the kidney.
The high blood pressure destroys the blood vessels in the kidneys, causing renal ischemia.
What’s unique in hyperplastic arteriolosclerosis is the kidneys themselves will look a bit like
they have insect bites everywhere.
That’s because the high-blood pressure ruptures the weakened renal blood vessel walls, causing
small hemorrhages all over the kidneys.
These small blood vessel hemorrhages give the kidney tissue the appearance that they have been
bitten by insects!
Narrowed and hardened arteries don’t generally cause symptoms until the blockage is
significant.
Once that happens there may be pain distal to the affected artery, including chest pain, or angina,
if it’s coronary artery or foot and leg pain if that blockage is in an artery in the leg.
If the artery goes to the brain it can cause stroke-like symptoms like confusion or weakness.
If the artery goes to the kidneys it can cause high blood pressure or renal failure.
Diagnosis usually starts with a physical examination which can show a weakened pulse below
the blockage or bruits, which is a whooshing sound over the arteries heard through a stethoscope.
In addition, an imaging study, like an angiogram, where a dye is injected into a blood vessel can
show narrowing of blood vessels.
These diseases can often be treated with lifestyle changes like stopping smoking and improving
diet and exercise, and that can help improve underlying conditions like diabetes
mellitus or hypertension. In some cases, medications may be required.
Cholesterol medications, like statins, can be used to improve lipid profiles; antiplatelet
medications, like aspirin, can be used to reduce blood clotting; and blood pressure medications,
like beta blockers, diuretics and Angiotensin-converting enzyme inhibitors (or ACE inhibitors)
can help lower blood pressure.
With severe atherosclerosis, angioplasty can be used to open a blocked artery with a balloon
followed by the placement of a stent to keep the artery open.
A surgery called an endarterectomy, often done with the carotid arteries, can also be done to
remove fatty deposits.
Finally, a blood vessel can be grafted in and used to bypass to go around a blocked artery.
Alright, as a quick recap … Arteriosclerosis literally means hardening of the arteries, and
describes diseases where arteries become thicker, harder and more stiff.
Arteriolosclerosis, specifically refers to the hardening of arterioles which often affects blood
flow to the kidneys, and atherosclerosis describes the buildup of atheromatous plaques in
medium to large arteries.

Sources
1. "The pathogenesis of atherosclerosis: a perspective for the 1990s" Nature (1993)
2. "Atherosclerosis — An Inflammatory Disease" New England Journal of
Medicine (1999)
3. "Robbins Basic Pathology" Elsevier (2017)
4. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
5. "What Are the Signs and Symptoms of Atherosclerosis? - NHLBI, NIH" NHLBI,
NIH (22 June 2016)
6. "Atherosclerosis" Harvard Health Publications Harvard Health Publications (2011)
Atherosclerosis and arteriosclerosis:
Pathology review
Mikhail is a 60 year old man with a history of hypertension, diabetes and dyslipidemia who
presents to your clinic complaining of sudden-onset retrosternal chest pain associated
with shortness of breath. He has a 35-pack-a-year smoking history, and he mentions that he also
develops lower limb pain when walking for more than 15 minutes. His father underwent a below
the knee amputation of his right lower extremity and died from a stroke. On physical
examination, his BMI is 32. On further workup, his ECG and high troponin levels suggest
a myocardial infarction. Mikhail goes to the cath lab to undergo per-cutaneous coronary
intervention, which showed a clot occluding the left anterior descending coronary artery. After
the procedure, his chest pain resolved. However, he started developing a web-like skin rash.
Mikhail suffers from arteriosclerosis, which is a hardening and thickening of the arterial wall,
causing it to lose its elasticity. A specific type of arteriosclerosis is atherosclerosis, which is a
chronic inflammatory disorder that affects the endothelium of medium and large arteries, and is
characterized by the buildup of cholesterol plaques within the arterial lumen. In a descending
order, the most common arteries affected by atherosclerosis are the abdominal aorta, coronary
artery, popliteal artery and then the carotid artery.
Risk factors for atherosclerosis can be divided into modifiable and nonmodifiable risk factors.
Modifiable risk factors include hypertension, diabetes mellitus, smoking and dyslipidemia,
particularly an increase in LDL levels or a decrease in HDL levels. Non-modifiable risk factors
include age, family history, and being of African-American descent.
The pathogenesis of atherosclerosis is essentially an inflammatory response to endothelial cell
injury. The endothelium is injured by stress against the arterial wall, like in hypertension. This is
especially more prominent at arterial bifurcations, such as the carotid artery bifurcation. Other
causes of endothelial injury include tobacco smoking and homocysteinemia, which is elevated
levels of the amino acid, homocysteine.
Regardless of the cause, when the endothelium is injured, LDL particles are allowed to leak into
the intimal layer, where it gets oxidized. When LDL is oxidized, it becomes a pro-inflammatory
antigen that induces an immune response in which inflammatory cells like macrophages come to
fight this antigen. These macrophages will enter the arterial walls and eat up the oxidized LDL
particles, creating what’s known as foam cells. Accumulation of foam cells underneath the
endothelium creates the first marker of atherosclerosis, a fatty streak. Fatty streaks might as well
be called “flatty” streaks, because they are not raised, meaning they don’t obstruct the lumen so
they don’t produce clinical symptoms like angina. Damage to the endothelium calls
upon platelets to join the party. Platelet and endothelial cells release factors like platelet derived
growth factor, or PDGF and fibroblast growth factor, or FGF, and transforming growth factor
beta, or TGF-beta. These factors stimulate smooth muscle cell proliferation and migration from
the tunica media to the tunica intima. Smooth muscle cells then proliferate and stimulate the
production of extracellular matrix. This results in the formation of a fibrous cap overlying a lipid
core in the center, and this structure is called a plaque. The lipid core is made
of cholesterol crystals that under the microscope look like white slit-like spaces. The fibrous cap
is what separates the lipid core from the blood vessel lumen. Unlike the fatty streak, an ath-
erosclerotic plaque could obstruct the lumen and produce symptoms. Keep in mind that although
fatty streaks can form as early as adolescence, they don’t always develop into plaques. Now over
time, foam cells within the lipid core undergo necrosis, and release matrix metallo-proteinases,
or MMPs. These enzymes begin chewing away at the fibrous cap, making it thinner and thinner,
until one day, it ruptures. When this happens, the atheroma is now exposed to the blood vessel
lumen. Platelets react as they should, by forming a fibrin clot at the site of rupture.
Unfortunately, these clots can occlude the lumen of the artery even more, or they may detach and
move to obstruct other blood vessels like the arteries in the brain.
Okay, complications of atherosclerosis include ischemia to the supplied organs. Typically, at
least 70% of the lumen must be occluded prior to the onset of the symptoms. Ischemia may
manifest as angina if the coronary arteries are involved, claudication in peripheral vascular
disease, or chronic mesenteric ischemia if the mesenteric arteries are involved. When the plaque
ruptures, clot formation may potentially result in acute infarction of the supplied organ, such
as myocardial infarction, ischemic stroke, acute limb ischemia or acute mesenteric ischemia.
Additionally, an atheroma may weaken the vessel wall, causing an aneurysm, especially at areas
where the arterial wall is weaker. For example, these can occur in the abdominal aorta below the
level of L2 since it lacks the vasa vasorum, which are small blood vessels in the tunica adventitia
supplying the aortic wall. Without this vasa vasorum, the tunica media doesn’t get enough
nutrients, causing it to weaken, which increases the risk of developing an abdominal aortic
aneurysm that could rupture and cause hemorrhaging.
An interesting complication of atherosclerosis are cholesterol emboli. This occurs when an
atherosclerotic plaque itself is dislodged and travels in the circulation as a cholesterol embolus.
A common exam question will have a person who underwent a cardiac procedure, such
as percutaneous coronary intervention, present with this complication right afterwards. This is
caused by a plaque that was accidentally dislodged during the procedure. Symptoms depend on
where the embolus ends up and include a web-like purplish rash called livedo reticularis, acute
kidney injury, or even gangrene formation at the extremities. Retinal emboli can be visualized on
fundoscopy, and are called Hollenhorst plaques. A good clue is that laboratory investigations,
interestingly, shows eosinophilia, and urinalysis shows eosinophil-uria. Microscopically,
cholesterol emboli are characterized by white needle-shaped cholesterol clefts within the
occluded vessel lumen.
Okay, another subtype of arteriosclerosis is arterio-lo-sclerosis. A bit of a tongue twister. From
the name, this affects smaller arterioles, and there are two types; hyaline and hyperplastic
arteriolosclerosis.
Hyaline arteriolosclerosis results from deposition of protein within the vessel wall, which on
microscopy, gives off a glassy, eosinophilic, pink appearance, hence the term hyaline.
Accumulation of protein thickens the blood vessel wall and make it rigid, occluding the arteriolar
lumen. Risk factors include chronic hypertension or diabetes. In hypertension, the increased
arterial wall stress literally pushes plasma proteins into the blood vessel wall. In diabetes, excess
glucose combines with the proteins of the arteriolar basement membrane, a process called non-
enzymatic glycation. Having too much sugar in the basement membrane is not a good idea,
because it can disrupt the structure and allow plasma proteins to leak in. Clinical manifestations
of hyaline arteriolosclerosis include hypertension and diabetic nephropathy, as well as small
lacunar infarcts in the brain.
Hyperplastic arteriolosclerosis on the other hand, typically happens as a reaction to severe, acute
elevations in blood pressure. This results in excessive growth of the basement membrane and
proliferation of the arteriolar smooth muscle, which occludes the lumen, and gives the blood
vessel the appearance of “onion-skin” on microscopy. Hyperplastic arteriosclerosis most
commonly affects the renal, retinal and intestinal arterioles.
The final form of arteriosclerosis is an uncommon and benign form called medial calcific
sclerosis, or Monckeberg sclerosis. This form is characterized by calcification of the internal
elastic lamina and tunica media, causing the vessel wall to become rigid. But the thing is,
although the blood vessel is rigid, the lumen is not occluded, so it’s not clinically significant and
should be ruled out as an answer choice if the person suffers from symptoms of ischemia. These
calcifications may appear on x-ray, giving the bloodvessel a pipestem appearance.
Okay to review, arteriosclerosis is hardening of the arteries, and has different subtypes,
including atherosclerosis, hyaline and hyperplastic arteriolosclerosis, and medial calcific
sclerosis. Atherosclerosis results from endothelial injury secondary to risk factors like
age, hypertension, diabetes and tobacco smoking. When the endothelium is injured, LDL
particles enter and are oxidized. Macrophages phagocytose LDL particles, forming foam cells,
which forms the fatty streak. Smooth muscle cells proliferate and migrate to the intimal layer,
where they lay down extracellular matrix. Over time, an atherosclerotic plaque made of a fibrous
cap and a lipid core is formed. This plaque may occlude the lumen, causing ischemia to distal
organs, which manifests as angina or claudication. When the plaque is disrupted, a thrombus is
formed, which may produce acute infarction, such as myocardial infarction or stroke. Atheromas
can also weaken the vessel wall, resulting in the formation of aneurysms, like abdominal aortic
aneurysm. Also, during cardiac procedures, atherosclerotic plaques can be dislodged, producing
cholesterol emboli. Hyaline arteriolosclerosis is associated with chronic
hypertension and diabetes, and is characterized by protein deposition in the vessel
wall. Hyperplastic arteriolosclerosis is associated severe, acute hypertension, and is characterized
by expansion of the basement membrane. Finally, medial calcific sclerosis is a benign condition
characterized by calcification of the tunica media, which can be visualized on x-rays.
Back to our case. Mikhail had multiple risk factors for atherosclerosis including old
age, hypertension, diabetes, obesity, tobacco smoking and dyslipidemia. He also has a family
history of atherosclerosis, as his father likely had peripheral vascular disease, and died from
a stroke. He presents with chest pain characteristic of myocardial ischemia, which was confirmed
by his ECG and troponin levels, and his lower limb pain on exertion is characteristic
of claudication, which is most likely caused by peripheral vascular disease. After his cardiac
procedure, he developed a web-like rash that is likely livedo reticularis, indicating that his
procedure was complicated by a cholesterol embolus.

Sources
1. "Rapid Review Pathology" Elsevier (2018)
2. "Fundamentals of Pathology" H.A. Sattar (2017)
 3. "Atherosclerotic Vascular Disease Conference: Writing Group III:
pathophysiology" Circulation. 2004 (2004)
4. "Pathophysiology of Heart Disease" Wolters Kluwer Health (2015)
5. "The pathogenesis of hyaline arteriolosclerosis" Am J Pathol (1986)

Coronary artery disease: Clinical practice

Coronary artery disease can lead to myocardial ischemia which is when the myocardium isn’t
getting a sufficient blood supply; so there isn’t enough oxygen to meet the heart’s demands.
And coronary artery disease is characterized by a type of chest pain called angina pectoris, which
can be due to either vasospastic disease and atherosclerotic disease.
Vasospastic disease, also called Prinzmetal angina, is when for unclear reasons there’s
transient vasoconstriction of a coronary artery, leading to transient ischemia.
These attacks generally occur at rest, during the night or early morning, and occur in clusters.
Atherosclerotic disease is when a coronary artery narrows due to build up of atherosclerotic
plaque, and it can be further divided into stable angina, unstable angina, and myocardial
infarction.
Unstable angina and myocardial infarction are collectively called acute coronary syndrome.
Patients with stable angina don’t feel pain at rest, but they do feel chest pain during
intense physical exercise, because that’s when the myocardium has increased oxygen demand,
which leads to transient or demand ischemia.
The chest pain stops when the exercise stops, so these patients often just rest rather than going to
the emergency department or ED.
Now, angina is considered unstable if it presents at rest, or if it becomes more frequent, lasts
longer, or occurs with less exertion than previous episodes of angina.
In unstable angina there’s prolonged myocardial ischemia, but there’s no myocardial cell death
yet, so it’s not a myocardial infarction.
But if it’s not taken care of promptly, the ischemia can get prolonged and can lead to myocardial
infarction, which is life-threatening.
When a patient comes into the ED with acute chest pain, a number of things have to be done
within 10 minutes to confirm or exclude a myocardial ischemia.
The differential diagnosis includes gastroesophageal reflux, pulmonary embolism, aortic
dissection, a pneumonia, or a panic attack.
The first step is to check the airway, breathing, and circulation, perform a quick physical exam,
and attach cardiac and oxygen saturation monitors. And supplemental oxygen should be given if
the oxygen level dips below 90%, and supplemental assisted ventilation should be given if the
oxygen level dips below 80%.
Emergency resuscitation equipment should be nearby, including a defibrillator and airway
equipment, just in case the patient goes into cardiac arrest.
All patients with suspected myocardial ischemia should be given 325 mg of aspirin, unless
there’s a contraindication, like a history of an anaphylactic reaction or if they’ve already received
it.
The aspirin can be given orally or as a rectal suppository.
In the meantime, IV access should be obtained, and blood should be drawn for initial laboratory
work, including a CBC, electrolytes, creatinine and blood urea nitrogen, coagulation
factors, lipids, and most importantly, cardiac biomarkers of acute myocardial damage, including
a troponin T and I, which are essential for diagnosing a myocardial infarction.
Other cardiac biomarkers like creatine kinase or lactate dehydrogenase are less sensitive and
specific than cardiac troponin, so the current guidelines recommend cardiac troponin as the only
cardiac biomarker that should be measured in a patient with suspected myocardial infarction.
Troponins are generally found inside cardiomyocytes, so when they die, the biomarkers are
released into the bloodstream, so their blood levels rise.
But it can take up to 6 hours for the elevation of cardiac biomarkers to be detectable, so troponin
levels should be checked initially and then again at 6 hours.
If troponins are negative it may be that a patient is having unstable angina, a short attack
of Prinzmetal angina, or a non cardiac cause of chest pain.
If troponins are positive, that means there’s cardiomyocyte death; which means that it’s
a myocardial infarction.
Next, it’s important to get a clear history of the chest pain - and the acronym OPQRST can help.
O stands for onset, which is usually sudden and at rest, but may also occur while exercising.
P stands for provocation - so which activities provoke pain - and palliation, so which activities
alleviate pain. Generally speaking, angina pectoris doesn’t improve or worsen with respiration or
position.
Q stands for quality, which may be described as a pressure, heaviness, tightness, fullness, or
squeezing.
R stands for radiation, which is most often to the neck, jaw, and left arm.
S stands for site, which typically is substernal or in the left chest, and the pain is usually diffuse
and difficult to localize. If a person can point to the site of pain with a single finger it’s less
likely due to cardiac ischemia.
Finally, T stands for time course, which typically lasts over 30 minutes.
Myocardial ischemia can also cause dyspnea, palpitations, nausea, and increased sweating.
And some important risk factors include being over 55 years old, being male, hypertension,
hypercholesterolemia, diabetes mellitus, smoking, obesity, and family history of first degree
relatives premature coronary artery disease, so males before the age of 55 years and females
before the age of 65.
Also, women, older adults, and patients with diabetes often have atypical presentations like
just dyspnea, epigastric pain or discomfort, syncope, or sudden death from cardiac arrest.
In individuals having myocardial ischemia - so those with unstable angina and myocardial
infarction as well as Prinzmetal angina, nitrates should be used immediately to help widen
the coronary arteries and help increase blood flow to the heart, which should relieve the pain and
decrease the blood pressure.
Three sublingual doses of 0.4 mg of nitrates are generally given, one every five minutes.
If the patient has Prinzmetal angina, nitrates will lead to an immediate and full recovery,
so nitrates help with both diagnosis and management.
And if the patient has unstable angina or a myocardial infarction, then pain and blood
pressure should improve, so if there’s really no improvement at all, then intravenous nitrates may
be needed.
Nitrates are contraindicated in case of hypotension, myocardial infarction of the right ventricle,
and recent use of PDE-5 inhibitors like Sildenafil, because in these situations nitrates can cause
really severe hypotension.
Additionally, some patients with ongoing chest pain or tachycardia should get beta blockers to
lessen cardiac demand.
And if the patient is hypertensive, intravenous beta blockers can be used.
However, beta blockers are contraindicated in Prinzmetal angina, because they can worsen the
coronary vasoconstriction.
They’re also contraindicated in bradycardia, cardiogenic shock, and acute decompensated heart
failure - all of which can worsen with beta blockers.
Beta blockers are also contraindicated in cocaine-related acute coronary syndrome.
That’s because cocaine triggers a big release of sympathomimetic amines, and if the beta
receptors are blocked by the beta blockers, then those sympathomimetic amines end up binding
to alpha receptors, causing severe coronary vasoconstriction.
Now, patients with underlying heart failure must be given an intravenous loop
diuretic like furosemide.
In addition, patients with severe and persistent chest pain can be given intravenous morphine
sulfate at an initial dose of 2 to 4 mg, repeated every 5 to 15 minute intervals.
Basically, every patient suspected of having myocardial ischemia should get a standard 12-
lead electrocardiogram or ECG within 10 minutes of arrival to an ED.
And the initial ECG is often not diagnostic, so it should be repeated at 5 to 10 minute intervals if
there is high suspicion for myocardial ischemia.
In addition to making sure that there’s a normal sinus rhythm, if we suspect myocardial
ischemia, the most important thing is to check the ST segment.
In healthy individuals the normal ST segment has a slight upward concavity.
In stable angina, the ST segment is normal, and in unstable angina, the ST segment is generally
normal or depressed.
Now, myocardial infarctions are divided into non ST segment elevation myocardial infarction or
NSTEMI, and ST segment elevation myocardial infarction or STEMI.
In NSTEMI, the ST segment may be normal, but there might be an ST depression that’s more
than 0.5 mm or 0.05 mV in two or more contiguous leads, or deep T wave inversions above 1
mm or 0.1 mV.
STEMI is when there’s an ST elevation above 1 mm or 0.1 mV in two or more contiguous leads
or new left bundle branch block.
ST elevation occurs when there’s full-thickness involvement of the myocardium.
The location of a myocardial infarction can be determined by which ECG leads show ST
elevation.
In anterior wall ischemia, ST elevation will show up in the precordial leads, so V1 to V6. In
anteroseptal ischemia, it will show up in leads V1 to V3.
Apical or lateral ischemia will show up in leads aVL and I, and leads V4 to V6.
Inferior wall ischemia will show up in leads II, III, and aVF.
Right ventricular ischemia will show up in the right-sided precordial leads which can be obtained
by placing leads V1 to V6 in a mirror image position on the right side of the chest, and posterior
wall ischemia will show in the septal precordial leads, so V1 and V2, and posterior precordial
leads.
Now, ST depression in V1 and V2 is also important because these anterior leads mirror the ST
elevation that might be happening in the posterior precordial leads V7, V8 and V9, which aren’t
included in the standard 12-lead ECG.
In other words, they represent a posterior STEMI, which needs to be treated as a STEMI and not
like an NSTEMI.
Now, Prinzmetal angina may present with a normal or depressed ST segment in short attacks,
or ST elevation in long attacks.
However, the ECG changes can only be found during the attack, so to spot it, the patient should
be put on Holter monitoring, which is a device that records ECG tracings for 24 hours or longer.
Now, if there’s no evidence of ischemia, you should do further testing in the ED setting, such as
a stress test, which measures the heart's ability to respond to external stress in a controlled
clinical environment.
The stress response is induced by exercise or by drug stimulation with dobutamine.
Cardiac stress tests compare the coronary circulation while the patient is at rest with the coronary
circulation during physical exertion.
A negative stress test means that the coronary arteries are able to dilate and provide more blood
to the myocardium when needed, and that the chest pain is likely form a non-cardiac cause.
A positive stress test means that the coronary arteries aren’t able to dilate, and that the chest pain
is likely due to unstable angina, which is managed the same way as a NSTEMI.
So a patient with unstable angina or NSTEMI needs urgent treatment
with antithrombotic therapy, both oral antiplatelet therapy with a P2Y12 inhibitor
like clopidogrel - in addition to aspirin - and anticoagulant therapy with heparin, to prevent
further thrombosis or embolism from an ulcerated plaque.
After that, individuals at high risk of short term adverse events should be identified - those are
the ones with hemodynamic instability or cardiogenic shock, left ventricular dysfunction or heart
failure, recurrent or persistent rest angina despite intensive medical therapy, new or
worsening mitral regurgitation, new ventricular septal defect, or sustained ventricular
arrhythmias.
These high-risk patients should get immediate coronary angiography as well as revascularization,
which is also called reperfusion therapy, to restore coronary perfusion.
Low-risk patients should get coronary angiography and reperfusion therapy within 12 hours of
symptoms.
Patients who lack these features should undergo early risk stratification to identify individuals at
high risk of long term adverse events, who therefore should be treated with an early invasive
strategy as well.
Two common scoring systems are the TIMI risk score and the GRACE score.
The TIMI score considers 7 risk factors, each accounting for one point in the final score: age
over 65 years, at least three risk factors for coronary artery disease, prior coronary artery stenosis
of 50% or more, ST depression, at least two anginal events in the prior 24 hours, elevated serum
cardiac biomarkers, and use of aspirin in the prior seven days.
The GRACE score considers 8 factors - age, systolic blood pressure, heart rate, ST segment
deviation - so either elevation or depression, cardiac arrest at admission, serum creatinine
concentration, serum cardiac biomarkers, and Killip class.
The highest total possible score is 363. Now, the Killip classification takes into account physical
examination findings like rales or crackles in the lungs, an S3 heart sound, elevated jugular
venous pressure, acute pulmonary edema, cardiogenic shock or hypotension, oliguria, cyanosis,
or sweating - as well as the development of heart failure.
Patients at high risk using the GRACE risk scores are usually referred for coronary angiography
and reperfusion therapy.
Specifically, if their GRACE score is higher than 140, they are referred for early therapy - so
within 24 hours from diagnosis.
And if their GRACE score is between 109 and 140, they are referred for delayed therapy - so
within 72 hours from diagnosis.
Lower risk patients might get noninvasive testing like a stress test, to determine their need for
coronary angiography and reperfusion therapy.
Moving on, patients with STEMI need immediate - so within 2 hours from diagnosis - coronary
angiography and reperfusion therapy, ideally within 12 hours from symptom onset.
The two ways to do reperfusion therapy are mechanical reperfusion with primary percutaneous
coronary intervention or PCI, which usually includes the insertion of a stent to keep vessels open
and is strongly preferred.
The alternative approach is to do reperfusion therapy using medications - sometimes called
pharmacological reperfusion - using fibrinolytics.
Typically that’s done when primary PCI can’t be done within two hours of arrival to the ED.
If more than 12 hours have passed since symptom onset, reperfusion should generally not be
performed, but emergent PCI may be done for patients with ongoing ischemia or those at high
risk of death.
After reperfusion therapy, or in cases where it wasn’t done, oral antiplatelet therapy
with aspirin and a P2Y12 inhibitor, plus anticoagulant therapy with heparin, is given to patients.

Summary
All right, as a quick recap, coronary artery disease can be due to either vasospastic disease,
so Prinzmetal angina, or atherosclerotic disease, so stable angina, unstable
angina and myocardial infarction, which is further divided into NSTEMI and STEMI.
Patients presenting to the ED with suspected myocardial ischemia should be
given aspirin, nitrates, morphine, get troponins sent, and an ECG looking for ST segment
changes - all within 10 minutes.
In Prinzmetal angina there’s immediate and full recovery with nitrates.
If the ST segment is normal or depressed and troponins are negative, it’s unstable angina.
If the ST segment is normal or depressed and troponins are positive, it’s NSTEMI.
If the ST segment is elevated, it’s a STEMI, so don’t need to wait for the results of the troponins,
but they would definitely be elevated.
Unstable angina and NSTEMI are managed with a combination of antiplatelet and
anticoagulation therapies, and a risk factor assessment is done to decide if they need immediate
coronary angiography and reperfusion therapy.
STEMI is managed with emergency reperfusion therapy, either with PCI or systemic
thrombolysis, and after reperfusion therapy, patients are given a combination of antiplatelet and
anticoagulation therapies.
Coronary artery disease: Pathology review
In an urban emergency department, 3 people came in for chest pain. The first is Anish, a 54 year
old man with a known history of hypertension, hyperlipidemia, and 25-pack year smoking. He’s
complaining of shortness of breath, and squeezing, retrosternal chest pain that radiates to his
neck, jaw and left arm. He’s been having these episodes but they only come after riding his
bicycle for at least 20 minutes, and is relieved once he rests. Investigations reveal a normal ECG
and normal troponin levels. Next, is Erica, a 66-year old woman with a history of diabetes
mellitus who complains of sudden-onset shortness of breath, fatigue and dizziness, but no chest
pain. An ECG reveals ST-segment depression, and troponin levels are elevated. Finally, There’s
Tyrion, a 45-year old man, with a known history of hypertension, diabetes, and hyperlipidemia.
He complains of epigastric abdominal pain at rest, shortness of breath, sweating and
lightheadedness for the past 30 minutes. His blood pressure is 80/60, and his heart is 45 beats per
minute. An ECG reveals ST-segment elevation in leads II, III and aVF.
All three have coronary artery disease which is defined as an imbalance between myocardial
oxygen demand and supply from the coronary arteries. Reduced oxygen supply to the heart is
defined myocardial ischemia, which results in a severely reduced ability of the heart
muscle ability to contract. If this is prolonged, it can go on to cause myocardial infarction,
otherwise known as heart attack, which refers to death of heart muscle. Now, coronary artery
disease is usually caused by atherosclerosis of the coronary arteries. Risk factors
for atherosclerosis can be divided into non-modifiable ones, which include age, with men greater
than 45 years and women greater than 55 years being at risk, and family history of coronary
artery disease, and modifiable ones, like lipid abnormalities including elevated LDL or low HDL
levels, as well as hypertension, diabetes mellitus and smoking. Coronary artery disease can
present in many ways, including stable angina, Prinzmetal angina, acute coronary syndrome -
which includes unstable angina, non-ST-segment elevation myocardial infarction, or NSTEMI,
ST-segment elevation myocardial infarction, or STEMI, chronic ischemic heart disease, and
sudden cardiac death.
Now, aside from atherosclerosis, there are other less common causes of coronary artery disease,
such as coronary artery embolus vasculitis and vasospasm. In a coronary embolism, pieces of a
clot from another site break off and can travel into a coronary artery, occluding it. Risk factors
for a coronary embolism include atrial fibrillation, infective endocarditis, a left atrial or
ventricular thrombus or in individuals undergoing cardiac catheterization. As
for vasculitis, coronary artery disease in young children should prompt you to consider Kawasaki
disease, a medium-vessel vasculitis that classically causes a coronary artery aneurysm. Also,
other vasculitides like polyarteritis nodosa can also cause coronary artery disease. Now, coronary
artery vasospasm, meaning the smooth muscles around the arteries constrict extremely tightly,
may also reduce blood flow and result in coronary artery disease. Then, another cause
of coronary artery disease is aortic valve stenosis. See, the right and left main coronary
arteries branch off the base of the aorta, and so in aortic stenosis, not enough blood gets through
the aorta and into the coronaries, resulting in myocardial ischemia. Also, any cause of concentric
ventricular hypertrophy, such as aortic valve stenosis, hypertension, or hypertrophic
cardiomyopathy may result in coronary artery disease, because you essentially have more heart
muscle to supply.
Now let’s take a look at the presentations of coronary artery disease, starting with stable angina!
This occurs secondary to myocardial ischemia, caused by a fixed atherosclerotic plaque
occluding more than 75 percent of the coronary artery lumen. What you must remember here is
that this results in reversible cell injury. An infarction, on the other hand, is when there’s
irreversible cell injury or cell death.Now, stable angina manifests as a deep, poorly localized,
squeezing, crushing or suffocating retrosternal pain that may radiate to the arm, jaw or neck. Lots
of adjectives. It’s often accompanied by other symptoms, such as shortness of breath, nausea,
vomiting, diaphoresis, fatigue or dizziness. A high yield fact is that this chest pain is
reproducible during any activity that increases myocardial oxygen demand, such as physical
exertion or emotional stress, and is relieved within 5 minutes by rest or sublingual nitroglycerin.
The term “stable” refers to the atherosclerotic plaque itself, which hasn’t ruptured yet and is
structurally stable. Now, sometimes in stable angina, an atherosclerotic plaque can cause near-
total occlusion of the coronary artery, yet individuals may not develop infarction. The reason is
because athersclerotic plaques grow slowly, giving time for the heart to develop collateral
circulation that supplies the hypoperfused area.
The ECG in stable angina is typically normal at rest, but may become abnormal on stress testing,
which measures the heart's ability to respond to external stress in a controlled clinical
environment. The stress response is induced by exercise or by stimulation with medications,
like dipyridamole. Now, when a vasodilating medication like dipyridamole is given to an
individual with stable angina, coronary steal syndrome may occur. That’s because it causes
vasodilation of all coronary arteries, except the ones which are obstructed - because beyond the
obstruction, the coronary artery is already maximally dilated. The end result is that blood is
diverted, or stolen, away from the ischemic myocardium to non-ischemic areas, which further
worsens the ischemia. This shows in the ECG as an ST-segment depression.
However, a high yield fact is that cardiac biomarkers like troponin levels are always normal
because there’s ischemia, but no infarction. A variant of angina is called well... variant angina,
or Prinzmetal angina. Here, there’s no atherosclerotic plaque occluding the lumen, instead
the coronary artery undergoes vasospasm, narrowing the lumen. Individuals typically
develop angina at rest, and triggers include smoking, cocaine, alcohol, and triptans. For example,
the exam may tell you about an individual with a history of migraines,
and triptans like sumatriptan are one of the treatment options for migraine. Due to
transmural ischemia, a 24-hour ECG called a Holter monitor classically shows transient
elevation of the ST-segment, but troponin levels are normal, because once again, there is no
infarction. To help with the diagnosis, low doses of vasoconstrictive medication
called ergonovine are given to provoke vasospasm which results in transient ST-segment
elevation. Treatment includes calcium channel blockers and nitroglycerin, which relax the
vascular smooth muscle, and cessation of the trigger.
Okay, in stable angina, the atherosclerotic plaque was fixed and not disrupted. But when
the atherosclerotic plaques are disturbed, we get the next three disorders: unstable angina,
NSTEMI and STEMI. These three are huddled together under the umbrella of acute coronary
syndrome, or ACS. An acute coronary syndrome typically manifests as sudden, new-
onset angina, or an increase in the severity of an existing stable angina. This may be an increase
in the frequency or intensity of episodes, when they can be triggered by less exertion than before,
or when symptoms occur at rest. Sometimes, though, there are atypical presentations. Older
people, females, and individuals with diabetes can present without chest pain. Instead, they come
with vague symptoms like shortness of breath, fatigue, and dizziness. Now, plaques are made of
a fibrous cap and a necrotic lipid core and the composition of the plaque determines the risk of
rupture. The high yield concept here is that a thin fibrous cap and a rich lipid core mean that the
plaque is at high risk of rupture. When a plaque ruptures, the underlying collagen is exposed, and
in response, platelets quickly aggregate, forming a thrombus.
Okay in unstable angina, the atherosclerotic plaque ruptures and causes near-total but incomplete
occlusion of the coronary artery. The ECG shows ST-segment depression or T-wave inversion,
but troponin levels are normal, because there is no myocyte necrosis.
But if the troponin levels are elevated, then we now call it NSTEMI, which signifies an
infarction beneath the endocardium, also called a subendocardial infarct. The infarct happens
here because the coronary vessels run along the epicardium, the outer one-third of the heart wall.
So this is the farthest area from the blood supply. Now, the reason we call it NSTEMI is because
on ECG, a subendocardial infarct manifests with changes like ST-depression or T-
wave inversion, however it never shows ST-segment elevation. If there’s ST segment elevation,
then it’s a STEMI, which happens when the thrombus occludes 100 percent of the lumen. The
ST-segment elevation signifies an acute transmural infarction, meaning it involves the whole
wall. Troponin levels are also elevated in a STEMI, but it’s the ST-segment elevation on an ECG
that immediately clinches the diagnosis.
The reason why we’re talking about troponin, of which there are two types, troponin I and T, is
that, together with CK-MB, which is a combination of creatine kinase enzymes M and B, they
make up what’s known as the key cardiac biomarkers. So, when there’s been irreversible damage
to heart cells, their membranes become damaged and these proteins and enzymes inside escape,
and can enter the bloodstream. Both troponin I and T levels can be elevated in the blood within
2-4 hours after infarction, and usually peak around 48 hours, but stay elevated for 7-10 days.
CK-MB starts to rise 2-4 hours after infarction, peaks around 24 hours, and returns to normal
after 48 hours. Since CK-MB returns to normal more quickly, it can be useful to diagnose
reinfarction, a second infarction that happens after 48 hours but before troponin levels go back to
normal. Bare in mind though that unlike troponins, CK-MB is not specific for cardiac injury and
it may also be elevated in cases of skeletal muscle damage elsewhere in the body, like trauma,
heavy exertion, and myopathy.
Now for your exam, you might be asked to locate the infarct and the vessel involved based on
the on the ECG. This can be done by locating which leads had the ST elevation: V1 and V2
involvement is an anteroseptal MI, which means the left anterior descending artery, or LAD is
involved. V3, V4 involvement is an anteroapical MI, which means the distal part of the LAD is
involved. V5, V6 involvement is an anterolateral MI, which involves the LAD or left circumflex
artery. Lateral MI involves leads I and aVL, and the left circumflex is occluded. Inferior MI
involves leads II, III and aVF with the right coronary artery being the culprit. Inferior
wall myocardial infarctions are very high yield because they can also present as epigastric
abdominal pain instead of chest pain. RCA occlusion can also cause right ventricular infarction,
but right sided leads would have to be obtained to see that. Finally, whenever there is ST
depression with tall R-waves in V1 to V3, then a posterior MI involving the posterior descending
artery is a possibility. Therefore, posterior leads V7-V9 must be obtained in such a scenario.
Okay, exams love to ask about the pathological manifestations and complications of
a myocardial infarction based on the time elapsed. Therefore, let’s take a look at a timeline
illustrating this. In the first 24 hours, the heart looks grossly normal. On light microscopy, after 4
hours, coagulative necrosis begins, and the necrotic myocardial cells hypercontract, giving them
a wavy appearance. During this period, arrhythmias can occur because the infarction disrupts the
electrical flow through the myocardium. Premature ventricular arrhythmias or PVCs are the most
common arrhythmia, but these are benign. On the other hand, ventricular arrhythmias
like ventricular tachycardia or fibrillation are the most common cause of sudden cardiac death,
which is death within 1 hour of symptom onset. A common way the exam might try to confuse
you, is by telling you that the individual is an athlete, which makes you inclined to
choose hypertrophic cardiomyopathy. However, ventricular arrhythmias due to coronary artery
disease are a more common cause of death in athletes over 35 years old,
whereas hypertrophic cardiomyopathy is more common in those under 35 years old. Other
complications include heart failure and cardiogenic shock, which are the most common cause of
death from MI in the hospital. In case of right coronary artery occlusion, the infarcted right
ventricle dilates, pushing the interventricular septum onto the left ventricular cavity, causing
decreased left ventricular filling, which results in a decreased stroke volume and hypotension.
You can differentiate between right and left ventricular failure clinically, because in a right
ventricular failure, the lungs are clear on auscultation, and there is elevation of jugular venous
pressure. It’s important to look for a right ventricular MI because veno-dilating medications
like nitroglycerin are contraindicated in these cases, as they further decrease the preload,
worsening the hypotension.
1 to 3 days after the infarction, the affected area appears grossly red. On light microscopy,
there’s extensive coagulative necrosis, and a large amount of neutrophils have infiltrated causing
acute inflammation. That inflammation can spread towards pericardium, causing postinfarction
fibrinous pericarditis. This presents with a low-grade fever, and sharp, pleuritic chest pain,
meaning it increases with inspiration.
Okay, 3 to 14 days after the infarction, macrophages come over to clean up the necrotic mess,
and soft, yellow granulation tissue begins to develop to repair the infarcted tissue. This soft
granulation tissue is quite weak, so there’s a risk of interventricular septum or ventricular free
wall rupture. Interventricular septum rupture typically presents at around 3 to 5 days as a left-to-
right ventricular septal defect, which presents as a new holosystolic murmur at the
left sternal border, and increased oxygen saturation in the right ventricle. Ventricular free wall
rupture classically occurs in anterior wall STEMIs, and presents at around 5 to 14 days. As a
result, large amounts of blood leak into the pericardial cavity, causing a pericardial tamponade.
Sometimes, the rupture is contained by the adherent pericardium, producing a balloon-like sack
of blood called a ventricular pseudoaneurysm. This pocket of blood is static, and stasis
promotes clotting, producing what’s called a mural thrombus. Bits of this thrombus
can embolize to the systemic circulation, resulting in peripheral complications like a stroke.
Okay, if someone had previously had an old MI, or they have ventricular hypertrophy because of
something like hypertension, then this actually protects them against wall rupture, due to the
fibrosis and a thick wall, respectively. A rare instance in which a pathology protects from
another pathology. Another complication is rupture of the papillary muscles, small muscles that
anchor to the atrioventricular valves by the chordae tendineae. This usually occurs 2 to 7 days
post-infarction. Normally, the anterolateral papillary muscle receives a dual blood supply from
both the LAD and the left circumflex artery. The posteromedial papillary muscle, however, is
solely supplied by the posterior descending artery, so it’s more at risk of rupture, and this can
cause acute-onset mitral regurgitation and pulmonary edema.
Alright, now 2 weeks to a couple of months post-MI, macrophages invade the tissue, and the
healing process begins with the formation of granulation tissue, which is a type of scar tissue
that’s yellow and soft, along with some new blood vessels, in a process called
neovascularization. This scar tissue may cause the ventricular wall to bulge out, forming a true
ventricular aneurysm. The affected segment is made of scar tissue, so it doesn't contract.
Therefore, there is a risk of developing heart failure, as well as a mural thrombus due to stasis
of blood flow in that area. But unlike a pseudoaneurysm, the ventricular wall is now strong, so
there’s no risk of rupture. Another complication during this period is Dressler syndrome, a
fibrinous pericarditis that occurs secondary to formation of autoantibodies that target serosal
surfaces like the pericardium.
Now, as for treatment, unstable angina and NSTEMI are managed with a combination of
antiplatelet and anticoagulation therapies to prevent further thrombosis or embolism from an
ulcerated plaque. After that, some patients may also need immediate coronary angiography and
revascularization, which is also called reperfusion therapy, to restore coronary perfusion. STEMI
is managed with emergency reperfusion therapy, either with percutaneous coronary
intervention or PCI, where a tiny catheter is used to place a stent in the coronary artery to
physically open up a blood vessel or fibrinolytic therapy, which uses medications to break down
fibrin in blood clots. Then, after reperfusion therapy, patients are given a combination of
antiplatelet and anticoagulation therapies.
Alright, so reperfusion therapy focuses on re-establishing blood flow to the dying heart heart
cells. Remember that within 60 seconds after the onset of total ischemia, we have myocardial
cell injury and contractility loss. However, for about 30 minutes, this remains reversible,which is
known as myocardial stunning. So, if we manage to re-establish blood flow within the first 30
minutes following blockage, these myocardial cells can be salvaged and contractility will be
gradually returning to normal over the next several hours to days. However, after about 30
minutes, ischemic injury becomes irreversible, so, no matter what we do, these cells will be
destroyed and removed.
Now an important complication of re-establishing perfusion, or reperfusion therapy, is
reperfusion injury, where tissue is damaged by returning blood flow. And, this is thought to
happen because of a couple mechanisms. First, blood flowing back to cells brings this influx of
calcium, and since calcium leads to muscle contraction, the irreversibly damaged cells contract,
and since they’ve been irreversibly damaged, they get stuck like that and can’t relax. This shows
up on histology as this characteristic contraction band necrosis. Also though, blood brings along
oxygen, which, paradoxically, can actually lead to more cellular damage. The conditions in
an ischemic heart seem to cause an increased conversion of the returning oxygen to reactive
oxygen species, which go on to damage more heart cells.
Okay, to review. Coronary artery disease is usually an atherosclerotic disease of the coronary
arteries and includes a variety of presentations including stable angina and acute coronary
syndrome. Stable angina occurs secondary to a stable athersclerotic plaque occluding at least
75% of the coronary artery, and presents with exertional chest pain relieved by rest
and nitroglycerin. ECG and troponin levels are normal. ACS occurs when the athersclerotic
plaque is disrupted, resulting in thrombosis. ACS includes unstable angina, NSTEMI and
STEMI. Unstable angina presents as new-onset angina or a change in the pattern of symptoms.
ECG shows ST-segment depression or T-wave changes, but troponin levels are normal. NSTEMI
is similar to unstable angina, but troponin levels are elevated. STEMI shows ST-segment
elevation, Q-waves, and elevated troponin levels. Prinzmetal angina is not due to atherosclerotic
disease but is caused by coronary vasospasm, and causes transient ST-segment elevation with
normal troponin levels.
Okay, back to our cases. Anish has multiple risk factors for atherosclerosis,
including hypertension, hyperlipidemia and smoking. He’s presenting with stable angina,
because his angina only comes when riding his bicycle, and is relieved during rest. Erica has two
risk factors for a silent MI: she’s an elderly lady with diabetes mellitus. Her type of MI is
NSTEMI, because there is no ST-segment elevation on the ECG, and troponin levels are
elevated. Tyrion came in with epigastric pain, and considering his risk factors and associated
symptoms, this is a potential presentation of inferior MI. This was confirmed as the ECG showed
STEMI in leads II, III and aVF. Fortunately, the MI was caught early, and he’s being treated
with percutaneous coronary intervention.

Sources
1. "Pathophysiology of Heart Disease" Wolters Kluwer Health (2015)
2. "Robbins Basic Pathology" Elsevier (2017)
3. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
4. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation
acute coronary syndromes: a report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines." Circulation. 2014 (2014)
5. "Immediate vs delayed intervention for acute coronary syndromes: a randomized
clinical trial" JAMA. 2009 (2009)
6. "Comparative early and late outcomes after primary percutaneous coronary
intervention in ST-segment elevation and non-ST-segment elevation acute
myocardial infarction (from the CADILLAC trial)" Am J Cardiol (2006)

Peripheral artery disease

Vascular refers to the blood vessels, and peripheral means the outer limits or edge of something,
which in peripheral vascular disease refers to any vessels that aren’t supplying the heart or the
brain, like ones in the legs, arms, or other organs. Peripheral vascular disease happens when one
of these arteries becomes narrowed, which reduces blood flow; this often affects the limbs.
Peripheral vascular disease, or PVD, usually involves the arteries, so sometimes it’s also referred
to as peripheral artery disease or PAD. PVD is usually caused by a blockage, called organic
PVD, that is most commonly created by atherosclerosis. Atherosclerosis is a buildup
of lipids and fibrous material just under the inner lining of the blood vessel, called the tunica
intima. When plaque builds up, it narrows the artery, which reduces perfusion to whatever tissue
it tends to supply; this buildup usually happens over the course of many years. However, the
vessel could be blocked by an embolus, which can happen suddenly if a blood clot from some
upstream artery lodges in a peripheral artery; this clot would obviously stop blood flow from
getting to the tissue the vessel supplies.
Besides organic PVDs, there are also functional PVDs. With functional PVDs, blood vessels
stop blood flow by changing diameter, such as with vasospasms, where the vessel constricts
and blood flow is reduced. This type of PVD is usually short term, and can come and go.
The arteries supplying the legs are the most commonly affected vessels in peripheral vascular
disease. When less blood gets to the muscle tissue in the legs, the tissue receives less oxygen and
becomes ischemic. Ischemic cells release adenosine, a type of signaling molecule, which is
thought to affect nerves in these areas; this is felt as pain. This pain in the legs is often referred to
as claudication. Sometimes, even though blood flow is narrowed with PVD, when a person is at
rest, there’s enough of blood to meet the tissue’s demands; thus, people are often asymptomatic
during rest.
However, if the person is walking or exercising, then the leg muscles start to work harder and
demand more oxygen; demand becomes greater than what’s supplied, which causes
the claudication, or pain. The location of the pain is a clue to which artery is involved. If it’s in
the hips and the buttocks, think of lower aorta or iliac. If it’s the thigh, think of the iliac or
common femoral artery. For the upper 2/3 of the calf, think of the superficial femoral artery; for
the lower ⅓ of the calf, think of the popliteal artery. Finally, for the foot, think of
the tibial or peroneal artery.
Other symptoms include leg or foot wounds, or ulcers, that don’t heal up normally,
and color changes of focal areas of the skin. For example, if the leg’s been affected, the foot
might turn pale white when it’s raised; this “elevation pallor” happens because gravity works
against blood flowing to the lower extremities, which already has a hard time getting through the
narrowed artery.
Likewise, the foot might turn red when it’s lowered, which is called dependent rubor, because
gravity is working with the blood flow in this direction. We can see that gravity seriously starts
to affect blood flow in the affected arteries. As the arterial blockage gets bigger, less and less
blood gets to the tissues, which can lead to more serious complications. First, “rest pain”
describes a continuous burning or pain in the forefoot and toes when the legs are elevated; this
pain is relieved when the limbs are lowered, such as by hanging the feet over the bed or walking
around the room, because doing so allows more blood to get down to the foot. If the blockage is
severe enough, the limb might be at risk of gangrene, or death of the tissue, because if deprived
of oxygen for long enough, the cells can actually die, or necrose. If this happens, the dead tissue
would likely have to be removed, and in some cases, the limb would have to be amputated.
The major risk factors and causes of peripheral vascular disease are the same as those
for atherosclerosis because they are similar processes. Remember, atherosclerosis in the neck
arteries can cause a stroke, and if involved in the coronary arteries, can cause a myocardial
infarction, or heart attack. Smoking seems to be the biggest contributor to PVD. Other diseases
and conditions that are also linked to a higher risk of PVD include: diabetes; dyslipidemia, or an
abnormal amount of lipids in the blood; and hypertension.
Diagnosing PVD usually involves listening to the pulse in the iliac arteries of the legs with a
stethoscope. Because that artery has been narrowed, it can make a whooshing sound, called a
bruit. Another test that can be done is a doppler ultrasound, which is a noninvasive way of
visualizing blood flow. The most common test to diagnose PVD is the ankle-brachial index, or
ABI, where blood pressure is taken in the ankle and in the arm, and then compared. PVD is
typically diagnosed if the systolic blood pressure in the ankle divided by the systolic blood
pressure in the arm is less than 0.9. In general, claudication is often seen in people with an ABI
between 0.4 and 0.9. Rest pain is likely present if an ABI is between 0.2 and 0.4. Tissue
loss, ulcers, and gangrene are likely if an ABI is between 0 to 0.4.
Treating PVD often requires significant lifestyle changes that address the underlying risk factors,
such as quitting smoking, adopting healthy eating habits, and exercising regularly. Sometimes in
addition to these changes, people with PVD will also get certain medications that aim to reduce
the likelihood of blood clotting and obstruction of the blood vessels. Surgical intervention, like
angioplasty or bypass surgery, is rarely needed.

Heart failure: Clinical practice

Heart failure is when the heart can’t supply enough blood to meet the body’s demands.
A variety of heart diseases like ischemia and valvular disease can impair the heart’s ability to
pump out blood, and over time can lead to heart failure.
This can happen in two ways, either the heart’s ventricles can’t pump blood hard enough during
systole, called systolic heart failure, or not enough blood fills into the ventricles during diastole,
called diastolic heart failure.
In both cases, blood backs up, causing congestion or fluid buildup, which is why it’s also often
called congestive heart failure.
All right, so the heart needs to squeeze out a certain volume of blood each minute, called cardiac
output, which is the heart rate - or the number of beats in a minute - multiplied by the stroke
volume – or the volume of blood squeezed out with each heartbeat.
Then the ejection fraction is the portion of blood that’s pumped out of the left ventricle- in other
words the stroke volume divided by the total left ventricular volume.
The ejection fraction is normally around 50 to 70%, between 40 to 50% is borderline, and
anything below 40% is systolic heart failure or heart failure with reduced ejection fraction.
There’s also diastolic heart failure, or heart failure with preserved ejection fraction.
That’s where the heart has very thick ventricular walls so that the chamber doesn’t get an
adequate load of blood, so the heart is squeezing hard enough but not filling up enough.
In this case, the stroke volume is low, but the ejection fraction is normal.
All right, so heart failure can affect the right ventricle, the left ventricle, or both ventricles, so
biventricular heart failure, which defines where the failure is happening - and then there’s
systolic or diastolic failure, which defines why the failure is happening.
With left ventricular or left sided heart failure, blood gets backed up into the lungs, and that
causes pulmonary hypertension and pulmonary edema.
Because of differences in diffusion rates, all the extra fluid makes oxygenation harder, but
ventilation of carbon dioxide still works pretty well.
Patients often have dyspnea, as well as orthopnea or difficulty breathing when lying down flat.
That’s because lying flat allows more venous blood to flow back to the heart and into
the pulmonary circulation -worsening the congestion.
All this extra fluid in the lungs causes crackles or rales on auscultation.
A sign of severe left ventricular systolic failure is pulsus alternans, which is when there’s
alternating strong and weak peripheral pulses.
This occurs because the ejection fraction is significantly decreased, which in turn causes a
reduction in stroke volume, so more blood will remain in the ventricle.
As a result, during the next systole, the myocardial muscle will be stretched more than usual,
leading to an increase in myocardial contraction and a stronger systolic pulse.
Now with right ventricular or right sided heart failure, blood gets backed up in the body.
That can cause jugular venous distention, which can be seen with the patient sitting at 45 degrees
as the jugular vein having a fluid wave that represents the filling level.
Normally it should be less than 3 centimetres vertical height above the sternal angle, but in heart
failure it goes higher than that.
Blood can also back up into the liver and the spleen, and both can get enlarged.
Excess fluid can also move into the interstitial spaces near the surface of the liver and spleen, and
collect in the peritoneum, causing ascites.
Finally, fluid that backs up into the interstitial spaces within soft tissues in the legs causes
pitting edema.
That’s where applying pressure with a finger leaves a pit in the tissue for a few moments.
This mostly affects the legs, because gravity causes most of the fluid to “pool” there.
Now, since the ventricles work in series, left sided heart failure can also cause right-sided heart
failure, and more rarely, right sided heart failure will cause left sided heart failure as well, since
the backing up of blood in the venous system will affect the arterial system over time. So patients
often develop signs of both right and left sided heart failure.
Now, if the ventricles are stiffened or dilated, eventually the atria will also undergo remodeling
to adapt to the higher filling pressures.
For this reason, in heart failure, there’s often a third heart sound or S3 heard on auscultation,
which occurs after S1 and S2.
Finally, in advanced heart failure, there’s decreased tissue perfusion leading to a resting sinus
tachycardia, cool, pale, sometimes cyanotic extremities, and diaphoresis or excessive
sweating due to hypotension, as well as narrow pulse pressure due to the drop in
ventricular stroke volume.
On a chest X ray there might be changes like pulmonary edema or cardiomegaly, but there are no
specific signs that point directly to heart failure.
On an ECG, there might be clues about the underlying cause of heart failure like an arrhythmia
or evidence of coronary artery disease.
In a patient with any type of congestive heart failure, the key lab value is the brain natriuretic
peptide or BNP.
A BNP level above 400 pg/ml is typical in heart failure, between 100 and 400 pg/ml
is borderline, so further testing needs to be done, and below 100 pg/ml is unlikely to be heart
failure.
BNP levels can also be used to monitor a response to treatment as well.
Echocardiography is then done to confirm the diagnosis of heart failure.
It can estimate the ejection fraction, as well as measure ventricular wall and chamber size which
helps distinguish systolic versus diastolic heart failure.
It can also assess the heart valves and estimate the pulmonary arterial pressure, to help identify
causes and effects of the heart failure.
Finally, a cardiac catheterization is the insertion of a catheter into a chamber, valve, or vessel of
the heart.
This can be done to measure the pressure in the chambers, study valvular function, and can be
used to inject contrast media into the ventricles to perform ventriculography, which measures
the ejection fraction.
In addition, a coronary angiogram can be done to assess the coronary circulation to look for
evidence of myocardial ischemia.
After diagnosing heart failure, it should be classified.
A widely used classification schema is from the New York Heart Association, and is adopted by
the European Society of Cardiology.
There are four classes. Class I patients experience symptoms like dyspnea only after
extreme exertion.
Class II patients get symptoms with moderate exertion, class III patients get symptoms with
mild exertion, and class IV patients get symptoms at rest.
In terms of treatment, right sided heart failure is treated similarly to left sided heart failure,
especially because it’s often a result of left sided heart failure.
Long term management of heart failure includes management of underlying associated
conditions, lifestyle modifications, medications, and in some cases, using a device.
Associated conditions include hypertension, ischemic heart disease, valvular heart
disease, diabetes, thyroid dysfunction, and rheumatic fever.
Lifestyle modifications include not smoking, not drinking alcohol, reducing sodium intake, and
maintaining a healthy weight.
The goals of medications are to improve symptoms, slow or reverse deterioration in myocardial
function, and reduce mortality.
Medications are given according to the New York Heart Association class.
All classes must reduce sodium intake to less than 2 grams per day, and fluid intake to less than 2
liters per day. This helps reduce blood volume and pressure, which in turn reduces the heart
strain.
Additionally, all classes get a beta blocker and either an ACE inhibitor, or an angiotensin
receptor blocker or ARB if a patient develops a chronic cough from the ACE inhibitor.
With each increase in class we add another medication to the treatment.
Class II patients also get either a loop diuretic like furosemide, or a thiazide
diuretic like hydrochlorothiazide, to further reduce the fluid overload and relieve congestive
symptoms.
Class III patients also get aldosterone antagonists like spironolactone, or a combination
of isosorbide dinitrate and hydralazine as vasodilators, to lower their blood pressure.
Finally, class IV patients also get inotropes like digoxin, which increase the strength of heart
muscle contractions, and should get a heart transplant if possible.
All of these drugs need to be titrated, which means that treatment starts with a very low dose, and
then increases progressively up to the highest tolerable level.
If the patient has ischemic heart failure, aspirin and statins should be added to the therapy,
regardless of the New York Heart Association class.
In patients with a left ventricular ejection fraction below 35%, or in those with
recurrent ventricular tachycardia or malignant arrhythmias, an automatic implantable
cardioverter defibrillator or AICD should be used to reduce the risk of severe life threatening
arrhythmias and sudden cardiac death.
In these patients, if the ECG reveals a QRS complex that’s longer than 120 milliseconds, the
patient should have a cardiac resynchronization therapy or CRT pacemakers.
CRT pacemakers can stimulate the ventricles to contract at the same time and improve
the cardiac output.
But if the QRS complex is shorter than 120 milliseconds, then the CRT pacemaker is optional,
and medications like digoxin can be used to improve contractility.
Alternatively, a combination of arterial and venous vasodilator medications -
like nitroprusside and nitroglycerin respectively - can be used to help reduce the systemic and
pulmonary pressure, in turn reducing the heart’s strain.
If all other measures have failed, a final option is heart transplantation or implantation of a left
ventricular assist device or LVAD, which takes blood from the left ventricle and pumps it
through the aorta.
An LVAD can offer temporary relief for patients waiting for a heart transplant, or be a
permanent solution for others.
Then there’s also acute decompensated heart failure, which is when congestive heart
failure rapidly worsens, resulting in the need for urgent therapy.
If oxygen saturation falls below 90%, the patient may get supplemental oxygen, and below 80%
they may get assisted ventilation.
These patients may have such a reduced cardiac output that they can’t adequately perfuse the
kidneys, causing the kidneys to retain water - worsening the volume overload and pulmonary
congestion. So the goal is to rapidly reduce volume overload and reduce the pulmonary
congestion.
To do this, initial therapy includes intravenous loop diuretics.
Also intravenous vasodilator therapy can be helpful in patients with increased systemic vascular
resistance due to severe hypertension, acute mitral regurgitation, or acute aortic regurgitation.
These patients should be continually monitored in terms of their vital signs, volume status and
daily weight, electrolytes, and symptoms of pulmonary congestion.
In patients with reduced ejection fraction that show severe hypotension and end-organ
dysfunction, intravenous inotropic agents like dobutamine can be used.
However, inotropes are not indicated for treatment of acute decompensated heart failure in
patients with preserved ejection fraction.
Finally, for patients with ejection fraction lower than 25% and severe hemodynamic
compromise, mechanical cardiac support with either a ventricular assist device or an artificial
heart can be used.
The ventricular assist device helps the failing heart pump more efficiently, while the artificial
heart replaces it.

Summary
All right, as a quick recap, right sided heart failure typically causes jugular venous distention,
hepatosplenomegaly, ascites, and pitting edema on the legs.
Left sided heart failure typically causes dyspnea or orthopnea.
A BNP serum level is usually over 400, and echocardiography can estimate the ejection
fraction and assess the heart valves.
The New York Heart Association groups heart failure into four classes depending on severity of
symptoms.
Treatment of heart failure includes management of associated conditions and lifestyle
modifications like not smoking, not drinking alcohol, reducing sodium intake, and maintaining a
healthy weight.
Additionally, drug therapy is given according to the NYHA class - class I gets beta blockers
and ACE inhibitors or ARBs, class II also gets diuretics, class III also gets spironolactone or a
combination of isosorbide dinitrate and hydralazine, and class IV also gets inotropes.
Patients with a left ventricular ejection fraction below 35%, or those with recurrent ventricular
tachycardia or malignant arrhythmias can get device therapy.
If all other measures failed, a final option is heart transplantation.

Heart failure
Heart failure’s used to describe a point at which the heart can’t supply enough blood to meet
the body’s demands.
This can happen in two ways, either the heart’s ventricles can’t pump blood hard enough during
systole, called systolic heart failure, or not enough blood fills into the ventricles during diastole,
called diastolic heart failure.
In both cases, blood backs up into the lungs, causing congestion or fluid buildup, which is why
it’s also often known as congestive heart failure, or just CHF.
Congestive heart failure affects millions of people around the world and since it means that
the body’s needs are not being met, it can ultimately lead to death.
Part of the reason why so many people are affected by heart failure, is that there are a wide
variety of heart diseases like ischemia and valvular disease that can impair the heart’s ability to
pump out blood and—over time—can ultimately cause the heart to fail.
Alright, first up is systolic heart failure, kind of a mathematical way to think this one is that the
heart needs to squeeze out a certain volume of blood each minute, called cardiac output, which
can be rephrased as the heart rate (or the number of beats in a minute) multiplied by the stroke
volume (the volume of blood squeezed out with each heart beat).
The heart rate is pretty intuitive, but the stroke volume’s a little tricky.
For example, in an adult the heart might beat 70 times per minute and the the left ventricle might
squeeze out 70ml per beat, so 70 x 70 equals a cardiac output of 4900 ml per minute, which is
almost 5 liters per minute.
So notice that not all the blood was pumped out right?
And the stroke volume is only a fraction of the total volume.
The total volume might be closer to 110 ml, and 70ml is the fraction that got ejected out with
each beat, the other 40ml kind of lingers in the left ventricle until the next beat, right?
In this example, the ejection fraction would be 70ml divided by 110 ml or about 64%, a
normal ejection fraction is around 50-70%, between 40-50% would be considered borderline,
and anything about 40% or less would indicate systolic heart failure because the heart is only
squeezing out a little blood each beat.
So in our example, if the total volume of the left ventricle was 110 ml, but only 44 ml was
pumped out with each beat (then you have 44 ml divided by 110 ml which is 40%), and we
would say that this person is in systolic heart failure.
Now in addition to systolic heart failure, you’ve also got diastolic heart failure, which is where
the heart’s squeezing hard enough but not filling quite enough.
In this case again the stroke volume is low, but the ejection fraction’s normal...how’s that?
Well it’s not filling enough so there’s a low total volume, say about 69 mL, well even though
both are low, 44 ml divided by 69 ml is still 64%.
In this situation, the failure’s caused by abnormal filling of the ventricle so that the chamber
doesn’t get fully loaded or stretched out in the first place.
Another term for this is having a reduced “preload” which is the volume of blood that’s in the
ventricle right before the ventricular muscle contracts.
An important relationship between systolic and diastolic function is the Frank-Starling
mechanism, which basically shows that loading up the ventricle with blood during diastole and
stretching out the cardiac muscle makes it contract with more force, which increases stroke
volume during systole.
This is kinda like how stretching out a rubber band makes it snap back even harder, except
that cardiac muscle is actively contracting whereas the rubber band is passively going back to its
relaxed state.
Alright, so heart failure can affect the right ventricle, or the left ventricle, or both ventricles, so
someone might have, right-sided heart failure, left-sided heart failure, or both (which is called
biventricular heart failure), each of which can have systolic or diastolic failure.
Having said that, if less blood exits either ventricle it’ll affect the other since they work in series,
so left-sided could cause right-sided, and vice versa, so these terms really refer to the primary
problem affecting the heart, basically which one was first.
Usually left-sided heart failure is caused by systolic (or pumping) dysfunction.
And, this is typically due to some kind of damage to the myocardium—or the heart muscle—
which means it can’t contract as forcefully and pump blood as efficiently.
Ischemic heart disease caused by coronary artery atherosclerosis, or plaque buildup, is the most
common cause.
In this case, less blood and oxygen gets through the coronary artery to the heart tissue, which
damages the myocardium.
Sometimes, if the coronary’s blocked completely and the person has a heart attack, they might be
left with scar tissue that doesn’t contract at all, which again means the heart can’t contract as
forcefully.
Longstanding hypertension is another common cause of heart failure.
This is because as arterial pressure increases in the systemic circulation, it gets harder for the left
ventricle to pump blood out into that hypertensive systemic circulation.
To compensate, the left ventricle actually bulks up, and its muscles hypertrophy, or grow so that
the ventricle can contract with more force.
The increase in muscle mass also means that there is a greater demand for oxygen, and, to make
things even worse, the coronaries get squeezed down by the this extra muscle so that even less
blood’s delivered to the tissue.
More demand and reduced supply means that some of the ventricular muscle starts to have
weaker contractions—leading to systolic failure.
Another potential cause would be dilated cardiomyopathy, where the heart chamber dilates, or
grows in size in an attempt to fill up the ventricle with larger and larger volumes of blood,
or preload, and stretch out the muscle walls and increase contraction strength, via the Frank-
Starling mechanism.
Even though this can actually work for a little while, over time, the muscle walls get thinner and
weaker, eventually leading to muscles that are so thinned out that it causes systolic left-sided
heart failure.
Ultimately the ventricle walls need to be the right size relative to the size of the chamber in order
for the heart to work effectively. Any major deviation from that can lead to heart failure.
Alright, even though systolic failure is most common in left-sided heart failure, diastolic heart
failure or filling dysfunction can also happen.
In hypertension, remember how the left ventricular hypertrophied?
Well that hypertrophy is concentric, which means that the new sarcomeres are generated in
parallel with existing ones.
This means that as the heart muscle wall enlarges, it crowds into the ventricular chamber space,
resulting in less room for blood, meaning that in addition to contributing to systolic
dysfunction, hypertension also can cause diastolic heart failure.
Concentric hypertrophy leading to diastolic failure can also be caused by aortic stenosis, which is
a narrowing of the aortic valve opening, as well by hypertrophic cardiomyopathy, an abnormal
ventricular wall thickening often from a genetic cause.
Restrictive cardiomyopathies are yet another cause.
In this case the heart muscle gets stiffer and less compliant, and therefore the left ventricle can’t
easily stretch out and fill with as much blood, which leads to diastolic heart failure.
When the heart doesn’t pump out as much blood, there’s decreased blood flow to the kidneys,
which activates the renin-angiotensin-aldosterone system, ultimately causing fluid retention.
Which fills the heart a bit more during diastole and increases preload, which increases
contraction strength again by the Frank Starling mechanism.
Unfortunately, just like the other strategies, in the long term, retaining fluid so that more fluid
remains in the blood vessels typically leads to a large portion of it leaking into the tissues and
can contribute to fluid buildup in the lungs and other parts of the body, which can worsen the
symptoms of heart failure.
Aright so a major, major clinical sign of the heart not being able to pump enough blood forward
to the body, is that blood starts to back up into the lungs.
A backup of blood in the pulmonary veins and capillary beds can increase the pressure in
the pulmonary artery and can also result in fluid moving from the blood vessels to the interstitial
space causing pulmonary edema, or congestion.
In the alveoli of the lungs, all this extra fluid makes oxygen and carbon dioxide exchange a lot
harder, since a wider layer of fluid takes more time for oxygen and carbon dioxide to diffuse
through, and therefore patients have dyspnea—trouble breathing, as well as orthopnea - which
is difficulty breathing when lying down flat since that allows venous blood to more easily flow
back from the legs and the gut to the heart and eventually into the pulmonary circulation.
This extra fluid in the lungs causes crackles or rales to be heard on auscultation while the patient
breathes.
If enough fluid fills some of these capillaries in the lungs, they can rupture, leaking blood into
the alveoli.
Alveolar macrophages then eat up these red blood cells, which causes them to take on this
brownish color from iron build-up.
And then they’re then called “hemosiderin-laden macrophages”, also known as “heart
failure cells”.
For left-sided heart failure, certain medications can be prescribed to help improve blood flow,
like ACE inhibitors which help dilate blood vessels, as well as diuretics to help reduce the
overall fluid buildup in the body which helps prevent hypertension from worsening the heart
failure.
Now let’s switch gears and think about right-sided heart failure, which is actually often caused
by left-sided heart failure.
K remember how fluid buildup increased pressure in the pulmonary artery?
Well this increased pulmonary blood pressure makes it harder for the right side to pump blood
into.
In this case the heart failure would be biventricular, since both ventricles are affected.
Someone can also have isolated right-sided heart failure, though, and an example of this would
be a left-to-right cardiac shunt.
In these cases, there might be a cardiac shunt like an atrial septal defect or a ventricular septal
defect, that allows blood to flow from the higher-pressure left side to the lower-pressure right
side, which increases fluid volume on the right side and can eventually lead to concentric
hypertrophy of the right ventricle, making it more prone to ischemia—which is a systolic
dysfunction, and have a smaller volume and become less compliant—which is a diastolic
dysfunction.
Another potential cause of isolated right-sided failure is chronic lung disease.
Lung diseases often make it harder to exchange oxygen, right?
Well in response to low oxygen levels, or hypoxia, the pulmonary arterioles constrict, which
raises the pulmonary blood pressure.
This, just like before, makes it harder for the right side of the heart to pump against and can lead
to right-sided hypertrophy and heart failure.
When chronic lung disease leads to right-sided hypertrophy and failure, it’s known as cor
pulmonale.
With left-sided failure, blood gets backed up into the lungs.
With right-sided failure, blood gets backed up to the body, and so patients have congestion in
the veins of the systemic circulation.
One common manifestation of this is jugular venous distention, where the jugular vein that
brings blood back to the heart takes on more blood and becomes enlarged and distended in the
neck.
Also in the body, when blood backs up to the liver and the spleen, fluid can move into the
interstitial spaces within those organs and they can become enlarged, called hepatosplenomegaly,
which can be painful, and if the liver is congested for long periods of time, patients can
eventually develop cirrhosis and liver failure, which would be called cardiac cirrhosis.
Excess interstitial fluid near the surface of the liver and spleen can also move right out into
the peritoneal space as well, and since that cavity can take a lot of fluid before there is any
increase in pressure, a lot of fluid can build up in the peritoneal space which is called ascites.
Finally, fluid that backs up into the interstitial space in the soft tissues of the legs causes
pitting edema, where the tissue is visibly swollen and when you apply pressure to it it leaves a
“pit” and takes awhile to come back to its original place.
This generally affects the legs in most people, because gravity generally causes the majority of
fluid to “pool” in the dependent parts of the body, which is the legs when you’re standing and
the sacrum, essentially the lower back, when you’re lying down.
Right-sided heart failure will be treated similarly to left-sided heart failure, especially because
it’s often a result of left-sided heart failure.
Therefore, medications like ACE inhibitors and diuretics may be prescribed.
With heart failure, we saw that sometimes the muscle wall can stretch and thin out, or sometimes
it can sometimes thicken and become ischemic.
In either case, those heart cells get irritated, and this can lead to heart arrhythmias.
With an arrhythmia, the ventricles don’t contract in sync anymore making them less able to
pump out blood and worsening the whole situation.
In some cases, patients might be treated with cardiac resynchronization therapy pacemakers,
which can stimulate the ventricles to contract at the same time and potentially improve the blood
pumped out.
Alternatively, for heart failure in general, some people might have ventricular assist devices
implanted, or VADs, which literally assist or help the heart pump blood.
In end-stage situations where other forms of treatment have failed, patients might have a heart
transplant.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-
Hill Education / Medical (2018)
4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education /
Medical (2019)
5. "The Impact of Frailty and Comorbidities on Heart Failure Outcomes" Cardiac
Failure Review (2022)
6. "Effects of Digoxin in Heart Failure (HF) With Reduced Ejection Fraction
(EF)" Cureus (2022)
7. "Advanced heart failure: guideline‐directed medical therapy, diuretics, inotropes,
and palliative care" ESC Heart Failure (2022)

Heart failure: Pathology review

On the cardiology ward, there were two people who had been admitted to the hospital repeatedly.
The first one is 70 year old Lidia, who had a myocardial infarction about 3 years ago.
She presents with fatigue, and dyspnea.
She says that she usually wakes up at night because of shortness of breath, but using more
pillows when sleeping helps relieve it somewhat.
On examination, she has pitting edema in her legs and on auscultation, an S3 sound is heard.
The other person is 81 year old Richard who has been a smoker for the past 50 years.
He is also experiencing fatigue, and has pitting edema, but on further examination, there’s also
jugular venous distention and hepatomegaly.
Okay, so, both these individuals suffer from heart failure.
Heart failure is a clinical syndrome used to describe the inability of the heart to pump enough
blood or a point at which the heart can’t supply enough blood to meet the body’s demands.
This can happen in two ways, either the heart’s ventricles can’t pump blood hard enough during
systole, called systolic heart failure, or not enough blood fills into the ventricles during diastole,
called diastolic heart failure.
In both cases, blood backs up into the lungs, causing congestion or fluid buildup, which is why
it’s also often known as congestive heart failure, or just CHF.
Alright, first up is systolic heart failure.
One way to think about this is that the heart needs to squeeze out a certain volume of blood each
minute, called cardiac output, which can be calculated as the heart rate multiplied by the stroke
volume.
The heart rate is pretty intuitive, but the stroke volume is a little tricky.
For example, an adult heart might beat 70 times per minute and the left ventricle might squeeze
out 70ml per beat, so 70 x 70 equals a cardiac output of 4900 ml per minute, which is almost 5
liters per minute.
Now, the stroke volume is only a fraction of the total volume.
The total volume might be closer to 110 ml, and 70ml is the fraction that got ejected out with
each beat, the other 40ml kind of lingers in the left ventricle until the next beat.
In this example, the ejection fraction would be 70ml divided by 110 ml or about 64%, a
normal ejection fraction is around 50-70%.
Now, in systolic heart failure, there’s decreased contractility of the left ventricle, which causes a
decreased cardiac output because the stroke volume is low.
This means there’s also a decreased ejection fraction.
During diastole blood returns to the ventricles and combines with the leftover blood that didn’t
get pumped out during systole, and this is called the EDV or end diastolic pressure volume.
With systolic heart failure, don’t forget that EDV is high, because there’s more blood leftover
after each heartbeat.
Regarding the end diastolic pressure or EDP, which is the pressure that’s found in the ventricle at
the end of diastole, this will also be high, because the volume at the end of diastole is high as
well.
Systolic heart failure is mainly caused by low contractility which can happen
with ischemia caused by myocardial infarction, where a part of the cardiac tissue is damaged so
it won’t contract properly anymore.
Another cause is dilated cardiomyopathy, where the ventricle is dilated and weakened.
Now in addition to systolic heart failure, you’ve also got diastolic heart failure, which is where
the cardiac contractility is sufficient but not enough blood is returning to the ventricles.
In this case, again, the stroke volume is low, but the ejection fraction is normal.
So for example, the total volume might be lower than normal, say about 69 mL, and we pump
out 44 mL, so if we divided 44 by 69, we get 64%, which is in the normal range.
With diastolic heart failure, we need to look at the end diastolic pressure, or the EDP, as well.
The problem is that the left ventricle isn’t compliant enough, so when the ventricle is filling
during diastole, the pressure within will rise, so keep in mind that EDP is elevated
during diastolic heart failure.
Also remember that with diastolic heart failure, EDV is normal, at least in the beginning, because
the atria are capable of squeezing more blood into the ventricle.
One cause of diastolic heart failure is ventricular hypertrophy, where the
ventricular myocardium gets thicker, and this decreases the ability of the chamber to stretch
when filling.
Alright, so heart failure can be systolic or diastolic and can affect the right ventricle, or the left
ventricle, or both ventricles, which is called biventricular heart failure.
Having said that, if less blood exits either ventricle it’ll affect the other since they work in series.
So these terms really refer to the primary problem affecting the heart, basically which one was
first.
For your exams, it’s important to remember that the main cause of right heart failure is left heart
failure.
When right heart failure isn’t caused by left heart failure, but by a pulmonary cause, we refer to
this as cor pulmonale.
In terms of symptoms, in left heart failure the blood starts to back up into the lungs, specifically
in the pulmonary veins and capillary beds which can increase the pressure in these vessels.
This leads to fluid moving from the blood vessels to the interstitial space causing pulmonary
edema, or congestion.
This is a very important sign and must be remembered!
In the alveoli of the lungs, all the extra fluid makes oxygen and carbon dioxide exchange a lot
harder, and therefore patients have dyspnea or trouble breathing.
Another symptom is orthopnea, which is difficulty breathing when lying down flat.
This is because there’s more venous return from the legs and the gut to the heart, which increases
the amount of blood backing up into the pulmonary circulation.
This also explains why these people experience paroxysmal nocturnal dyspnea, which is when
the sensation of not being able to breathe wakes a person at night.
Such individuals often sleep using more pillows in order to keep their upper body a bit elevated.
This will lower the venous return and ease lung congestion.
The extra fluid in the lungs causes crackles or rales on auscultation.
If enough fluid fills the capillaries in the lungs, they can rupture, causing blood to leak into
the alveoli.
Alveolar macrophages then eat up these red blood cells, which causes them to take on this
brownish color from iron build-up.
And then they’re called “hemosiderin-laden macrophages”, also known as “heart failure cells”.
Next, since there’s decreased cardiac output, not enough blood is reaching vital organs. As a
result, an individual with heart failure may also present with fatigue.
Decreased blood flow to the kidneys activates the renin-angiotensin-aldosterone system, which
will increase sodium and water reabsorption in the kidneys, ultimately causing fluid retention.
You’d think this is good, because it increases blood volume which increases end diastolic
volume and based on the frank starling mechanism, it will increase contractility.
Unfortunately, in the long term large portions of this extra fluid will end up leaking into the
tissues, which worsens the pulmonary edema and it will also lead to peripheral edema.
This is sometimes called “pitting edema” because the tissue is visibly swollen and when you
apply pressure to it - it leaves a “pit.”
Apart from this, the low cardiac output will also activate the sympathetic nervous system, which
increases left ventricle contractility, but also activates the renin-angiotensin-aldosterone system.
Finally, an important thing to remember is that with left heart failure, on auscultation, you can
hear an extra sound, either S3, or, less commonly, S4. S3 is a low-pitched sound that comes right
after S2.
This occurs when there’s a lot of blood filling of the ventricle rapidly.
Normally, you wouldn't hear this, but in systolic heart failure, the ventricle is overly compliant,
allowing more blood to gush into the chamber, so S3 is also called ventricular gallop.
S4, on the other hand, comes right before S1.
Once again, this is normally not heard, but in diastolic heart failure, when the ventricles are extra
stiff, the atria have to contract extra hard to push that blood in, when this blood is forcefully
pushed into the ventricle and hits the chamber wall, it produces a S4, or atrial gallop.
Now let’s switch gears and talk about right-sided heart failure, and remember, the most common
cause is left heart failure.
Since left heart failure increases the pressure in the pulmonary artery, this will make it harder for
the right ventricle to pump blood into it.
Other causes of right-sided heart failure include chronic lung disease.
Lung diseases, such as emphysema or pulmonary embolism, make oxygen exchange harder.
In response to low oxygen levels, or hypoxia, the pulmonary arterioles constrict, and the
pulmonary blood pressure rises.
This makes it harder for the right side of the heart to pump against and can lead to right-sided
hypertrophy and heart failure.
In right-sided heart failure, blood gets backed up to the body, and so individuals will have
congestion in the veins of the systemic circulation.
One common manifestation of this is jugular venous distention, where the jugular vein that’s
relatively close to the heart becomes enlarged and distended.
Also in the body, when blood backs up to the liver, it causes venous congestion there and
eventually, fluid can move into its interstitial spaces, causing the liver to become enlarged, which
is called hepatomegaly.
There’s a special name for this particular type of hepatopathy, called congestive hepatopathy.
On pathology, there’s a so called “nutmeg liver”, because you can see the congested
hepatic venules and veins as dark spots and it actually looks like a grated nutmeg!
If the liver is congested for long periods of time, patients can eventually develop cirrhosis and
liver failure, which is called cardiac cirrhosis.
Finally, fluid that backs up into the interstitial space in the soft tissues of the legs causes
pitting edema.
In terms of treatment, a high-yield topic for your exams is the list of medications that decrease
mortality and slow down the progression of heart failure.
This includes Angiotensin-converting enzyme or ACE inhibitors, Angiotensin Receptor
Blockers or ARBs, aldosterone receptor antagonists, like spironolactone, and certain beta
blockers, specifically carvedilol, bisoprolol and metoprolol.
Bear in mind though that beta blockers must be used with caution in decompensated heart
failure, which is when heart failure rapidly worsens.
That’s because of their ability to decrease heart rate and their negative inotropic effect, meaning
that they decrease the force of heart’s contraction.
Also, a new type of mortality decreasing medication are the neprilysin inhibitors.
These work by inhibiting neprilysin, an enzyme that breaks down the helpful endogenous
peptides that normally promote urine sodium excretion and vasodilation.
In contrast, thiazide or loop diuretics may be used to relieve symptoms by reducing the overall
fluid buildup in the body.
And then, hydralazine combined with nitrates, as vasodilators, has been shown to improve both
symptoms and mortality in select patients.

Summary
Okay, let’s review! Heart failure is a clinical syndrome where the heart is unable to pump
enough blood or a point at which the heart can’t supply enough blood to meet the body’s
demands.
This can happen in two ways, either the heart’s ventricles can’t pump blood hard enough during
systole, called systolic heart failure, or not enough blood fills into the ventricles during diastole,
called diastolic heart failure.
Heart failure can affect the right ventricle, or the left ventricle, or both ventricles.
If less blood exits either ventricle it’ll affect the other since they work in series, so left-sided
could cause right-sided, and vice versa, so these terms really refer to the primary problem
affecting the heart, basically which one was first.
Actually, the main cause of right heart failure is left heart failure.
When right heart failure isn’t caused by left heart failure, but by a pulmonary cause, we refer to
this as cor pulmonale.
Now, since both ventricles are affected, let’s remember that symptoms of heart
failure include dyspnea, orthopnea, fatigue due to low perfusion, rales, jugular venous distention,
pitting edema, and an S3 or rarely an S4 heart sound on auscultation.
Treatment includes medications that decrease mortality and ones that are used for symptom
relief.
Now, back to our cases! Lidia came in with a history of myocardial infarction.
She’s experiencing fatigue, shortness of breath.
Examination shows pitting edema and an S3 sound.
An echocardiogram showed that her ejection fraction was pretty low, which indicates systolic
heart failure.
Her other symptoms point towards a left heart failure and the key symptoms
were dyspnea, paroxysmal nocturnal dyspnea and orthopnea.
Next is 81 year old Richard, who presents with fatigue, pitting edema, jugular venous distention
and hepatomegaly.
His echocardiogram showed that his ejection fraction is normal, but there’s hypertrophy in
his right ventricle.
This and his symptoms like jugular venous distention and hepatomegaly point towards right-
heart failure with a pulmonary cause.
Now, since Richard has been a smoker for the past 50 years, pulmonary emphysema could be the
cause of his right-sided heart failure, so the next steps involve doing a chest X-
ray and spirometry.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Heart failure" Lancet (2005)
4. "Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement
From the American Heart Association" Circulation (2018)
 5. "2013 ACCF/AHA guideline for the management of heart failure: a report of the
American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines"  J Am Coll Cardiol (2013)

Angina pectoris
Angina comes from the latin angere, which means to strangle, and pectoris comes from pectus,
meaning chest—so angina pectoris loosely translates to “strangling of the chest”, which actually
makes a lot of sense, because angina pectoris is caused by reduced blood flow which
causes ischemia to the heart muscle, or lack of oxygen to the heart, almost like the heart’s being
strangled which causes terrible chest pain.
Stable angina or chronic angina is the most common type of angina and it usually happens when
the patient has greater than or equal to 70% stenosis, meaning 70% of the artery is blocked by
plaque buildup.
This small opening that blood flows through might be enough to supply the heart during rest, but
if the body demands more blood and oxygen, like during exercise or stressful situations, the heart
has to work harder, and therefore needs more blood and oxygen itself.
It’s during these time of exertion or emotional stress that people with stable angina have chest
pain, since the blood flow isn’t meeting the metabolic demands of the heart muscle,
or myocardium.
But the pain usually goes away with rest.
In the majority of cases, the underlying cause of stable angina is atherosclerosis of one or more
the coronary arteries—arteries supplying blood to the heart muscles.
Other heart conditions that might lead to stable angina are ones that cause a thickened heart
muscle wall, which would require more oxygen.
This increase in muscle size can be due to hypertrophic cardiomyopathy from a genetic cause, or
as a result from the heart having to pump against higher pressures, as is the case in aortic
stenosis, which is a narrowing of the aortic valve, or hypertension.
These larger, thicker heart muscles require more oxygen, and if the patients can’t meet increasing
demands, they feel pain in the form of angina.
Whatever the case, the heart needs blood, and if we look at the heart wall, there’s three layers—
the outermost layer, the epicardium, then the myocardium in the middle, and
the endocardium inside the heart.
The coronary arteries start up in the epicardium, and then dive down and supply all the heart
tissue.
If blood flow’s reduced or the myocardium is thicker, blood has a harder time reaching this
deeper layer just under the endocardium, called the subendocardium.
Therefore the classic finding with angina is subendocardial ischemia, meaning less oxygen is
reaching the region just under the endocardium.
This ischemia is thought to trigger release of adenosine, bradykinin, and other molecules that
stimulate nerve fibers in the myocardium that result in the sensation of pain.
That chest pain is usually described as feeling like pressure or squeezing and it can radiate to the
left arm, jaw, shoulders, and back, and sometimes is accompanied by shortness of
breath and diaphoresis or sweating.
Usually the pain and symptoms last less than 10 minutes, generally 2 to 5 minutes, and subside
after the exertion or stress is taken away, and therefore the heart muscle isn’t demanding as much
blood.
Now, unlike stable angina which describes when patients have pain only during periods
of exertion or stress, but not during rest, there is also unstable angina which is when patients
have pain during exercise or stress as well as during rest—it never really goes away.
Unstable angina is usually caused by rupture of atherosclerotic plaque with thrombosis, meaning
a blood clot forms on top of a mound of plaque.
Although the occlusion might not block the entire vessel, there is now even less room left for
blood to flow by, and the heart tissue is starting to feel starved for oxygen even while pumping at
a normal rate.
Unstable angina, for the same reason as stable angina, involves subendocardial ischemia and it
should be treated as an emergency, because patients are at a high risk of progressing
to myocardial infarction, or heart attack.
The key distinction is that unstable angina means that the heart tissue is alive but ischemic or
starving for oxygen, whereas myocardial infarction means that the areas of heart tissue have
already begun to necrose or die.
Now a third type of angina is vasospastic angina, also known as prinzmetal angina, and patients
may or may not also have atherosclerosis.
Ischemia, and resulting chest pain is due to coronary artery vasospasms, meaning the smooth
muscles around the arteries constrict extremely tightly and reduce blood flow enough to
cause ischemia.
Episodes of vasospastic angina don’t correlate with exertion and can happen anytime, including
at rest.
The underlying mechanism causing vasospasms isn’t well understood, but likely
involves vasoconstrictors like platelet thromboxane A2.
Unlike both stable and unstable angina, in this case the coronary artery’s constricted so severely
that all layers of the heart wall being supplied are affected, therefore it’s referred to as
transmural ischemia.
Alright, so if we line these three up side-to-side, there’s some important clinical similarities and
differences.
First, it’s super important to remember that in each case, the injury to cardiomyocytes isn’t
permanent, meaning it’s reversible and the cardiomyocytes don’t die (which is how this differs
from myocardial infarction).
On an electrocardiogram, or ECG, both stable and unstable angina show an ST-
segment depression since ischemia’s limited to the subendocardium.
In contrast, vasospastic angina shows ST-segment elevation due to transmural ischemia.
Rest tends to relieve stable angina, whereas unstable angina and vasospastic angina can occur
anytime, including at rest.
In terms of medications, all three can be treated with Nitroglycerin which is a vasodilator that
increases blood vessel diameter to allow more blood flow.
In addition, vasospastic angina also responds to calcium channel blockers.

Summary
All right, as a quick recap…. Angina pectoris is chest pain caused by reduced blood
flow resulting in a lack of oxygen in the heart muscle.
There are three types: stable angina, unstable angina, and vasospastic angina.
Rest tends to relieve stable angina, but not the other two types, and all three can be treated
with nitroglycerin.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-
Hill Education / Medical (2018)
4. "Pathogenesis of angina pectoris"  (1982)
5. "Unstable angina pectoris: Pathogenesis and management" Current Problems in
Cardiology (1989)
6. "Management of Chronic Stable Angina" Critical Care Nursing Clinics of North
America (2017)

Hypertension: Clinical practice

Hypertension, or high blood pressure, affects over a billion people around the world.
Now, ‘normal’ systolic blood pressure is defined as less than 120 mmHg, and normal diastolic
pressure is less than 80 mmHg.
Elevated blood pressure is when systolic blood pressure is between 120 and 129 mmHg and less
than 80 mmHg on the diastolic side.
Stage 1 hypertension is between 130 and 139 mmHg on the systolic side, and between 80 and 89
mmHg on the diastolic side.
Stage 2 hypertension is defined as anything that is 140 mmHg or higher on the Systolic side and
90 mmHg or higher on the diastolic side.
Typically, both systolic and diastolic pressures tend to rise or fall together, but that’s not always
the case.
Sometimes, you can have systolic or diastolic hypertension, when one number is normal and the
other is really high. This is referred to as isolated systolic hypertension or isolated
diastolic hypertension.
There are two main types of blood pressure measurements - office blood pressure, which is taken
in a clinic, emergency department, or hospital, and an out-of-office blood pressure.
The out-of-office blood pressure is either a home blood pressure, which is taken by the patient at
home, or an ambulatory blood pressure monitoring or ABPM, which involves 24-hour
monitoring of blood pressure as the patients live their normal daily life, and while they sleep, to
see if the blood pressure falls at night compared to during the day. It uses a small digital blood
pressure machine that is attached to a belt around the body and it’s connected to a cuff around
the upper arm.
Ambulatory blood pressure monitoring is the best way to diagnose hypertension, but it’s not
always feasible, so it’s usually done when office and home blood pressure measurements are
really discordant from one another.
Now, the first step for an office blood pressure, is to make sure that the patient has rested for at
least five minutes and is positioned properly - sitting with their arms and back supported, and
their feet flat on the floor. And the measurement should be repeated at least twice.
Most of the time, blood pressure is taken in the brachial artery in the upper arm, because if the
pressure is high there, it’s probably high throughout the arteries.
And keep in mind that just being in the office can cause blood pressure to change.
In white coat hypertension - a person’s blood pressure rises, and in masked hypertension - a
person’s blood pressure falls.
So, the diagnosis of hypertension should be done by looking at both office and out-of-
office blood pressure measurements.
The second step is taking the patient’s history and physical examination.
Now, there are two main types of hypertension - primary or essential hypertension has no clearly
identifiable underlying reason, and secondary hypertension, which does have a specific,
identifiable underlying condition.
Primary hypertension is way more common, and it generally isn’t accompanied by symptoms.
It’s sometimes called a “silent killer”, because over time, pressure in the arteries silently creeps
up, and causes blood vessel damage which is a risk factor for serious problems, like myocardial
infarctions, aneurysms, and strokes.
Risk factors for primary hypertension include: old age, obesity, family history, a salt-heavy diet,
a sedentary lifestyle, heavy alcohol consumption, smoking, and race - for example, people of
african descent are more likely to develop hypertension.
And some of these risk factors can be improved with lifestyle changes that can help
reduce hypertension.
Now, secondary hypertension often is accompanied by a variety of symptoms associated with the
underlying cause.
In general, the younger the patient, the more likely it’s secondary hypertension.
For example, anything that limits the renal blood flow can cause hypertension, like
fibromuscular dysplasia, which generally affects young women, but also atherosclerosis in older
patients. Other examples include obstructive sleep apnea, atherosclerosis, vasculitis, or aortic
dissection, as well as pheochromocytoma, Cushing’s syndrome, and other endocrine disorders.
It’s also important to identify signs of end-organ damage, and whether the patient takes any
medications or exogenous substances that can worsen hypertension, sympathomimetic agents
like decongestants or even cocaine, cyclosporine or tacrolimus, sodium-containing antacids,
stimulants like amphetamines, atypical antipsychotics like clozapine, antidepressants, oral
contraceptives, erythropoietin, and even NSAIDS and liquorice - that delicious chewy black
candy!
A basal metabolic panel and electrocardiography should be performed to screen for secondary
forms of hypertension.
Management for hypertension is mainly based on the hypertension stage, risk of developing
cardiovascular events and organ damage, as well as taking into account any concomitant
diseases, such as diabetes or chronic kidney disease.
Lifestyle changes are crucial for all patients, especially in the long term, and include things
like quitting smoking, drinking alcohol in moderation, maintaining a healthy weight, reducing
dietary sodium, and staying physically active.
Not all patients with hypertension need antihypertensive drug therapy.
In fact, medication is generally suggested for only patients with out-of-office daytime blood
pressures higher than 135mm Hg systolic or higher than 85 mmHg diastolic, or an average
office blood pressure higher than 140/90 mmHg if out-of-office readings aren’t available. It’s
also recommended for patients with an out-of-office blood pressure higher than 130 mmHg
systolic or 80 mmHg diastolic or, if out-of-office readings are unavailable, or an average
office blood pressure higher than 130 mmHg systolic or 80 mmHg diastolic who also have other
features.
Specifically they need to have at least one of the following: cardiovascular disease, type 2
diabetes mellitus, chronic kidney disease, be over 65 years old, or have an elevated risk
of coronary artery disease.
On the flip side, it’s generally recommended not to give antihypertensive medication to patients
with stage 1 hypertension and are either over age 75 years old or have no organ damage.
There are four main classes of medications that are used to treat hypertension, ACE
inhibitors, Angiotensin Receptor Blockers or ARBs, thiazide diuretics, and long-acting calcium
channel blockers like dihydropyridine.
There is a lot of variability in terms of how individuals respond to different medications, so it’s
important to follow up to see how the medications are working.
Usually, therapy begins by choosing one medication.
Broadly speaking, ACE inhibitors are started in patients at high risk for coronary artery disease,
including those with a prior STEMI, heart failure, asymptomatic left
ventricular dysfunction, diabetes, and chronic kidney disease.
A common side effect of ACE inhibitors is chronic cough, so ARBs are often started in patients
who don’t tolerate ACE inhibitors, mostly because of cough.
Thiazide diuretics and calcium channel blockers show very similar efficacy to ACE inhibitors,
and they’re first line therapy in patients of african descent. But diuretics have a lot
of metabolic effects, so they can’t be given to patients with high blood glucose
and cholesterol levels.
The blood pressure goal while on medications varies based on the initial blood pressure, age, and
other health conditions.
But, in general, it’s ideal to have an out-of-office blood pressure below 135/85 mmHg and an
office blood pressure below 140/90 mmHg.
If the blood pressure isn’t improving within a month, then the dose is usually increased or a
second medication from a different class is often started.
Some combinations are useful, while others aren’t. ACE inhibitors and ARBs should not be
combined; and instead either can be combined with a thiazide diuretic or a calcium channel
blocker.
In some cases, diuretics may be combined with beta blockers.
If blood pressure is not kept under control after combining two medications, then an ACE
inhibitor or ARB should be combined with both a thiazide diuretic and a calcium channel
blocker.
If a thiazide diuretic isn’t well tolerated or is contraindicated - for instance in patients
with metabolic conditions - then a mineralocorticoid receptor antagonist
like spironolactone or eplerenone can be used instead. And if those medications also can’t be
used because it isn’t well tolerated or is contraindicated, then a beta blocker can be used.
If the blood pressure isn’t controlled with a combination of three antihypertensive medications,
including a diuretic, then it’s considered drug-resistant hypertension.
Oftentimes, patients with hypertension feel pretty well and forget to take
their hypertension medications. That’s why regimens of daily pills have got better medication
adherence as compared to twice daily pills.
In fact, when there’s a patient with drug-resistant hypertension, it’s important to confirm that
they are actually taking the medication.
Finally, if the blood pressure gets really high, really fast, it’s called a hypertensive crisis.
In hypertensive crisis, either the systolic pressure is greater than 180 mmHg or the diastolic
pressure is greater than 120 mmHg.
Hypertensive crisis can be further split into hypertensive urgency and hypertensive emergency.
With hypertensive urgency, there hasn’t yet been damage to end organs like the brain, kidneys,
heart, and lungs.
In hypertensive emergency, there is damage to end organs, and patients can have symptoms like
confusion, drowsiness, chest pain, and dyspnea.
The most common cause of hypertensive crisis is not taking antihypertensive medications, but it
can also be due to causes of secondary hypertension like renovascular
disease, pheochromocytoma, hyperaldosteronism, and erythropoietin intake.
For treatment, it’s important to gradually reduce the blood pressure over 1 to 2 days, to make
sure that the brain never gets underperfused.
Treatment of a hypertensive urgency is done with oral medications like ACE inhibitors.
On the other hand, in a hypertensive emergency, the goal is to lower the mean arterial pressure
by 20% within the first hour, and treatment is given intravenously with medications like beta
blockers, calcium channel blockers, and vasodilators like nitroprusside or nitroglycerin.

Summary
All right, as a quick recap. Stage 1 hypertension is defined as 130 to 139 mmHg for the systolic
blood pressure and between 80 to 89 mmHg for the diastolic pressure, while Stage 2
hypertension is defined as greater than 140 mmHg on the systolic side and greater than 90
mmHg on the diastolic side.
Hypertension usually doesn’t cause any symptoms, and the first line of treatment is lifestyle
changes, like changes to the diet, exercise, and stress reduction.
In addition, drug therapy may be given to patients with really high blood pressure or risk of
adverse events.
The four main medication classes used are ACE inhibitors, ARBs, thiazide diuretics, and long-
acting calcium channel blockers like dihydropyridine.
Hypertension: Pathology review
Anthony is a 40 year old male with a history of type 2 diabetes mellitus presenting to a family
medicine clinic for his annual health check-up. His blood pressure measurement is 145 over 95
millimeters of mercury, and his BMI is 32. On further history, he explains that his job as a truck
driver has prevented him from exercising regularly. His father had a history of hypertension and
passed away from a stroke. A follow-up appointment showed a blood pressure of 150 over 90.
Alicia is a 30 year old female who came in because she’s concerned that she might be pregnant.
Her pregnancy test is negative, however, her blood pressure is 170 over 90. On her second
appointment, her blood pressure remains elevated. She is placed on lisinopril. A couple of days
later, she presents with decreased urine output, and an elevated blood urea nitrogen and
creatinine. Finally, Vikander is a 62 year old-male with a history of hypertension. He complains
of headache, altered mental status, and visual changes. On further history, he mentions he is
“sick of all the medications he has to take”. Fundoscopic examination reveals a swollen optic
disk, and his blood pressure is 200 over 120.
Okay so all three people present with hypertension. Now normal blood pressure is less than 120
systolic over 80 diastolic. According to the recent 2017 American Heart Association and
American College of Cardiology guidelines, hypertension is currently defined as a blood
pressure over 130 systolic and 80 diastolic. Now, typically, both systolic and diastolic
pressures tend to rise or fall together, but that’s not always the case. Sometimes, you can have
systolic or diastolic hypertension. This is referred to as isolated systolic hypertension or isolated
diastolic hypertension.
Okay, just because you see an elevated blood pressure on the exam, it does not mean that
individual has hypertension. The blood pressure must be persistently elevated in order to define
it as hypertension. So on your exam, remember that the diagnosis requires at least 2 separate
readings on 2 separate visits. The reason for this is because of the phenomenon of “white coat
hypertension”. This is hypertension on physical exam that occurs because of anxiety experienced
by the individual.
Hypertension is classified into primary, or essential hypertension, and secondary
hypertension. Primary hypertension occurs without a known secondary cause, and accounts for
90 percent of cases. The pathophysiology of primary hypertension is thought to be related to
decreased renal sodium excretion. Reduced sodium excretion increases plasma volume,
increasing the stroke volume, and as a result the systolic blood pressure. Also, the increased
plasma volume causes decreased renin release from the juxtaglomerular apparatus, producing
what’s called low-renin hypertension, and this can be high yield. Additionally, decreased sodium
excretion promotes vasoconstriction of the peripheral arterioles, increasing the systemic vascular
resistance, which increases diastolic blood pressure.
Okay, so risk factors for primary hypertension include age, physical inactivity, obesity, diabetes
mellitus, smoking, family history of hypertension, as well as excess salt or alcohol consumption.
It’s thought that in type II diabetes, high levels of insulin promote renal sodium retention.
Okay, before diagnosing an individual with primary hypertension, the causes of secondary
hypertension must be ruled out. Your exams will often try to clue you towards this by
mentioning that the individuals were on multiple antihypertensives and they didn’t work, or by
having a relatively young individual with hypertension. The best approach is to look at different
organ systems, starting with the adrenal gland. Important causes include primary
hyperaldosteronism, or Conn syndrome, Cushing syndrome and tumors
like pheochromocytoma and neuroblastoma. Clues in the question stem will help you identify
which one it is. Hypokalemia, metabolic alkalosis and an increase in the aldosterone-to-renin
ratio indicate Conn syndrome. Abdominal striae, supraclavicular fat pads, truncal obesity, and
hyperglycemia point towards Cushing syndrome. Paroxysmal hypertension, that
is hypertension that comes and goes, associated with headaches, palpitations and sweating
indicate a pheochromocytoma. Neuroblastomas are common in children, and present with an
abdominal mass.
Next is the kidney. Renal artery stenosis, also called renovascular disease is usually caused by an
atherosclerotic plaque occluding the renal artery, especially in 60 to 70 year old males. Less
commonly, it can be caused by fibromuscular dysplasia, especially in 20 to 30 year old females.
This classically causes the “string of beads” appearance of the renal artery. Regardless of the
cause, renal artery stenosis decreases renal perfusion. This makes your body think it’s in
a hypotensive state. So in response, the renin-angiotensin-aldosterone system, or RAAS, is
activated, resulting in vasoconstriction and increased renal sodium and water reabsorption, and
eventually hypertension. Decreased renal perfusion causes the affected kidney to shrink, and
histologically, there will be glomerular tubulointerstitial atrophy and fibrosis.
A high yield fact to remember for your exams is that unilateral renal artery stenosis does not
cause CKD because the contralateral kidney is functioning normally, and in fact it hypertrophies
to compensate. However, bilateral renal artery stenosis results in CKD because both kidneys are
affected. Also, it’s important to not give ACE inhibitors to people with bilateral renal artery
stenosis. This is because angiotensin II constricts the efferent arteriole in the glomerulus, which
maintains the GFR. If an ACE inhibitor is given, the efferent arterioles dilate, causing a drop in
the GFR.
Okay, renal parenchymal diseases like diabetic nephropathy, glomerulonephritis or polycystic
kidney disease can also cause hypertension by retaining sodium.
Moving on, Coarctation of the aorta is also an important cause of hypertension, especially in
children. And the mechanism is quite similar to renal artery stenosis, since renal perfusion is
decreased, just that the obstruction is more proximal. Speaking of the aorta, aging causes the
amount of elastin in the arterial wall to decrease, and the amount of collagen to increase,
producing a stiff, non-compliant aorta. This manifests in elderly adults as isolated
systolic hypertension, which means an elevated systolic blood pressure, but a normal diastolic.
Moving on, both hyperthyroidism and hypothyroidism can
cause hypertension. Hyperthyroidism increases the cardiac output, causing an elevated systolic
blood pressure. For some reason, hypothyroidism increases renal retention of sodium, and
interestingly causes an isolated elevation of the diastolic blood pressure. The
adjacent parathyroid glands are also potential suspects, because primary
hyperparathyroidism causes hypercalcemia which increases vasoconstriction of the peripheral
arterioles, resulting in an increased total peripheral vascular resistance.
Alright, if the person presents with hypertension, bradycardia and an irregular respiratory
pattern, think of an increased intracranial pressure, which triggers a reflex that results in the
Cushing’s triad. In pregnancy, it’s crucial to consider preeclampsia and eclampsia.
Finally, always be aware of what medications the individual is taking. Estrogen-containing oral
contraceptives are common causes of hypertension, especially in young women. Estrogen works
by increasing the synthesis of angiotensinogen in the liver, which is ultimately converted to
angiotensin one and two. Cocaine is another potential drug that can cause hypertension by
increasing sympathetic activity. Additionally, in people take monoamine-oxidase inhibitors,
ingestion of tyramine-containing foods like cheese and wine may initiate an acute hypertension.
Remember that sometimes the exam might not mention the medication but simply state that the
person has a history of atypical or drug-resistant depression, which is an indication for MAOIs.
Alright, chronic hypertension can result in multiple complications affecting different organ
systems. Let’s start with the heart. Hypertension increases the afterload, that is the resistance the
heart has to pump against. In response, the left ventricle hypertrophies to overcome that
resistance. Concentric hypertrophy increases the myocardial oxygen demand, which means the
heart needs more coronary blood supply than usual. Also, concentric hypertrophy makes the
heart stiff, which limits diastolic relaxation. This is why heart failure from hypertension is
a diastolic heart failure, so the ejection fraction will actually be normal. Hypertension is also a
risk factor for atherosclerosis, so there’s an increased risk of coronary artery disease, which is the
most common cause of death from hypertension. Aortic dissection is another important
complication, and hypertension is the most important risk factor contributing to it.
Alright, onto the brain. Hypertension can weaken the walls of the small brain vessels, resulting
in Charcot-Bouchard aneurysm, which can rupture and cause an intracerebral bleed. Larger
arteries can form berry aneurysm, which can rupture and cause a subarachnoid hemorrhage.
Also, hyaline arteriosclerosis of the small blood vessels can occlude them, resulting in small
lacunar infarcts. In fact, properly managing hypertension has been shown to provide the greatest
reduction in the risk of stroke.
Okay, in the kidneys, hyaline arteriosclerosis of the afferent and efferent arterioles can lead
to ischemia and atrophy of the renal tubules. Over time, renal failure manifests.
Finally we have to keep an eye on the eyes. Remember for your exams that hypertensive
retinopathy manifests as dot and flame-shaped hemorrhages that result from rupture
of microaneurysms; arteriovenous nicking when enlarged arteries compress veins, as well as
silver and copper-wiring which are occluded arteries that appear white or orange instead of red.
Alright, aside from the chronic complications, hypertension can also result in acute presentation.
Both hypertensive urgency and emergency have a blood pressure greater than 180 over 120. The
difference is that in hypertensive emergency, there is evidence of acute end-organ damage. Now
both usually develop when someone is not consistently taking their antihypertensive
medication. Hypertensive urgency is usually found incidentally, so there’s no evidence of end-
organ damage. In hypertensive emergency, end-organ damage can manifest in a variety of ways.
For example, CNS manifestations include headache, altered mental status seizures, papilledema,
or stroke. Cardiac manifestations include myocardial infarction, acute left ventricular
failure resulting in pulmonary edema, and aortic dissection. Renal manifestations include acute
kidney injury, presenting as an elevation in the BUN and creatinine, hematuria and
microalbuminuria.
Now, let’s switch gears and discuss treatment of hypertension. The first choice of treatment is
lifestyle changes, like low sodium diet, exercise, and stress reduction techniques. In some cases,
antihypertensive medications can be given as well.
In general, for essential hypertension there are four main classes of medications that are used,
Angiotensin-converting enzyme or ACE inhibitors, Angiotensin Receptor
Blockers or ARBs, thiazide diuretics, and long-acting calcium channel blockers like
dihydropyridine. But what the examiners often do is try to clue you towards the medication you
should choose based on the comorbidity of the patient. So, if there’s hypertension with heart
failure, it’s high yield to remember the treatment should include ACE inhibitors or ARBs,
diuretics, aldosterone antagonists and beta blockers. Bear in mind though that beta blockers must
be used with caution in decompensated heart failure, which is when heart failure rapidly
worsens. That’s because of their ability to decrease heart rate and their negative inotropic effect,
meaning that they decrease the force of heart contraction.
Moving on, if there’s hypertension with diabetes mellitus, the optimum treatment is ACE
inhibitors or ARBs, thiazide diuretics, Calcium channel blockers, or beta blockers. What’s
important to remember is that ACE inhibitors or ARBs are protective against diabetic
nephropathy. And when using beta blockers, hypoglycemia is the side effect to watch out for, as
it may go unnoticed, since beta blockers blunt the counter- regulatory effects and symptoms of
catecholamines, like tachycardia and tremors. That’s particularly dangerous for people
with diabetes, who already take a bunch of other hypoglycemic medications like insulin.
Next, hypertension in individuals with asthma should be treated with ARBs, thiazide
diuretics, calcium channel blockers or cardioselective beta blockers. What we should avoid here
is ACE inhibitors, since their most common side effect is cough. And non-selective beta
blockers, which also block beta2 receptors in the lungs, cause bronchoconstriction. Finally,
for hypertension in pregnancy, choose hydralazine, methyldopa, labetalol, or nifedipine. To
remember this, you can use the mnemonic Hypertensive Moms Love Nifedipine.
Another thing to know is treatment of acute complications
of hypertension. Hypertensive urgency just needs adjustment of oral antihypertensive
medication, so there is no need to lower the blood pressure acutely. On the flip side,
in hypertensive emergency, it’s crucial to lower the blood pressure immediately with intravenous
medications like nitroprusside or labetalol.
All right, as a quick recap, Hypertension is defined as an elevation of blood pressure above 130
over 80 as per the AHA. Hypertension can be classified into primary, or essential hypertension,
and secondary hypertension. Risk factors for primary hypertension include age, obesity, diabetes
mellitus, smoking, and family history. Secondary hypertension causes are classified based on the
organ of origin. Examples include Conn syndrome from the adrenals, renal artery stenosis in the
kidney, or coarctation of the aorta. Drugs like cocaine and oral contraceptives are also potential
causes.
Chronic complications of hypertension can affect a variety of organ systems, and include left
ventricular hypertrophy, coronary artery disease, stroke and subarachnoid hemorrhage, renal
failure and hypertensive retinopathy. Hypertension can also present acutely
as hypertensive urgency, which has a blood pressure greater than 180 over 120 without end-
organ damage, or hypertensive emergency, which is with end-organ damage. Treatment
of hypertension varies depending on any concomitant conditions, like heart
failure, diabetes, asthma or even pregnancy.
Back to our cases. Anthony has multiple risk factors for primary hypertension, including a
history of diabetes, obesity, lack of exercise and family history of hypertension. After performing
a physical exam to check for the chronic complications of hypertension, he’s given
antihypertensive medication. Alicia presented with hypertension and was placed on lisinopril,
an ACE inhibitor. However, she developed oliguria and an elevated BUN and creatinine,
signifying that her GFR declined after the initiation of lisinopril. This is characteristic of renal
artery stenosis. Labs showed elevation of renin and aldosterone levels, and an angiogram
confirmed the stenosis. Vikander is presenting with hypertensive emergency, as his blood
pressure is above 180 over 120, and his symptoms include headache, altered mental status
and papilledema, which means there’s end organ damage. His probable history of medication
non-compliance also supports this diagnosis. Intravenous esmolol is given to quickly lower
his blood pressure and prevent further damage.

Sources
1. "Rapid Review Pathology" Elsevier (2018)
2. "Fundamentals of Pathology" H.A. Sattar (2017)
3. "Williams Textbook of Endocrinology" W B Saunders Company (2008)
4. "Pharmacotherapy for hypertension in adults aged 18 to 59 years" Cochrane Database Syst
Rev (2017)
5. "Hypertensive crisis" Cardiol Rev (2010)

Abnormal heart sounds

If you put a stethoscope over the chest, you’ll usually hear something that sounds like lub dub,
lub dub, lub dub, which repeats over and over again, with each cardiac cycle, or heartbeat.
In total, our heart has four valves- two atrioventricular valves, between the atria and the
ventricles, which are the tricuspid valve, on the Left side, and the mitral valve, on the left side,
and two semilunar valves, between the ventricles and the large arteries coming off of them,
which are the pulmonary valve, on the right side, and the aortic valve, on the left side. Normally,
in every heartbeat, some valves open, allowing blood to pass through and others close to hold
blood within a chamber. The sound of the closing of each of these valves is projected onto the
chest wall. The two normal heart sounds are S1, which is basically the tricuspid and mitral valve
closing, and S2 which is the aortic and pulmonic valve closing. Between S1 and S2, we have
systole, which is when ventricles are contracting and pushing blood out, and between S2 and S1
of the next heart cycle, we have diastole which is when blood is filling the relaxed ventricles.
Together, S1 and S2 form the “lub dub” of the heart beat.
Alright, now in addition to S1 and S2, there are two other "extra" sounds that are sometimes
heard in the cardiac cycle, called S3 and S4. S3 and S4 are heard in different parts of diastole. In
early diastole, which is right after S2, the atrioventricular valves are open and blood is flowing
from the atria into the ventricles. If there’s a lot of blood coming in, the ventricles fill up quickly,
and fluid waves bounce off of the walls of the ventricles which makes them vibrate, creating a
third heart sound, or S3. S3 sounds kind of like “lub-dub-ta”. In trained athletes and also in
pregnancy this is totally normal and just means that the ventricles are handling extra blood
volume. But an S3 can also be a sign of volume overload, like in congestive heart failure, where
there’s too much volume coming into the ventricles. Now, at the end of diastole, just before S1,
the atria are contracting to get that last bit of blood into the ventricles. If the ventricles are stiff,
meaning that they can’t easily relax, the atria will have to contract extra hard to push that blood
in, creating the fourth heart sound, or S4. So, S4 sounds kind of like "ta-lub-dub". Oftentimes,
this stiffness is because the ventricular muscles have hypertrophied, or increased in size, in order
to pump against high blood pressure in the aorta or pulmonary artery. In other words, S4 is
typically a sign of pressure overload, or severe hypertension.
In addition to these extra heart sounds, there are also heart murmurs, which are the result of
turbulent, or rough blood flow through the heart. Depending on how loud these murmurs are,
they are graded on a scale from 1 through 6, where 1 is the slightest possible murmur, 3 is
moderate and 6 is heard without even putting the stethoscope on the chest. Now, some children,
whose hearts are perfectly healthy, have what are called “innocent” heart murmurs which are just
sounds that come from the fact that their heart walls are thin and vibrate with rushing blood, and
disappear as a child gets older and the heart walls thicken. An example is the so- called
Still’s murmur, which is very common among young children, and is heard best at the left
lower sternal border of the heart. But other murmurs are not “innocent” and can indicate a
problem with the heart.
Now, systolic murmurs are the ones that can be heard between S1 and S2, kind of like “lub-
whoosh-dub”. This is when the aortic and pulmonary valves are normally open, and the mitral
and tricuspid valves are closed. There are four main causes for a systolic murmur - either from
an aortic or pulmonary valve that’s not able to fully open, called stenosis, or from the mitral
or tricuspid valve that’s not able to fully close, called regurgitation or insufficiency.
In aortic or pulmonary valve stenosis the valve resists opening up for a moment before finally
snapping open, and this causes a characteristic “ejection click.” Because the blood has to flow
through a narrow opening in that first moment, we get increased turbulence, which creates
a murmur. The murmur initially gets louder as more blood tries to squeeze through, and then as
there’s less and less blood left in the ventricle that needs to go by, the murmur becomes more
quiet again. This is described as a crescendo-decrescendo murmur. Aortic valve stenosis is best
heard if you place a stethoscope between the second and third rib, known as the right
second intercostal space, just next to the upper border of the sternum. And you can hear
the murmur of pulmonary valve stenosis if you place a stethoscope in the left second intercostal
space, at the left upper sternal border.
Alright, now, in tricuspid or mitral valve regurgitation, these valves aren’t able to make a perfect
seal, and that allows blood to leak back from the ventricles into the atria. This movement of
blood can be heard as a holosystolic murmur, because it’s possible to hear blood flowing through
the valve for the duration of systole. If that comes from tricuspid valve regurgitation, it’s best
heard between the fourth and fifth rib, next to the left lower border of the sternum, whereas
a mitral valve regurgitation can be heard between the fifth and sixth rib, so in the left
fifth intercostal space, near the midclavicular line. Another thing that helps differentiate
a tricuspid valve regurgitation from a mitral valve regurgitation murmur is the presence of the
Carvallo’s sign. The Carvallo’s sign is when a tricuspid valve regurgitation murmur gets louder
with inhalation, because the negative pressure in the chest brings more blood back into the right
atrium, and that makes the tricuspid valve regurgitation murmur even noisier. The leading cause
of mitral valve regurgitation, and the most common of all valvular conditions, is mitral valve
prolapse. This is when the mitral valve actually prolapses or flails back into the atrium, because
the papillary muscles and connective tissue, called chordae tendineae, are too weak to keep the
valve tethered. In mitral valve prolapse, there’s a mid-systolic click, which is a result of the
leaflet folding into the atrium and being suddenly stopped by the chordae tendineae. If mitral
valve prolapse gets severe enough, it can often progress to mitral regurgitation, meaning that the
leaflets won’t make a perfect seal, so a little bit of blood leaks backward from the left
ventricle into the left atrium. This will be heard as a late- systolic murmur, after the click.
The mitral valve prolapse murmur is somewhat unique in that when patients squat down, the
click comes later and the murmur is shorter, but when they stand or do a valsalva maneuver, the
click comes sooner and the murmur lasts longer. This is because squatting increases venous
return, which fills the left ventricle with more blood; increasing left ventricle volume. A
roomier left ventricle means that the mitral valve leaflets have more space to hang out, and as the
ventricle contracts and gets smaller, it takes just a little longer for the leaflet to get forced into the
atrium. On the other hand, standing reduces venous return, making the left ventricle a bit smaller,
and that forces the leaflet out earlier in the contraction.
Another cause of a systolic murmur is hypertrophic obstructive cardiomyopathy, and it causes
the crescendo-decrescendo type of murmur. In hypertrophic obstructive cardiomyopathy the
muscle of the interventricular septum grows so large that it gets in the way of blood leaving
the left ventricle during systole. When there’s an obstructed left ventricular outflow tract, it
means that blood gets forced through a tiny opening, which creates a murmur that gets louder as
more blood rushes out, and then gets softer as there’s less blood left in the left ventricle that
needs to get by - and that results in the crescendo-decrescendo murmur, best heard between the
mitral valve area and the left sternal border. What makes this murmur special is that its intensity
changes depending on how much the outflow tract is obstructed. If a person with hypertrophic
obstructive cardiomyopathy squats or does a handgrip maneuver, systemic vascular
resistance increases and that increases afterload. When there’s increased afterload, the left
ventricle is under higher pressure and it stretches out a bit and becomes less obstructed, making
the murmur less intense. On the other hand, if that person stands up to reduce afterload or does a
valsalva maneuver to diminish venous return and reduce preload, then the left ventricle is less
stretched out, and the obstruction becomes more significant, making the murmur more intense.
Another cause of a systolic murmur is a ventricular septal defect, which is when there’s a gap in
the wall separating the two ventricles. During systole, some of the blood in the left ventricle,
which has a higher pressure, flows over to the lower pressure right ventricle. This can be heard
as a holosystolic murmur at the lower left sternal border.
Now, on the flip side, diastolic murmurs are heard between S2 and S1 of the next cycle, kind of
like “lub-dub-whoosh”. This is when the aortic or pulmonary valves are normally closed, and the
mitral and tricuspid valves are open. There are four main causes for a diastolic murmur - either
from an aortic or pulmonary valve that’s regurgitant, or from a mitral or tricuspid valve that’s
stenotic. In aortic or pulmonary valve regurgitation, most of the blood leaks back right away
from the aorta or pulmonary artery back into the left or right ventricle, and then it tapers down
over time. That causes an early-diastolic decrescendo murmur, meaning that it starts out loudest
in the early part of the diastolic phase and then becomes more quiet over time. Now, with mitral
or tricuspid valve stenosis, there’s typically an opening “snap” in the middle of diastole as blood
pushes open the stenotic valve, and then a diastolic rumble as blood is forced through the smaller
opening. Sometimes, mitral valve stenosis can be mistaken with an Austin Flint murmur. An
Austin Flint murmur is when aortic regurgitation is so severe that there’s a jet of regurgitant
blood that strikes the mitral valve, and forces it shut prematurely. This causes a rumbling mid-
diastolic murmur, best heard in the mitral valve area, but without the opening snap sound.
Finally, there are continuous murmurs which can be heard throughout systole and diastole - most
commonly caused by patent ductus arteriosus. In patent ductus arteriosus there’s a connection
between the aorta and the pulmonary artery, which remains open after birth.
Normal aortic systolic/diastolic pressures are 120/80 mm of mercury and normal pulmonary
artery systolic/diastolic pressures are 25/5 mm of mercury. So that means that there’s a pressure
difference of about 95 mm of mercury during systole and 75 mm of mercury during diastole,
which causes blood to flow continuously from the aorta to the pulmonary artery, creating a
continuous “machine-like” murmur.
All right, as a quick recap, apart from the two normal heart sounds- S1 and S2, two extra heart
sounds may be present- S3, in cases of volume overload, and S4, in cases of pressure overload.
There are also systolic murmurs, mainly due to aortic or pulmonary valve stenosis or mitral
or tricuspid valve regurgitation, and sometimes hypertrophic obstructive
cardiomyopathy or ventricular septal defect. Diastolic murmurs are mainly caused
by aortic or pulmonary valve regurgitation or mitral or tricuspid valve stenosis.
Continuous murmurs, all throughout systole and diastole, may be heard in cases of patent ductus
arteriosus.

Sources
1. "Medical Physiology" Elsevier (2016)
2. "Physiology" Elsevier (2017)
3. "Principles of Anatomy and Physiology" Wiley (2014)
4. "Aortic origin of innocent murmurs" The American Journal of Cardiology (1977)
5. "Still's-like innocent murmur can be produced by increasing aortic velocity to a
threshold value" The American Journal of Cardiology (1991)
6. "Human Anatomy & Physiology" Pearson (2018)

Anatomy clinical correlates: Heart

Have you ever wondered what the secret to someone’s heart is? That's right, a chest x-ray! All
right, so, here at Osmosis we don't actually have the secret to one’s heart, but we do know how
to identify the different medical conditions that can affect the heart.
Let's start off by identifying the heart borders on a chest x-ray. The heart silhouette is between
the lungs, and the right border, made up by the right atrium, as well as the left border, made up
by the left ventricle and part of the left auricle, can be clearly seen. Above the left auricle, we can
identify the pulmonary artery and the aortic arch. And in some clinical circumstances, the
silhouette sign can be present, which is when the normal heart silhouette of the heart compared
to the lungs is lost. More appropriately, you might want to think about it as a “loss of the heart
silhouette”. The loss of the heart silhouette only occurs when the pathological process is in direct
anatomical contact with the heart. Usually, the middle lobe is seen close to the right border of the
heart. So, consolidation in the right middle lobe can also obscure the x-ray silhouette of the right
heart border.
All right, now, even though the heart is protected by the sternum and thoracic cage, it’s still
susceptible to injury. During penetrating trauma, like, for example, a stab wound, the right
ventricle is the most commonly injured structure because of its anterior position in the chest and
the fact that it forms the majority of the anterior surface of the heart, followed by the left
ventricle which forms the apex of the heart and may be injured as far laterally as the left
midclavicular line at the 5th intercostal space. The atria are less commonly injured than the
ventricles. It’s also worth noting that the lungs overlap most of the anterior surface of the heart,
so many penetrating injuries to the heart will also result in concurrent lung injury particularly to
the parietal pleura.
Are you ready to listen to your heart? We’re now going to talk about heart auscultation! The gist
of it is to listen to the areas that best project the sound coming from each heart valve. Blood
tends to carry the sounds in the direction of its flow so each area is situated superficial to the
chamber or vessel into which the blood has passed and in a direct line with the valve orifice.
Let’s start with the aortic valve, which is located posterior to the left of the sternum at the level
of the third intercostal space. To auscultate the aortic valve, you need to move your stethoscope
at the second intercostal space, right of the sternal angle. Moving on to the pulmonary valve, it’s
located at level of the left third costal cartilage and is auscultated at the second intercostal space,
left to the sternal angle. The tricuspid valve is posterior to the body of the sternum to the right
side at the level of the fourth and fifth intercostal space, and it’s auscultated at the 4th or 5th
intercostal area, left to the sternal edge. The mitral valve is located posterior to the sternum at the
level of the fourth costal cartilage to the left and is auscultated at the left 5th intercostal space on
the midclavicular line
And now let’s talk about conditions that may affect the heart. First, there’s dextrocardia, which is
a rare embryological folding defect where the heart is reversed so the apex is misplaced to the
right instead of the left. Dextrocardia is associated with mirror image positioning of the great
vessels and arch of the aorta. Basically, everything that normally is on the left is on the right and
vice-versa. This condition might be part of something called situs inversus, which is a general
transposition of the thoracic and abdominal viscera, or it occurs as isolated dextrocardia, where
the transposition only affects the heart. When dextrocardia is associated with situs inversus, the
incidence of other cardiac defects is low and the heart usually performs normally. However, in
isolated dextrocardia, the congenital anomaly is complicated by severe cardiac anomalies, such
as transposition of the great arteries.
Clinically, dextrocardia can be determined by palpating the apex beat over the right chest.
Typically the apex beat, which is the most lateral inferior palpable portion of the heart on the
chest wall typically found in the 4th or 5th intercostal space at the mid clavicular line, is on the
right side. An x-ray can then be done to confirm dextrocardia.
And while dextrocardia is rare, a myocardial infarction, unfortunately, is not uncommon. That’s
when an artery of the heart is blocked by an embolus, and the myocardium supplied by the
occluded vessel no longer receives blood. If that area can undergo necrosis, resulting in
a myocardial infarction. Symptoms of a myocardial infarction include severe crushing chest pain
that can often radiate to the back, jaw, left arm, right arm, shoulder, or atypical chest pain that is
felt in the abdomen. Associated symptoms include dyspnea, diaphoresis, which means profuse
sweating, as well as nausea and vomiting. The three most common sites of coronary
artery occlusion are: the anterior interventricular branch of the left coronary artery approximately
40-50% of the time, the right coronary artery approximately 30-40% of the time, and the
circumflex branch of the left coronary artery approximately 15-20% of the time.
Now, dominance of the coronary arterial system also affects what areas of the heart are affected
during a myocardial infarction, as dominance determines whether the right or left coronary
artery gives off the posterior interventricular branch. Therefore, during an occlusion to the right
or left coronary artery, dominance will determine if the area supplied by the posterior
interventricular branch will be affected.
In 67-85% of people, the right coronary artery gives rise to the posterior interventricular branch.
In about 8-15% of cases, the left coronary artery is dominant and the posterior interventricular
branch comes from the circumflex artery.
In 7-18% of people, there is codominance and both right and left coronary arteries give rise to
branches that run in or near the posterior interventricular groove. So, if the right coronary
artery is occluded, then the right atrium, parts of both ventricles and the sino-atrial
and atrioventricular nodes are affected along with the area supplied by the posterior
interventricular branch which is the inferior adjacent area of ventricles and the posterior third of
the interventricular septum. If the left coronary artery is occluded, then the left atrium, along
with parts of both ventricles, the AV bundle, the anterior 2 thirds of the interventricular septum,
along with the area supplied by the posterior interventricular artery if it is dominant. Also
remember, the right coronary artery supplies the SA node via the SA nodal branch 60% of the
time, and the AV node via the AV nodal branch when it has dominance, so the loss of blood
supply to these two nodes also varies during a myocardial infarction.
Following a myocardial infarction, the conducting system of the heart might be damaged.
The left coronary artery gives off the anterior interventricular branch which gives rise to the
septal branches that supply the AV bundle in most people. Additionally, the branches of the right
coronary artery mainly supply both the sinoatrial and atrioventricular nodes as we have said
before. The occlusion of one of these arteries can lead to a heart block. In this case, the ventricles
will begin to contract independently at their own rate which is approximately 25 to 30 per minute
as they do not receive a signal from the SA or AV node, which is slower than their slowest
normal rate of 40 to 45 per minute.
If the sinoatrial node has been spared, the atria continue to contract at the normal rate, but the
impulse generated by the sinoatrial node doesn’t reach the ventricles. Damage to either the left or
right AV bundle branches leads to a bundle branch block, where excitation passes along the
unaffected branch and causes a normal systole of that ventricle only, and the affected ventricle
receives conduction via muscle propagation to produce a late asynchronous contraction.
Now, individuals with obstruction of their coronary circulation and severe angina might undergo
a coronary bypass graft operation. This is when a segment of an artery or vein is connected to the
ascending aorta or to the proximal part of a coronary artery and then to the coronary artery distal
to the stenosis. This procedure provides a detour or ‘bypass’ around the stenotic area or blockage
re-establishes blood flow to the obstructed cardiac muscle. It is preferred to use arterial grafts
compared to venous grafts as patency is higher in arterial grafts - meaning they are more likely to
stay open and allow blood flow than venous grafts. Preferred graft choices are the internal
thoracic artery followed by the radial artery, however in multiple coronary artery
disease the great saphenous vein may need to be harvested as it offers lengthy portions.
In some individuals with a myocardial infarction, a percutaneous coronary intervention can be
done. This is when a catheter with a small inflatable balloon attached to its tip is placed through
the obstructed coronary artery. When the catheter reaches the obstruction, the balloon is inflated
and the vessel is stretched to increase the size of the lumen and to improve blood flow. After
dilation of the vessel, an intravascular stent can then be introduced to maintain the vessel open.
The catheter can be introduced through the femoral or radial artery to reach the heart and the
affected vessel. However, there is always the risk of arterial hemorrhage when undergoing these
procedures.
Now, before we move on, can you recall what are the three most common sites of coronary
artery occlusion? Another type of heart catheterization is venous catheterization, where a venous
catheter enters the heart to measure intracardiac pressures and study circulation of the
functioning heart for things such as congenital heart defects or arrhythmogenic foci. The cardiac
venous catheter is inserted in the femoral vein and travels into the right atrium through the IVC.
In order to access the left side of the heart, the catheter must transverse the interatrial septum at
the site of the foramen ovale, which is covered in adults by a thin membrane and can be easily
punctured, to enter the left atrium. In addition to cardiac venous catheters, there are also cardiac
ablation catheters which we’ll talk about shortly. These deliver radiofrequency ablation to parts
of the heart to help correct electrical abnormalities such as supraventricular tachycardias.
Supraventricular tachycardias often arise from abnormal electrical activity in the AV node,
an accessory electrical pathway, or the atria such as in atrial fibrillation. Generally, these lead to
a ventricular heart rate of over 100 beats per minute, and can lead to things such as shortness of
breath, chest pain, and hemodynamic instability.
To fix these electrical abnormalities, we can use cardiac ablation catheterization like we
mentioned previously. The cardiac catheter can then be directed to specific structures of the heart
such as the right atrium, right ventricle and pulmonary veins where radiofrequency ablation is
done to eliminate these accessory electrical pathways to try and restore normal heart function.
One area in the heart where supraventricular tachycardias can occur is the crista terminalis in
the right atrium. However, the right phrenic nerve courses along the pericardium over the right
atrium, and is at risk of injury during right atrial ablation. Damage to the right phrenic
nerve would cause paresis on the right side of the diaphragm, and can be recognized by elevation
of the right hemidiaphragm on x-ray.
Now, a subtype of supraventricular tachycardias is atrial fibrillation, which is actually the most
common cardiac arrhythmia. Atrial fibrillation is when the normal atrial heart contractions are
replaced by rapid, irregular, and uncoordinated contractions in different parts of the atrial wall.
These irregular contractions are associated with a major risk of thrombus formation and
subsequent systemic thromboembolism such as a stroke. This occurs because ineffective atrial
contraction leads to blood stasis and arterial inflammation. The most common site of thrombus
formation is the left atrial appendage, a small sac-like structure of the left atrium.
Speaking of the atria, let’s see what happens when the left atrium of the heart becomes enlarged,
which is often the result of pressure or volume overload. This can result from mitral valve
stenosis or regurgitation, as well as left ventricular dysfunction. Now as the most posterior
chamber of the heart, the increasing size of the atrium can compress near-by structures, such as
the esophagus, leading to difficulty swallowing or dysphagia, or it can compress the
left recurrent laryngeal nerve, leading to hoarseness of the voice.
Ok, now, remember that the heart is contained in a sac called the pericardium? Well, you
guessed it, this also has clinical implications. First, the pericardium has a sweet spot called the
transverse pericardial sinus that’s very important for cardiac surgeons. After the pericardial sac is
opened anteriorly, a finger can be passed through the transverse pericardial sinus just posterior to
the ascending aorta and pulmonary trunk. By passing a surgical clamp or a ligature around these
large vessels, inserting the tubes of a coronary bypass machine and then tightening the ligature,
the surgeon can stop or divert the circulation of blood in these arteries during cardiac surgery.
Alternatively, the pericardium can be affected when fluid accumulates in the pericardial cavity.
When there’s too much fluid in the pericardial cavity, it can compress the heart, causing cardiac
tamponade.This excess fluid can be removed during a procedure called pericardiocentesis, which
is when a wide-bore needle is inserted through the left 5th or 6th intercostal space near
the sternum. This approach is possible, because the cardiac notch in the left lung and the
shallower notch in the left pleural sac leaves part of the pericardial sac exposed. The pericardial
sac can also be reached through the infrasternal angle, also called the subcostal angle formed by
the right and left costal margins, by passing the needle supero-posteriorly. At this site, the needle
avoids the lung and pleura and enters the pericardial cavity. However, there’s a risk of
puncturing the internal thoracic artery or its terminal branches.
All right, as a quick recap. On a chest x-ray, the heart silhouette is between the lungs, and the
right border, made up by the right atrium, as well as the left border, made up by the left
ventricle and part of the left auricle, can be clearly seen. Dextrocardia is when the heart is
positioned on the right side of the body. It can be isolated or it can be associated with situs
inversus, where the organs that are supposed to be on the left are on the right and vice-versa.
The three most common sites of coronary artery occlusion are: the anterior interventricular
branch of the left coronary artery, the right coronary artery and the circumflex of the left
coronary artery. A myocardial infarction is when an artery of the heart is blocked by an embolus,
and the myocardium supplied by the occluded vessel no longer receives blood. A coronary
bypass graft operation is when preferably a segment of artery is connected to the ascending aorta
or to the proximal part of a coronary artery and then to the coronary artery distal to the stenosis.
A percutaneous transluminal coronary angioplasty is when a catheter with a small inflatable
balloon at its tip is placed through the obstructed coronary artery to reinstall flow in the
respective artery. Other types of cardiac catheterization include venous catheterization which
measures pressures in the heart and arrhythmia foci and ablation catheterization to correct
abnormal cardiac pathways. Atrial fibrillation is a common cardiac arrhythmia which may lead
to left atrial appendage thrombus formation. Pericardiocentesis can be done by inserting a needle
through the left 5th or 6th intercostal space near the sternum or by inserting the needle through
the infrasternal angle.

Sources
1. "Essential Clinical Anesthesia Review" Cambridge University Press (2015)
2. "Textbook of Cardiovascular Medicine" Lippincott Williams & Wilkins (2006)
3. "Understanding Heart Disease" Univ of California Press (1992)
4. "Cardiac tamponade" Journal of the American Academy of Physician
Assistants (2014)
5. "A Historical Review of Penetrating Abdominal Trauma" Critical Care Nursing
Clinics of North America (2006)
6. "Paroxysmal Supraventricular Tachycardia" Critical Care Nursing Clinics of North
America (2016)
7. "The development of coronary artery surgery: personal recollections" Tex Heart Inst
Journal (2002)

Pulmonary hypertension
Pulmonary hypertension refers to increased blood pressure in the pulmonary circulation, more
specifically a mean pulmonary arterial pressure that is greater than 25 mmHg.
The pulmonary circulation starts with the right ventricle.
From there - blood is pumped into the large pulmonary trunk, which splits to form the
two pulmonary arteries – one for each lung.
The pulmonary arteries divide into smaller arteries known as pulmonary arterioles and then
eventually into pulmonary capillaries which surround the alveoli - which are the millions of
tiny air sacs where gas exchange happens.
At that point, oxygen enters the blood and carbon dioxide enters the alveoli.
The pulmonary capillaries drain into small veins that join to form the two pulmonary
veins exiting each lung, and these pulmonary veins complete the circuit by delivering oxygen-
rich blood into the left atrium.
The blood pressure in the pulmonary circulation is normally much lower than the systemic blood
pressure.
The normal pulmonary artery pressure is about 25/10 mmHg with a mean arterial pressure of 15
mmHg.
Pulmonary hypertension most commonly develops as a result of left heart disease.
Here the pulmonary blood vessels are normal and undamaged, but the left side of the heart is
unable to pump efficiently – for example because of heart failure or valvular dysfunction.
This causes a backup of blood in the pulmonary veins and capillary beds, which can increase the
pressure in the pulmonary artery.
Another cause of pulmonary hypertension is chronic lung disease, which typically causes
hypoxic vasoconstriction.
That’s when some area in the lung is diseased and is unable to deliver oxygen to the blood.
To help adapt to this, the pulmonary arterioles in that area, start to constrict - and this effectively
shuttles blood away from those damaged areas of the lung, and towards healthy lung tissue. But
if the problem is widespread, like in individuals with emphysema, the mechanism can backfire.
That’s because there’s widespread vasoconstriction of pulmonary arterioles, and that
increases pulmonary vascular resistance in general.
Increased resistance makes it hard for the right ventricle to pump out blood – a bit like pushing
water through a narrow pipe as opposed to a wider one.
So to make the same amount of blood flow through the pulmonary arterioles, the right side of the
heart has to generate increased pressure and that results in pulmonary hypertension.
Another cause of pulmonary hypertension is chronic thromboembolic pulmonary hypertension -
which is when there are recurrent blood clots in their pulmonary vessels.
The clots can form because of an underlying clotting disorder, and can embolize or travel to the
lungs.
The clots can block pulmonary vessels which increases the resistance to blood flow, and they can
also endothelial cells in the vessels to release histamine and serotonin, which constricts the
pulmonary arterioles.
Together the blockage and the narrowing of the blood vessels causes a rise in the
pulmonary blood pressure.
One type of pulmonary hypertension is pulmonary arterial hypertension which is when there’s
elevated pressure in the pulmonary arterioles, but the pressure in their capillaries and pulmonary
veins is still normal.
Some congenital heart defects can cause pulmonary arterial hypertension.
A long-standing left-to-right cardiac shunt caused by a ventricular septal defect, atrial septal
defect, or less commonly, a patent ductus arteriosus can result in pulmonary hypertension and
eventual reversal to a right-to-left shunt, which is called Eisenmenger’s syndrome.
Pulmonary arterial hypertension can also be seen in connective tissue disorders like lupus,
infections like HIV, thyroid disorders, and inherited genetic mutations.
In these situations, the process begins with damage to the endothelial cells lining the pulmonary
arteries.
Once that happens, the damaged endothelial cells release chemicals like endothelin-1, serotonin,
and thromboxane.
These chemicals make the pulmonary arterioles constrict and cause hypertrophy of the smooth
muscle surrounding them.
The damaged endothelial cells also produce less nitric oxide and prostacyclin; which have the
opposite effect - they make the pulmonary arterioles dilate and inhibit smooth
muscle hypertrophy.
Regardless of the cause, once there’s pulmonary hypertension, it has important consequences on
the lungs and the heart.
Fluid can start to squeeze out of the blood vessels in the lungs and can get into the interstitial
space.
The presence of excess fluid in the pulmonary interstitium is called pulmonary edema, and it can
make it more difficult for gas exchange to happen.
Pulmonary hypertension also makes it a lot harder for the right ventricle to pump blood and over
time it hypertrophies.
This helps in the beginning, but eventually the muscles of the right ventricle get so bulky that
their oxygen demand exceeds the oxygen supply and it can lead to right-sided heart failure.
When chronic lung disease causes right-sided heart failure, it’s called cor pulmonale.
Right-sided heart failure causes blood to get backed up in the venous system. And this leads to
elevated jugular venous pressure, fluid buildup in the liver - causing hepatomegaly, and fluid
buildup in the legs causing edema.
Also, right-sided heart failure means that the left ventricle receives less blood, and to compensate
for that it has to pump harder and faster.
Pulmonary hypertension can lead to severe shortness of breath.
When pulmonary hypertension is caused by left-sided heart failure, there can also
be orthopnea which is when the shortness of breath is worse while lying flat.
That happens because lying flat pulls more blood back from the veins into the heart, and extra
blood only increases the hydrostatic pressure in pulmonary capillaries.
The diagnosis of pulmonary hypertension is usually made with an echocardiogram that shows
evidence of increased pressure in the pulmonary arteries and right ventricle.
Follow up tests can be done to identify the underlying cause, for example spirometry can be done
to look for chronic lung disease.
Treatment for pulmonary hypertension typically involves giving supplemental oxygen.
Other treatments are dependent on the underlying cause - if the cause is cardiogenic in nature,
medications aimed at boosting the heart’s performance or lowering the blood pressure can be
helpful.
In people with pulmonary arterial hypertension, medications like endothelin receptor antagonists
and prostacyclins can be given.

Summary
Alright, as a quick recap, in pulmonary hypertension the mean pulmonary arterial pressure is
greater than 25 mm Hg.
It can be due to left heart disease, chronic lung disease, or conditions that specifically
cause pulmonary arterial hypertension.
Regardless of the cause, it can lead to right-sided heart failure which causes physical findings
like elevated jugular venous pressure, hepatomegaly, and edema in the legs.

Summary
Pulmonary hypertension (PH) is a condition characterized by an increase in blood pressure in
the pulmonary artery, pulmonary vein, or pulmonary capillaries. It can be due to left heart
disease, chronic lung disease, or other conditions that specifically cause pulmonary arterial
hypertension. Regardless of the cause, it can complicate right-sided heart failure, what's referred
to as cor pulmonale. Symptoms of PH include shortness of breath, dizziness, fainting, and leg
swelling. Treatment focuses on the underlying cause and may include supplemental oxygen, and
medications like endothelin receptor antagonists and prostacyclins.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-
Hill Education / Medical (2018)
4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education /
Medical (2019)
5. "Pathogenesis of Pulmonary Arterial Hypertension" Circulation (2005)
6. "ACCF/AHA 2009 Expert Consensus Document on Pulmonary
Hypertension" Journal of the American College of Cardiology (2009)
7. "Updated Clinical Classification of Pulmonary Hypertension" Journal of the
American College of Cardiology (2013)
Apnea, hypoventilation and pulmonary
hypertension: Pathology review
Joseph, a 42 year old man comes to the clinic because he’s been waking up many times at night,
which makes him very sleepy during the day.
His partner also complains that Joseph has always snored but recently it’s louder than ever.
On physical examination he has a BMI of 35 kilograms per square meter, and has a blood
pressure of 140 over 90 millimeters of mercury.
You decide to conduct a sleep study, which reveals a very low partial pressure of oxygen.
Later, a 35 year old woman called Robin also comes to the clinic.
She tells you that, lately, she’s been experiencing shortness of breath and fatigue.
Robin is quite worried, and mentions that she has a congenital heart defect.
On physical examination, she has a mean pulmonary arterial pressure of 28 millimeters of
mercury.
You decide to perform an electrocardiogram or ECG test, and a chest X-ray, which show that
Robin has right ventricular hypertrophy.
Based on the presentation, both cases seem to have some respiratory disease, associated with
some cardiovascular issues.
Now, for your exams, some important conditions include sleep apnea, obesity hypoventilation
syndrome, and pulmonary hypertension.
So, let’s begin with sleep apnea!
This is when a person, during their sleep, experiences recurrent and intermittent episodes in
which they stop breathing for more than 10 seconds.
In addition, since fresh air is not getting into the lungs, individuals with sleep apnea will have
nocturnal hypoxia.
This puts the body under stress, which in turn responds by releasing epinephrine.
Now, the recurrent epinephrine surges have several effects.
Firstly, this wakes up the person so that they can breathe again.
This causes disrupted sleep, which in turn leads to somnolence or sleepiness during the day or
while awake.
Secondly, the body tries to compensate for the hypoxia by increasing the amount of red blood
cells, or erythrocytes, available to carry the oxygen in blood to our tissues.
To do so, our kidneys produce a hormone called erythropoietin, or EPO, which stimulates the
bone marrow to produce more red blood cells, and this process is known as erythropoiesis.
The problem with sleep apnea though is that, even if we increase the number of red blood cells,
the amount of oxygen that’s entering the body is not enough, so there’s still hypoxia.
Third, having high epinephrine levels can cause vasoconstriction, increasing the vascular
resistance.
Over time, this can result in vascular remodeling, which can lead to the development of both
pulmonary and systemic hypertension.
Pulmonary hypertension is when the blood pressure in the lung arteries is increased,
while systemic hypertension involves the arteries of the rest of the body.
Over time, this can put too much strain on the heart, and ultimately cause abnormal heart
rhythms, like atrial fibrillation or atrial flutter, heart failure, and even sudden death.
Diagnosis of sleep apnea involves a sleep study, also known as polysomnography, which counts
the number of apnea episodes, and monitors several parameters like heart rhythm and oxygen
saturation.
Another important diagnostic value is partial pressure of oxygen in the arteries, since it helps us
understand if the tissues are receiving adequate oxygen supply.
This value can be easily and indirectly obtained with a pulse oximeter, or directly obtained via
blood gas sampling.
For your exams, remember that people with sleep apnea have low oxygen saturation levels, and
thus low partial arterial pressure of oxygen during sleep, but bear in mind that this partial
pressure is typically normal when they’re awake.
Now, when the cause of sleep apnea originates in the central nervous system, it’s called central
sleep apnea.
Most often though, sleep apnea is caused by an obstruction of airflow in the airways, which is
known as obstructive sleep apnea.
And when a person experiences both obstructive and central sleep apnea, it’s called complex or
mixed sleep apnea.
Okay, let’s start with central sleep apnea or CSA for short.
Central sleep apnea is caused by an imbalance in the respiratory center of the brain, so during
sleep it fails to activate the muscles that control breathing.
The main causes of central sleep apnea include central nervous system injury involving the
respiratory center, as well as central nervous system toxicity, often due to use
of opioid medications.
Another major risk factor for central sleep apnea is congestive heart failure.
What’s important for your exams is that congestive heart failure leads to increased
chemosensitivity, which is how the body senses and responds to changes in the partial pressures
of oxygen and carbon dioxide.
So when there’s an apnea episode, oxygen levels decrease while carbon dioxide levels rise.
Now, keep in mind that carbon dioxide is the main stimulus for the respiratory center, so when
there are high levels of carbon dioxide, the respiratory center responds by increasing
our respiratory rate.
Now, when there’s increased chemosensitivity, the increased CO2 triggers an exaggerated
response in the form of hyperventilation, and ends up decreasing the carbon dioxide too much.
So now the CO2 level is too low, and this ultimately causes depression of the respiratory center
and thus another apnea episode.
As a result, there’s a vicious cycle that leads to central sleep apnea.
Now, when central sleep apnea is associated with congestive heart failure, it often manifests as
an abnormal breathing pattern called Cheyne-Stokes respiration, also known as
cyclic respiration.
This is a periodic breathing characterized by oscillation between periods of apnea alternated with
deep breaths or hyperpnea.
So, for your exams, remember that the three main things you need to know all start with a ‘C’ for
central sleep apnea!
The first is central nervous system injury or toxicity, the second ‘c’ is congestive heart failure,
and the third ‘c’ is for- Cheyne-Stokes respiration.
Treatment of central sleep apnea mainly involves positive airway pressure therapy, as well as
taking care of the underlying cause.
And then we have obstructive sleep apnea, or OSA for short.
As the name suggests, it is caused by a narrowing or obstruction of the airways.
Now, normally, the airway muscles relax while sleeping
In healthy people though, the airway muscle tone is strong enough to counteract factors that
would cause the airway to collapse, such as gravity while lying down, and the negative
pressure in the airway during inspiration.
In obstructive sleep apnea, the airway muscle tone is not strong enough to counteract these
factors, and so the airway collapses.
In adults, the most common cause is an excess of parapharyngeal tissue, which basically means
that there’s excess fat in the neck region.
That’s why obstructive sleep apnea is most common in obese individuals, so those with a BMI
over 30 kilograms per square meter.
On a test question, the most important clue suggesting obstructive sleep apnea is loud snoring in
an obese individual, like they’re trying to gasp for air until they wake up.
This leads to disrupted sleep, which in turn causes excessive sleepiness during the day or while
awake.
Sometimes though, obstructive sleep apnea may affect children; in this case, the most common
cause is adenotonsillar hypertrophy, meaning an enlargement of the pharyngeal and palatine
tonsils.
Treatment of obstructive sleep apnea involves continuous positive airway pressure, or CPAP
therapy, which delivers a steady stream of pressure, in order to keep the airway open.
In addition, weight loss is highly recommended for overweight people.
Finally, one last option is surgery to remove the excess parapharyngeal tissue.
Now, another important respiratory disease that’s very often related to obstructive sleep
apnea is obesity hypoventilation syndrome, or OHS for short.
Obesity hypoventilation syndrome is also named Pickwickian syndrome after Charles Dickens’
novel “The Pickwick Papers”, in which there is an overweight character who’s constantly falling
asleep at any time of the day.
As the name suggests, obesity hypoventilation syndrome only affects obese individuals.
That’s because the excess weight can restrict the movement of the diaphragm and chest wall,
which impairs lung expansion.
As a result, affected individuals develop hypoventilation, meaning slow or shallow breathing.
In most cases, obesity hypoventilation syndrome also causes obstructive sleep
apnea and hypoventilation during sleep, but bear in mind that these individuals also
experience hypoventilation while awake.
And that’s a high yield fact!
Because of that, diagnosis of obesity hypoventilation syndrome includes an increased partial
pressure of carbon dioxide while awake, and while sleeping, they’ll also have a decreased partial
pressure of oxygen.
Treatment is mainly focused on weight loss, and some cases can also get positive airway
pressure during sleep.
Okay, let’s switch gears to pulmonary hypertension, or PH for short, which is defined as a mean
pulmonary pressure at rest that’s greater than 25 millimeters of mercury.
And this often results in four hallmark pathological changes to the pulmonary arteries.
Now, to remember these four pathological changes, think of the mnemonic “Ants In My Pants”.
The first change is arteriosclerosis, in which the arterial walls become thicker, harder, and lose
elasticity.
Another change is intimal fibrosis, which is similar to arteriosclerosis, but only involves the
tunica intima, which is the innermost layer of the arteries.
Then there’s medial hypertrophy, meaning a thickening of the tunica media, which is the middle
layer of the arteries.
Now, these three changes can lead to a narrowing or even closing of the pulmonary arteries,
which compensate by forming new networks of vascular channels between the arterial branches.
These channels are known as plexiform lesions, and are the fourth pathological change.
Over time, pulmonary hypertension can progress to severe respiratory distress, and individuals
may present cyanosis or bluish skin discoloration due to poor blood oxygenation.
In addition, since the lung arteries are narrowed, the pressure inside increases.
And since the afterload of the right ventricle is proportional to the pulmonary pressure, it
becomes harder for the heart to pump blood, so it backs up, leading to an overload in the right
heart.
In response, the heart muscle will try to compensate by progressively remodelling its shape and
size and becoming thicker.
This is called right ventricular hypertrophy or RVH.
Ultimately, the heart isn’t able to compensate anymore, which leads to cor pulmonale, meaning
right-sided heart failure that’s caused by a lung condition.
If not treated, decompensated cor pulmonale is fatal.
Now, pulmonary hypertension can be classified based on the underlying cause into five groups.
Group 1 is pulmonary arterial hypertension, or PAH for short.
Now, pulmonary arterial hypertension refers specifically to pulmonary hypertension that’s
caused by a progressive stiffening and constriction or narrowing of the arteries in the lungs.
This is often associated with endothelial dysfunction, meaning that the endothelial cells start
producing more vasoconstrictors, such as endothelin, but less vasodilators like nitric oxide and
prostacyclins.
Now, the reason why this happens is most often idiopathic, meaning its cause is unknown.
However, there are some well understood causes that you must know for your exams.
These causes include congenital heart disease associated with left-to-right shunts, which is when
an anatomical defect of the heart’s septum causes blood to leak from the left side into the right
side; as well as portal hypertension, which refers to increased pressure in the portal vein, that
drains blood from the gastrointestinal tract into the liver.
Other causes include connective tissue diseases, such as lupus or scleroderma, as well as some
infectious diseases like HIV infection, or schistosomiasis, which is caused by the parasitic
flatworm Schistosoma.
Pulmonary arterial hypertension can also be caused by some abuse drugs
like cocaine and amphetamines.
In addition, some cases of pulmonary arterial hypertension can be inherited.
Now, heritable pulmonary arterial hypertension is caused by an inactivating mutation in the
BMPR2 gene.
Normally, the BMPR2 gene codes for a protein that inhibits the proliferation of smooth muscle
cells, and this is particularly important in blood vessels.
What’s important for you to know is that the inactivation of BMPR2 leads to medial hypertrophy
of the lung arteries, and this generally has a poor prognosis.
All right, now let’s go back to the causes of pulmonary hypertension.
Group 2 is left sided heart disease, which can be due to congenital heart defects, systolic or
diastolic dysfunctions, or a valvular disease.
Remember that the left side of the heart receives oxygenated blood coming from the lungs, and
then pumps this blood to the rest of the body.
So when the heart’s ability to pump blood is compromised, the backflow of blood leads to
increased pressure in the pulmonary circulation.
Group 3 is pulmonary hypertension caused by chronic lung diseases like chronic obstructive
pulmonary disease or COPD, in which the lung parenchyma is destroyed; as well as interstitial
lung disease, in which there’s inflammation and fibrosis of the lungs.
Group 3 also includes any condition that causes hypoxia, such as living at high altitudes or
having sleep apnea.
To compensate for the hypoxia, the lungs try to divert blood into lung segments with better
oxygenation by constricting the small pulmonary arteries of poorly oxygenated alveoli.
This mechanism is known as hypoxic pulmonary vasoconstriction.
Group 4 is for chronic thromboembolic pulmonary hypertension, which is when there’s recurrent
or chronic formation of thrombi or blood clots that may block or damage the pulmonary arteries.
As a result, blood cannot flow properly through the affected arteries, ultimately causing an
increased pressure in the pulmonary arterial tree.
Chronic thromboembolic pulmonary hypertension can be associated with clotting disorders,
chronic inflammatory diseases, or systemic diseases like cancer.
The fifth and last group is multifactorial, meaning multiple causes, and mainly refers to less
common causes of pulmonary hypertension that don’t fit into the other groups.
Multifactorial causes include metabolic disorders like thyroid disorders, blood disorders like
anemia, systemic disorders like sarcoidosis, and tumors that compress the pulmonary vessels.
Okay!
We’re near the end!
Diagnosis of pulmonary hypertension is usually made with right heart catheterization, where
a catheter is inserted through the right heart to measure the pulmonary pressure.
Pulmonary hypertension is diagnosed when the mean arterial pressure is greater than or equal to
25 millimeters of mercury.
Follow up tests can be done to identify the underlying cause, and can include an ECG and
imaging, among others.
Finally, treatment of pulmonary hypertension generally involves giving supplemental oxygen,
and further treatment options will depend on the underlying cause.
So for instance, if the cause is pulmonary arterial hypertension, medications like endothelin
receptor antagonists and prostacyclins can be given.
If the cause is left heart disease, treatment can involve medications aimed at boosting the heart’s
performance or lowering the blood pressure.
And if the cause is chronic thromboembolic pulmonary hypertension, treatment can involve
long-term anticoagulants, as well as surgery to remove the thrombi when possible.
All right, as a quick recap… Sleep apnea is when an individual intermittently stops breathing for
at least 10 seconds during sleep, and it’s typically associated with snoring, disruptive sleep, and
daytime sleepiness, as well as nocturnal hypoxia, that over time can lead to hypertension,
arrhythmias, and sudden death.
Sleep apnea could be central, due to an imbalance of the respiratory center in the brain during
sleep, and is associated with central nervous system toxicity or injury, congestive heart failure,
and Cheyne-Stokes respiration; whereas obstructive sleep apnea most often occurs in obese
individuals and is associated with airway obstruction and loud snoring.
A potentially related disease is obesity hypoventilation syndrome, also known as Pickwickian
syndrome, which affects obese individuals, presenting shallow or slow breathing, and increased
partial pressure of carbon dioxide both during sleep and while awake.
Treatment of sleep apnea can include weight loss, positive airway pressure, or surgery.
Lastly, pulmonary hypertension is characterized by a mean pulmonary pressure at rest that’s
greater than 25 millimeters of mercury.
Its four hallmark pathological changes include arteriosclerosis, intimal fibrosis, medial
hypertrophy, and plexiform lesions.
Eventually there’s a severe respiratory distress leading to cyanosis, right ventricular hypertrophy,
decompensated cor pulmonale, and death.
The causes of pulmonary hypertension are classified into 5 groups, including pulmonary arterial
hypertension, left heart disease, chronic lung diseases or hypoxia, chronic thromboembolic
pulmonary hypertension, and multifactorial causes.
Okay, back to our cases.
Joseph is a 42 year old man who experiences sleeping problems associated with loud snoring
and sleepiness during the day.
This is already pretty suggestive of obstructive sleep apnea.
This is further supported by the fact that Joseph is obese and has systemic hypertension.
The final clue is given by the sleep study, which reveals nocturnal hypoxia.
And since Joseph has none of the three main ‘Cs’, you can rule out central sleep apnea.
Next, Robin is a 35 year old woman complaining of shortness of breath and fatigue that may be
related to her congenital heart disease.
This, combined with her high mean pulmonary arterial pressure, should make you think of group
2, or left sided heart disease causing pulmonary hypertension.
In addition, Robin’s ECG and chest X-ray show right ventricular hypertrophy, which is a
common compensation mechanism to pulmonary hypertension.
If Robin doesn’t get treatment, she might eventually develop cor pulmonale.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-
Hill Education / Medical (2018)
3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill
Education / Medical (2018)
4. "Diagnostic and Statistical Manual of Mental Disorders" A.P. Association and
A.P.A.T.F.O.N.A. Statistics (1980)
5. "Robbins Basic Pathology" Elsevier (2017)
6. "Sleep Apnoea In The Older Adult" Drugs & Aging (2003)
7. "Obesity hypoventilation syndrome" European Respiratory Review (2019)
8. "Pathology of Pulmonary Hypertension" Clinics in Chest Medicine (2007)
9. "Plexiform Lesions in Pulmonary Arterial Hypertension" The American Journal of
Pathology (2011)
10. "Heart rate and blood pressure responses during hypoxic cycles of a 3-week intermittent
hypoxia breathing program in patients at risk for or with mild COPD" International Journal
of Chronic Obstructive Pulmonary Disease (2015)
11. "Cheyne-Stokes respiration in patients with congestive heart failure: causes and
consequences" Clinics (2005)
12. "Congestive Heart Failure and Central Sleep Apnea" Critical Care Clinics (2015)
13. "Pulmonary hypertension due to lung diseases: Updated recommendations from the
Cologne Consensus Conference 2018" International Journal of Cardiology (2018)
14. "Update on Chronic Thromboembolic Pulmonary Hypertension" Circulation (2014)

Dyslipidemias: Pathology review

Jamie is a 24-year-old male presenting to the emergency department complaining of sudden
onset chest pain and shortness of breath  when playing soccer.
On further evaluation, his ECG showed ST-segment elevation and laboratory evaluation showed
elevated troponin I levels.
After instituting treatment, Jamie and his family inquire about the odd early onset of his disease.
The physical examination of the skin showed numerous xanthomas.
A lipid panel is ordered and shows marked elevation of LDL.
Jamie had a myocardial infarction which was caused by an underlying lipid disorder.
Lipid disorders include both hyper and hypolipidemia.
Hyperlipidemia can manifest as a high level of cholesterol, a high level of triglycerides, or a
combination of both.
Hypolipidemia is the opposite where there’s a low level of these lipids.
So let’s do a quick overview of the physiology of lipid metabolism.
After eating a fatty meal, cholesterol and fatty acids enter the intestinal cells.
The fatty acids are assembled into triglycerides, and then they, along with a small amount
of cholesterol, are packaged together with lipoproteins to form chylomicrons.
Chylomicrons move into the lymphatic vessels and eventually end up getting emptied into the
left and right subclavian veins where they enter into the blood.
Now an enzyme in capillaries called lipoprotein lipase breaks down the chylomicrons to free the
triglycerides, and then it also breaks the triglycerides down into fatty acids.
These can be taken up by nearby tissues to generate energy, like in the muscle cells, or for
storage, like in adipocytes.
The remains of the chylomicrons will contain lipoproteins and a small amount of triglyceride
and cholesterol, so these chylomicron remnants head to the liver to deposit the leftover lipid
molecules.
The Liver is also synthesizing fatty acids and cholesterol and it will combine these with the ones
from the chylomicron remnants and package them together.
But instead of chylomicrons, they are packaged into very low density lipoproteins, or VLDLs.
Compared to chylomicrons, these are made of different lipoproteins and contain a bit
more cholesterol.
VLDLs are released from the liver and enter into the blood where lipoprotein lipase in
the capillaries break them down again to release triglycerides for nearby tissue to use.
As more and more triglycerides leave the VLDL, it becomes an IDL or intermediate density
lipoprotein, and when there’s more cholesterol left than triglyceride, it becomes an LDL.
LDLs then travel around in the blood, where they are endocytosed by cells with LDL receptors.
This can happen when they go back to the liver, or in peripheral tissues that need cholesterol to
function.
Alright, the causes of hyperlipidemia can be broadly classified into primary hyperlipidemias,
which are the familial, inherited hyperlipidemias, and secondary, or acquired hyperlipidemias,
which are caused by various other diseases and medications.
Depending on the type and severity, hyperlipidemia can result in various clinical manifestations,
or it can be completely asymptomatic.
Beginning from the outside, skin manifestations include xanthomas, which are deposits of
fat under the skin and in the tendons.
These occur when extremely high levels of lipoproteins or triglycerides in the blood leak out of
the blood vessels.
When these deposits occur around the eyelid, it gets a special name; xanthelasma.
Speaking of the eyes, lipids can deposit around the cornea, creating a brown ring of fat called
a corneal arcus. Lipid deposition in the liver can cause fatty liver disease, also called hepatic
steatosis.
Now, the most worrisome complication of hyperlipidemias is atherosclerotic cardiovascular
disease, including coronary artery disease, stroke, peripheral vascular disease and carotid artery
stenosis..
Okay, so let’s look at the primary, or Familial hyperlipidemias, which are inherited in either an
autosomal dominant or recessive manner.
Although there are many, the most high yield ones often tested on exams are types 1 through 4.
Type 1 hyperlipidemia is an autosomal recessive disorder characterized by elevation of
chylomicrons in the blood, so it’s also referred to as hyperchylomicronemia.
This occurs secondary to a deficiency in lipoprotein lipase.
This enzyme also normally requires a cofactor called apolipoprotein C2, so deficiency of this
cofactor can also lead to type 1 hyperlipidemia.
This condition is characterized by the rapid development of many xanthomas on the back and
buttocks that can be itchy.
Due to the rapid nature of their development, they’re referred to as eruptive xanthomas.
In addition, the high concentration of triglycerides in chylomicrons can often lead to the
development of acute pancreatitis.
This occurs because when the pancreatic cells encounter triglycerides, they release the enzyme
lipase, which breaks them down into free fatty acids.
Too many free fatty acids can be toxic to the pancreatic cells, leading to acute pancreatitis.
Another unique feature of type 1 hyperlipidemia is that atherosclerotic cardiovascular disease is
not a complication.
That’s because the development of an atherosclerotic plaque is usually related to the elevation of
other lipoproteins like low-density lipoprotein, or LDL, and not related to the elevation of
chylomicrons.
Finally, people with this condition can develop hepatosplenomegaly.
An important clue that might appear on your exams is that when fasting serum is chilled, the
chylomicrons will form a creamy layer at the top of the test tube.
Alright, type 2 familial hyperlipidemia is an autosomal dominant condition also known
as familial hypercholesterolemia.
It’s characterized by the elevation of LDL cholesterol if it’s type “A,” and both LDL and VLDL
if it’s type B.
Okay, so normally, the liver can decrease cholesterol levels by recycling LDL in the blood.
LDL attaches to its own LDL receptor on the surface of liver cells, and with the help of a protein
called apolipoprotein B-100, or ApoB-100, it enters the liver cells.
So in this condition, either the LDL receptor or ApoB-100 are absent or defective, causing LDL
levels go up.
Because the liver cells aren’t getting any LDL back, they begin to “think” that cholesterol is
actually low in the blood, and so they start making even more cholesterol, and sending them out
in VLDL.
As you can imagine, this would worsen the problem.
Unlike type 1, type 2 hyperlipidemia will increase the risk of developing atherosclerosis, and this
is high yield.
In fact, individuals may present with coronary artery disease as early as 20 years old!
In addition, tendon xanthomas, particularly on the Achilles tendon, and corneal arcus are
common in this type.
On the exam, think of this disorder in someone with a family history of myocardial infarction at
an early age.
Alright, type 3 familial hyperlipidemia is a rare, autosomal recessive disorder also known as
familial dysbetalipoproteinemia.
In this disorder, the apolipoprotein E or ApoE is defective.
This protein normally assists with the uptake of chylomicron remnants and VLDL by the liver,
so they are elevated in this condition.
It’s also characterized by the development of premature atherosclerosis, however unlike type
2 hyperlipidemia, the xanthomas in this condition tend to develop on the palms.
Okay, type 4 familial hyperlipidemia is also known as familial hypertriglyceridemia.
In this subtype, for some unknown reason, the liver pumps out large amounts of VLDL.
In addition, lipoprotein lipase activity is decreased, so VLDLs are not broken down.
This also applies to chylomicrons which will also be elevated.
The high yield concept here is that since VLDLs and chylomicrons both contain mainly
triglyceride, serum triglyceride levels can increase dramatically.
This condition is characterized by premature atherosclerosis and the risk of developing acute
pancreatitis.
Alright, onto the acquired causes of hyperlipidemia, starting with the most common
cause, diabetes mellitus.
Normally, one of the functions of insulin is to increase lipid uptake in adipose tissue.
It does this by increasing the activity of lipoprotein lipase to liberate fatty acids from VLDL and
chylomicrons.
In both type 1 and type 2 diabetes, insulin levels eventually drop, causing a decrease in
lipoprotein lipase activity.
So now instead of being broken down and stored, large amounts of VLDL particles just
awkwardly sit in the blood, and these eventually get converted to LDL, the culprit
in atherosclerosis.
In hypothyroidism, the body’s metabolism slows down.
This includes synthesizing LDL receptors.
Without LDL receptors, LDL particles can’t return to the liver, so they lurk in the blood.
In nephrotic syndrome, plasma proteins like albumin are lost in the urine.
In attempt to compensate for the decrease in plasma protein, the liver starts making VLDL.
Through various mechanisms, certain groups of medications can also cause hyperlipidemia.
These include estrogen-containing oral contraceptives, beta-blockers, and thiazide diuretics.
Alright, now let’s look at hypolipidemia and the most common cause that will show up on your
exams is abetalipoproteinemia.
Normally, a protein called microsomal triglyceride transfer protein, or MTP, is responsible for
packaging triglycerides into lipoproteins like VLDL and chylomicrons, so that they can be
carried in the blood.
In abetalipoproteinemia, an autosomal recessive genetic defect happens to the MTP protein.
There’s also a deficiency of ApoB-48 protein which is also made in the small intestine and are
found in chylomicrons, and ApoB-100 which is made in the liver and found in VLDL and LDL.
So the result is low levels of VLDL, LDL and chylomicrons and both cholesterol and triglyceride
levels will be low.
Abetalipoproteinemia presents early in infancy.
A key symptom is malabsorption of fat in the small intestine due to low levels of chylomicrons,
so infants don’t grow properly, a condition called failure to thrive.
In addition, the lipids accumulate inside intestinal cells and the intestinal lumen, resulting in
diarrhea that contains large amounts of fat, also called steatorrhea.
On the exam, a clue towards steatorrhea would be malodorous stools that float in the toilet bowl
and are difficult to flush down.
Over time, individuals develop signs and symptoms of fat-soluble vitamin deficiency, and this is
another high yield fact.
This includes osteomalacia from vitamin D deficiency, retinitis pigmentosa from vitamin A
deficiency, as well spinocerebellar degeneration and acanthocytosis on peripheral blood smear
from vitamin E deficiency.
To confirm the diagnosis, an intestinal biopsy is performed, which shows intestinal cells that
contain large amounts of fat.
The treatment of the disease is based on reducing dietary fats, especially long chain
saturated fatty acids to reduce gastrointestinal problems.
Vitamin supplements should also be taken, the most important of which are vitamin E to prevent
neurological problems, and vitamin A to prevent retinal damage.

Summary
Alright, as a quick recap, Lipid disorders cause abnormal changes in the levels of blood lipid
components such as triglycerides, cholesterol, and lipoproteins.
Hyperlipidemia can be divided into primary, or familial, which is usually caused by an inherited
genetic defect, or acquired, caused by various systemic disorders and medications.
Familial hyperlipidemias are subclassified into four major types.
Type 1, caused by a deficiency of lipoprotein lipase or its cofactor; apolipoprotein C2, results in
elevation of chylomicrons.
Type 2 is caused by an absent or defective LDL receptor, resulting in elevation of LDL in type
A, and both LDL and VLDL in type B.
Type 3 is caused by defective ApoE, leading to elevation of VLDL and chylomicrons.
Type 4 hyperlipidemia is characterized by increased hepatic production of VLDL.
Acquired causes include diabetes, hypothyroidism and medications like thiazide diuretics.
Hypolipidemia can be caused by abetalipoproteinemia which is a genetic disorder that affects the
MTP protein.
This leads to decreased levels of chylomicrons, VLDLs, and LDLs. The symptoms are caused by
malabsorption of fats and fat soluble vitamins.
Okay, back to our case.
Jamie is presenting with an acute myocardial infarction.
Considering his relatively young age, it’s important to consider familial hyperlipidemias.
Tendon xanthomas on examination, combined with elevation of LDL on lab testing all point
towards type 2 familial hyperlipidemia, usually caused by a decrease in the number of LDL
receptors or ApoB-100 protein in the liver.

Sources
1. "Fundamentals of Pathology" H.A. Sattar (2017)
2. "Hyperlipidemia: diagnostic and therapeutic perspectives" J Clin Endocrinol
Metab (2000)
3. "Lecture Notes: Cardiology" Wiley-Blackwell (2008)
4. "Pathophysiology of Heart Disease" Wolters Kluwer Health (2015)
5. "Familial hypobetalipoproteinemia: genetics and metabolism" Cell Mol Life
Sci. (2005)

Lipid-lowering medications: Statins

Statins lower overall lipid levels in the body, and work by inhibiting the enzyme HMG-CoA
reductase, which is the rate-limiting step of cholesterol metabolism.
They are an incredibly important class of medications because they’ve been shown to decrease
complications associated with cardiovascular disease like strokes, heart attacks, and peripheral
vascular disease.
Although it’s got a bad reputation, cholesterol is actually a critical component of our cells and is
used to build the cell membrane.
It also has other uses like the synthesis of steroid hormones, vitamin D, and bile. Normally, we
get our cholesterol from the food we eat, but it can also be synthesized by the liver.
So when we eat a box of chili fries, the fats and cholesterol are absorbed in the small intestine.
However, they’re not water soluble, so they can’t travel freely in the blood.
To fix this, our body makes shipping boxes called lipoproteins.
These containers consist of a shell made of phospholipids and protein tags that act as instructions
for their destination.
So after absorption, the small intestinal cells package the fats and cholesterol into the largest but
least dense lipoproteins, called chylomicrons.
These are released into the lymphatic system and then enter the bloodstream via the subclavian
vein. Then they travel through the blood to reach adipose tissue and the liver.
Now, the liver can also synthesize intrinsic cholesterol through the mevalonate pathway, which
happens in the smooth endoplasmic reticulum of liver cells.
It begins with 2 acetyl-CoA molecules getting joined together by the enzyme acetyl-CoA acyl-
transferase.
The result is a 4-carbon molecule called acetoacetyl-CoA.
Next, the enzyme HMG-CoA synthase combines acetoacetyl-CoA and acetyl-CoA to form a 6-
carbon molecule called 3-hydroxy-3-methylglutaryl CoA, or HMG-CoA.
Then, an enzyme called HMG-CoA reductase reduces HMG-CoA into mevalonate.
This step with HMG-CoA reductase is the rate-limiting step of cholesterol synthesis.
In other words, the rate of this reaction determines the overall rate of cholesterol synthesis, it’s
like the slowest step of an assembly line in a factory.
Mevalonate is the precursor molecule that will eventually become cholesterol.
Okay, in the liver, cholesterol and a lot of triglycerides are packed into the next kind of
lipoproteins called very-low-density lipoproteins or VLDL, which are smaller and more dense
than chylomicrons.
This package is sent into the bloodstream and carry the energy-rich triglycerides to the rest of
the body.
Now, after unloading their triglycerides, the VLDL and the remaining cholesterol become a new
kind of lipoprotein, called a low-density lipoprotein, or LDL, which are even smaller and more
dense than VLDL.
These will travel around the bloodstream and deliver cholesterol to cells in the rest of the body.
The final lipoprotein is the HDL, or high-density lipoprotein, which are smaller but denser than
LDLs. These are like the boxes you get when you try to return an item you bought online.
In this case, the liver produces HDL and released them into the blood, where they pick up
excess cholesterol from the peripheral tissues and brings them back to the liver.
So in essence, it’s the opposite of LDL, which carries cholesterol from the liver to the peripheral
tissues.
Now, the tissues in the body will take in the LDLs, as well as the cholesterol that’s contained in
them.
So, if we have too much LDL, we get cholesterol build up in these tissues.
One of the most clinically relevant tissues is the endothelium that lines the blood vessels.
Increased cholesterol here will lead to the formation of fatty deposits called plaques, and these
will increase the risk of cardiovascular complications like strokes, myocardial infarctions,
and peripheral vascular disease.
Okay! So, statins are a group of medications that are used to prevent these complications.
Common statins include simvastatin, lovastatin, and pravastatin, while the
newer atorvastatin and rosuvastatin are more potent, with a longer half-life.
Now, all of the statins work by inhibiting cholesterol synthesis in the liver.
They are structurally similar to HMG-CoA, so they can bind to HMG-CoA reductase and
prevent the actual substrate from binding.
Since HMG-CoA reductase is the rate-limiting step, statins can dramatically decrease cholesterol
synthesis in the liver.
Now when the liver can’t make any more cholesterol, it will try to get it from the rest of
the body.
So hepatic cells will increase the number of LDL receptors on their surface, which facilitates the
uptake of cholesterol-rich LDLs, thus further lowering cholesterol level in the blood.
These LDL receptors also increase the uptake of VLDLs to a smaller degree, which provides a
moderate decrease in triglyceride level.
Next, to get even more cholesterol, the liver will increase production of HDLs, which will
carry cholesterol back from the peripheral tissues.
So to sum it up, there’s a major decrease in LDL, a major increase in HDL, a major decrease
in cholesterol, and a moderate decrease in VLDL and triglycerides.
Statins are metabolized by cytochrome p450 enzymes in the liver, so medications that enhance or
inhibit their activity should be avoided.
For side effects, statins are very well tolerated.
Common side effects include gastrointestinal symptoms and rashes.
Some of the more serious toxicities of statins include myalgia, or muscle pain;
and rhabdomyolysis, or muscle breakdown.
This side effect is thought to be due to the fact that a downstream product of mevalonic acid is
farnesyl pyrophosphate, which is required for the production of Coenzyme Q. This is a necessary
cofactor in the electron transport chain of all cells.
When the electron transport chain experiences decreased functionality, less overall ATP will be
produced. This will affect the energy-intensive cells like muscle cells more heavily, so we end up
with muscle damage.
Next, although rare, statins can be hepatotoxic, especially in people who already have liver
diseases.
Finally, these medications are teratogenic so they should be avoided in pregnant women.
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharm
facts! So first, let’s set the scene at a train station, for statins. Now, there’s a top rail track and a
bottom rail track. On the top rail, let’s put a train that’s carrying heavy metal crates representing
HDL. The fact that it’s on the higher track will help you remember statins increase HDL.
Now on the lower track, we have decreased LDL and VLDL. So let’s have a train full of LDL
wooden crates, and another one with cardboard boxes for VLDL.
Now, notice how there are a lot more wooden crates? That’s because statins have a much larger
effect on LDL compared to VLDL.
Okay moving on, let’s decorate all 3 trains with happy little hearts since they all benefit the
cardiovascular system and help prevent strokes and heart attacks.
So guarding the train station, we have a soldier with a Heavy Machine Gun, or HMG. He’s
reduced to tears because he hates his job, which also represents the main enzyme affected by
these drugs: HMG-CoA reductase.
For the important side effects, the soldier has been target practicing with a cardboard cutout of a
super muscular lady, who represents the muscular problems like myalgias and rhabdomyolysis.
She’s holding a liver over her head to help you remember these medications are
occasionally hepatotoxic. Finally, she’s pregnant to help you remember statins are teratogenic.

Summary
All right, as a quick recap, statins work to lower overall lipid levels in the body, and function by
inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting step of cholesterol
synthesis.
They decrease LDL and VLDL, while increasing HDL, which leads to a large decrease
in cholesterol and a mild decrease in triglyceride levels.
They are commonly used to prevent heart attacks, strokes, and peripheral vascular disease.
Their main side effects include gastrointestinal upset and rashes, muscle pain, and in rare
cases, liver damage.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the
video so you can test yourself to see what you remember. Stay tuned for the answers after the
credits.

Sources
1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th
Edition" McGraw-Hill Education / Medical (2018)
2. "Rang and Dale's Pharmacology" Elsevier (2019)
3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th
Edition" McGraw-Hill Education / Medical (2017)
4. "Statin-induced myopathies" Pharmacological Reports (2011)
5. "Pleiotropic Effects of Statins on the Cardiovascular System" Circulation
Research (2017)
6. "Statins: mechanism of action and effects" Journal of Cellular and Molecular
Medicine (2001)
7. "Diagnosis and Management of Statin Intolerance" Journal of Atherosclerosis and
Thrombosis (2019)
Lipid-lowering medications: Fibrates
Fibrates are a group of lipid-lowering medications, along with statins and niacin.
These medications are very effective at lowering triglyceride levels in the blood, but are less
effective at controlling cholesterol.
Now, triglycerides make up most of your body fat, and they consist of a glycerol and 3 fatty
acids.
So when we eat a box of chili fries, the fatty acids and cholesterol are absorbed into the cells in
the small intestine.
The fatty acids are then converted into triglycerides.
However, triglycerides and cholesterol are not water soluble, so they can’t travel freely in the
blood. To fix this, our body makes “shipping boxes” called lipoproteins.
These containers consist of a shell made of phospholipids and protein tags that act as instructions
for their destination.
So after absorption, the small intestinal cells package the triglycerides and cholesterol into the
largest, but least dense lipoproteins, called chylomicrons.
These are released into the lymphatic system and then enter the bloodstream via the subclavian
vein. Then, they travel through the blood to reach the liver and other tissues in the body.
Now in the blood vessels near these tissues, we have an enzyme called lipoprotein lipase, which
can break down triglycerides into fatty acids.
Cells in the nearby tissue can then use these fatty acids to generate ATP.
Adipose tissue can synthesize a lot of lipoprotein lipases, which means they have access to a lot
of fatty acids.
Now, instead of using the fatty acids for energy, they pick them up, convert them back into
triglycerides, and store them for later use.
Okay, so we can also synthesize fatty acids from glucose in the liver which are then converted
into triglycerides.
These triglycerides and some cholesterol are packed into the next kind of lipoproteins called
very-low-density lipoproteins or VLDL, which are smaller and more dense than chylomicrons.
This package is sent into the bloodstream to carry the energy-rich triglycerides to the rest of
the body.
Now, lipoprotein lipases in the blood vessels will once again convert the triglycerides in the
VLDLs into fatty acids, which can enter the cells; and the leftover VLDLs are called VLDL
remnants.
This and the remaining cholesterol are converted into a new kind of lipoprotein, called a low-
density lipoprotein, or LDL, which are even smaller and more dense than VLDL.
These will travel around the bloodstream and deliver cholesterol to cells in the rest of the body.
The final lipoprotein is the HDL, or high-density lipoprotein, which are smaller and denser than
LDLs.
These are like the boxes you get when you try to return an item you bought online.
In this case, the liver produces HDL and releases them into the blood, where they pick up
excess cholesterol from the peripheral tissues and brings them back to the liver.
So in essence, it’s the opposite of LDL, which carries cholesterol from the liver to the peripheral
tissues.
Now, triglycerides are atherogenic which means they can cause atherosclerosis, increasing the
risk of cardiovascular complications like strokes and myocardial infarctions.
Extremely high triglyceride levels can also lead to acute pancreatitis.
Okay, so if we want to lower triglyceride levels we can use a class of medications called fibrates.
Common medications in this class include gemfibrozil, bezafibrate, and fenofibrate.
They all work by activating an intranuclear receptor called PPARα, or peroxisome proliferator-
activated receptor alpha.
PPARα is a major regulator of lipid metabolism and when activated by fibrates, it’ll cause
adipose cells to produce more lipoprotein lipase, which increases the conversion of the
triglycerides in chylomicrons and VLDLs into fatty acids, thus lowering triglyceride levels.
Next, in the liver, fibrates increase the breakdown of triglycerides through beta oxidation so we
make less VLDLs which also results in lower triglyceride levels.
Finally fibrates also increase the synthesis of HDL, which can provide a moderate decrease
in cholesterol.
Now unlike statins, which are the more commonly used lipid lowering agent, fibrates have little
effect on LDLs, so they don’t lower cholesterol as much.
On the other hand, statins are not as effective in lowering triglyceride, so the two can be
combined to tackle mixed dyslipidemia, where both triglyceride and cholesterol levels are
elevated.
Okay for side effects, the most common ones include GI disturbances and rashes.
A more serious side effect is that fibrates can damage the muscles and lead to rhabdomyolysis, or
muscle break down.
Since statins can also cause this problem, when they are combined, the risk is increased.
Next in the liver, fibrates decrease the activity of an enzyme called cholesterol 7 alpha-
hydroxylase, which is needed to convert cholesterol into bile acid.
So we end up with a lot of cholesterol in the bile, and this promotes the formation of gallstones.
Now another class of lipid lowering medications called bile acid resins also cause gallstone
formation, so if used together with fibrates, the risk of developing gallstones is increased even
more!
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharm
facts! So let’s have a lady at a loom making fabrics, for fibrates.
Now the finished fabrics are placed on the top shelf inside a heavy metal box, which represents
HDL.
Since it’s on the top shelf, it means fibrates lead to a higher level of HDL.
Now, her supplies are on the bottom shelf and they are in a very light cardboard box for VLDL
and a wooden box for LDL.
Now notice the largest of the boxes is the cardboard box, while the smallest box is the wooden
one.
So fibrates are most effective at lowering VLDL, and triglycerides have a moderate effect at
increasing HDL, and very low effect on lowering LDL.
Okay for some of the important side effects, let’s use the lady’s husband. He’s a super muscular
guy but his muscles are all red and swollen from carrying all the boxes, and this
represents rhabdomyolysis. He has the word “Statin” tattooed to his arm to help you
remember statins can worsen this problem if used together with fibrates.
Next, let’s have him hold a giant gallstone, which is another side effect. On top of
the gallstone is a raisin covered in green, slimy bile, since bile resin will increase the risk even
more.

Summary
All right, as a quick recap, fibrates increase triglyceride clearance from the body and work by
inducing lipoprotein lipase via activation of PPARα nuclear receptors.
While less commonly used, they are very effective at lowering triglyceride levels or are
sometimes combined with statins to lower both triglyceride and cholesterol.
The main toxicity of fibrates includes myositis and rhabdomyolysis.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the
video so you can test yourself to see what you remember. Stay tuned for the answers after the
credits.

Sources
1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th
Edition" McGraw-Hill Education / Medical (2018)
2. "Rang and Dale's Pharmacology" Elsevier (2019)
 3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th
Edition" McGraw-Hill Education / Medical (2017)
4. "PPAR Agonists and Metabolic Syndrome: An Established Role?" International
Journal of Molecular Sciences (2018)
5. "Fibrates for primary prevention of cardiovascular disease events" Cochrane
Database of Systematic Reviews (2016)
6. "PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-
Reactive CD8+ T Cells and Facilitates Anti–PD-1 Therapy" Cancer Immunology
Research (2018)
7. "Use of fenofibrate on cardiovascular outcomes in statin users with metabolic
syndrome: propensity matched cohort study" BMJ (2019)

Hypertriglyceridemia
With Hypertriglyceridemia, hyper means high, -emia refers to blood levels, and triglycerides are
the most abundant fatty molecules in an organism.
So, hypertriglyceridemia is when there’s excess triglycerides in the blood.
Specifically, hypertriglyceridemia is when there are more than 150 mg of triglycerides per
deciliter of blood.
Triglycerides can be deposited in subcutaneous tissue and around organs and function as energy
storage in the body.
We can either get triglycerides from our diet, which are called exogenous triglycerides; or our
liver can synthesize them from other molecules, in which case they’re called endogenous
triglycerides.
Now, exogenous triglycerides are first absorbed in the small intestine, and then they undergo a
series of changes in order to be transported and deposited in the body.
So, after triglycerides are absorbed, they enter the intestinal mucosal cells, inside of which
they’re coupled with various apolipoproteins and phospholipids to create chylomicrons , which
are one type of lipoprotein.
Lipoproteins are made up of lipids (like triglycerides or cholesterol) or phospholipids and
proteins (like apolipoproteins CII, CIII, or E).
The main job of lipoproteins is to carry insoluble molecules, like triglycerides, from
the intestines to the circulation.
That's because, normally, triglycerides are insoluble in liquid environments like blood.
Now, the newly created chylomicrons enter the bloodstream and bind to the wall
of capillaries in adipose and skeletal muscle tissue.
At the binding site, they interact with the lipoprotein lipase enzyme leading to the breakdown of
the triglyceride core and liberation of free fatty acids directly into the adipocytes or skeletal
muscle cell, where they’re either stored or used for energy.
After triglycerides leave the chylomicron, what’s left is called a remnant chylomicron.
Remnant chylomicrons are high in cholesterol esters and they’re cleared from circulation by the
liver when the apolipoprotein E binds to Apo-B100/E receptor on the hepatic cell membrane.
The remnant chylomicrons are then degraded by acid hydrolases to a mixture of amino acids,
free fatty acids, and cholesterol.
Now let’s switch gears and look at how endogenous triglycerides are synthesized.
First, the liver makes another type of lipoproteins called very low-density lipoproteins, or VLDL.
The fatty acids are either synthesized from scratch from carbohydrates or released from adipose
tissue.
Then, the liver exports the triglyceride-rich VLDL molecules into the bloodstream, which carries
them to muscle and adipose cells.
Here, VLDL are cleaved by lipoprotein lipase to intermediate-density lipoproteins(IDL), also
called VLDL remnants.
The IDL are further metabolized to low-density lipoproteins, LDL, and are released into the
bloodstream, which are taken up by the LDL receptor in numerous tissues including the liver.
Ok, so hypertriglyceridemia can result from anomalies in either the exogenous or the endogenous
pathways, but in either case, excessive triglyceride levels accumulate in the body.
Depending on where they accumulate, they may cause complications
like atherosclerosis and acute pancreatitis.
Now, atherosclerosis can occur via a pathway that involves an endothelial dysfunction.
This dysfunction allows small triglycerides remnants to reach the intimal layer where they get
taken up by the macrophages, leading to the formation of foam cells.
Foam cells promote fatty streak formation: the precursor of atherosclerotic plaque.
Acute pancreatitis, on the other hand, occurs due to high concentrations of large chylomicrons in
the blood which can obstruct the capillaries leading to ischemia of the pancreas.
Now, hypertriglyceridemia is commonly classified as either primary (or
familial) hypertriglyceridemia and secondary (or acquired) hypertriglyceridemia.
Secondary causes are more common, and they may be associated with obesity, diabetes mellitus,
high carbohydrate diets, hypothyroidism, or increased alcohol intake, all of which impact lipid
metabolism.
Alright, so three of the most common secondary forms of hypertriglyceridemia are
obesity, diabetes mellitus type 1 and 2, and high carbohydrate diets.
With obesity-associated hypertriglyceridemia, there is a hepatic overproduction of VLDL and
decreased circulating triglycerides breakdown.
On the other hand, in uncontrolled diabetes mellitus, both type 1 and type
2, hypertriglyceridemia is associated with a lipoprotein lipase that is either ineffective or less
effective than normal.
Finally, high-carbohydrate diets, where carbohydrates make up more than 60% of the total
caloric intake, lead to increased carbohydrate breakdown and increased production of free fatty
acids as a consequence.
The excess free fatty acids can be used to synthesize more triglycerides, therefore
causing hypertriglyceridemia
Other conditions cause hypertriglyceridemia through different mechanisms.
For example, in hypothyroidism, triglycerides are elevated due to reduced hepatic lipase activity
which slows VLDL remnant catabolism.
Next, excessive alcohol intake causes hypertriglyceridemia, mainly because alcohol impairs lipid
breakdown, causing increased plasma VLDL with or without hyperchylomicronemia.
Finally, several drugs, like glucocorticoids, beta blockers, thiazide
diuretics, HIV antiretroviral agents, retinoids, and oral estrogen replacement can also
cause hypertriglyceridemia, although the mechanisms are not well understood.
On the other hand, primary or familial hypertriglyceridemia usually occurs due to genetic causes,
such as mutations of the genes encoding a type of apolipoprotein.
Primary hypertriglyceridemia is included in what is known as familial dyslipidemias.
There are 4 hyperlipidemias, of which only 3 cause hypertriglyceridemia.
Type 1 is called familial hyperchylomicronemia and is defined as high levels of chylomicrons in
the blood. It occurs due to autosomal recessive mutations.
Now, mutations in at least five different genes cause hyperchylomicronemia, but the ones
encoding for lipoprotein lipase and its cofactor, apolipoprotein CII, are most common.
Basically, these mutations lead to a severely reduced or absent lipoprotein lipase enzyme activity
and to an absent or nonfunctional apolipoprotein CII.
With lipoprotein lipase being the primary enzyme for triglycerides breakdown and release
of fatty acids in the circulation, its absence or reduction will lead to high levels of these lipids.
Type 3 or familial dysbetalipoproteinemia occurs when the chylomicron remnants cannot be
removed by the liver.
The mechanisms through which it is produced are not fully revealed yet, but it is suspected that
since the clearance of chylomicrons remnants from the circulation is done with the help of
apolipoprotein E, any defects related to apolipoprotein E or its receptor will affect this process,
leading to hypertriglyceridemia.
Finally, type 4, or familial hypertriglyceridemia, involves autosomal dominant mutations of the
lipoprotein lipase gene. In this case, there’s an increase in hepatic synthesis of VLDL and a
decreased removal of VLDL, resulting in hypertriglyceridemia.
Now, regarding symptoms, hypertriglyceridemia usually doesn't cause symptoms until
triglyceride levels are greater than 1000-2000 mg/dL, which is why most people have
asymptomatic hypertriglyceridemia.
Above that level, due to excessive accumulation of triglycerides in the body, signs and symptoms
may include hepatosplenomegaly and lipemia retinalis which can be observed as a creamy
appearance within retinal blood vessels.
Hypertriglyceridemia can also manifest as small papules on the skin known as xanthomas.
With atherosclerosis, symptoms can include chest pain and shortness of breath, while with acute
pancreatitis, symptoms like epigastric pain, nausea, and vomiting can occur.
The initial diagnosis of hypertriglyceridemia is m ade with blood tests, usually as the lipid profile
part of a cardiovascular risk assessment.
Then, hypertriglyceridemia can be classified as mild when triglycerides blood level is from 150
to 499mg/dL, moderate: from 500-886mg/dL, and severe when the triglycerides blood level is
higher than 886 mg/dL.
Then, other tests may be done to distinguish between primary and
secondary hypertriglyceridemia.
These may include lipid analysis, liver function tests, urinalysis, fasting blood glucose level,
or genetic testing.
So when it comes to treatment, hypertriglyceridemia may be improved with the help of diet,
exercise, and alcohol reduction.
Medication is required when triglyceride levels are above 886 mg/dL.
Fibrates, such as fenofibrate, are the best initial medical treatment for hypertriglyceridemia.
Niacin and omega-3 fatty acids may also be used.
HMG-CoA reductase inhibitors also known as statins, such as atorvastatin or simvastatin, are the
first choice drugs for moderate hypertriglyceridemia.

Summary
Ok, quick recap: Hypertriglyceridemia is characterized by high blood levels of triglycerides.
Hypertriglyceridemia can be primary or secondary.
Primary is mainly caused by genetic defects, while secondary hypertriglyceridemia occurs due to
several conditions, among which obesity or diabetes are most common.
The diagnosis is made based on blood tests but other tests are required to differentiate between
primary and secondary hypertriglyceridemia.
Treatment includes diet and exercising to help improve the level of triglycerides, but when those
are not enough, medication, such as fibrates or statins, are required.

Summary
Hypertriglyceridemia is a condition characterized by high levels of triglycerides in the blood. If
individuals' serum triglyceride concentrations are above 150 mg/dL, they are
considered hypertriglyceridemia. High levels of triglycerides in the blood are associated with a
high risk of developing heart disease, stroke, and other health problems. There are many
different causes of hypertriglyceridemia, including genetics, obesity, eating too much processed
or unhealthy foods, not getting enough exercise, smoking cigarettes, and drinking alcohol.

Sources
1. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
2. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education /
Medical (2019)
3. "Yen & Jaffe's Reproductive Endocrinology" Saunders W.B. (2018)
4. "Bates' Guide to Physical Examination and History Taking" LWW (2016)
5. "Robbins Basic Pathology" Elsevier (2017)
6. "Hypertriglyceridemia: its etiology, effects and treatment" Canadian Medical
Association Journal (2007)
7. "Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical
Practice Guideline" The Journal of Clinical Endocrinology & Metabolism (2012)
8. "Hypertriglyceridemic Pancreatitis: Presentation and Management" The American
Journal of Gastroenterology (2009)

Portal hypertension
Portal hypertension means increased blood pressure in the hepatic portal system - or portal
venous system.
Most commonly, this happens because of hepatic cirrhosis, which is when the liver tissue is
replaced by fibrotic, functionless tissue.
Now, the portal venous system comprises the portal vein and its tributaries - namely, the splenic,
and mesenteric veins.
This blood contains all the nutrients absorbed in the GI tract, but it also carries toxins that the
liver metabolizes so that they can be safely excreted by the kidneys.
Once the liver processes all these substances, it sends the blood to the heart, through the inferior
vena cava, to enter the systemic venous system.
Now, there’s a few points in the boundaries of the hepatic portal system, where it could be
connected with the systemic venous system that collects blood from the rest of the body: the
inferior portion of the esophagus, the superior portion of the anal canal, and the round ligament
of the liver - which used to be the umbilical vein during fetal life.
At birth, the umbilical cord is cut, and the umbilical vein collapses to form the round ligament.
Normally, the round ligament stays shut because pressures in the portal venous system and the
systemic venous system are the same, between 5 and 10 Millimeters of Mercury
But in some situations, an obstruction may prevent blood flow from the portal vein towards
the inferior vena cava.
When this happens, venous blood accumulates in the hepatic portal system, causing pressure to
rise above 5 to 10 12 mmHg - which defines portal hypertension of mercury.
Portal hypertension leads to the formation of portosystemic shunts - which is when blood is
diverted away from the portal venous system and backs up into systemic veins.
So first, less blood gets to the liver, causing diminished liver function and decreased blood
detoxification, which leads to a buildup of toxic metabolites, like ammonia, in the blood.
Ammonia and other toxins can pass through the blood brain barrier, and cause hepatic
encephalopathy.
Second, blood backing up in the systemic veins leads to portosystemic shunts, which happens in
the three points where the systemic venous system and the hepatic portal system are connected.
In the esophagus, this causes esophageal varices, or enlarged esophageal veins.
In fact, portal hypertension is the most common cause of esophageal varices.
These varices are very fragile, and could easily rupture, causing massive upper GI bleeding.
In the rectum and anal canal, there may be hemorrhoids, which are also enlarged veins that can
bleed as well.
Finally, portal hypertension causes the round ligament to re-channel, allowing blood from
the portal system to pass into the systemic veins of the abdomen, which dilate, making the
abdomen look like the head of the greek mythological creature “Medusa” - the one with snakes
for hair.
So this consequence is frequently termed caput medusae.
Portal hypertension can also cause blood to back up into the spleen, causing
congestive splenomegaly, meaning an enlarged spleen.
This causes hypersplenism, meaning the spleen traps blood elements like red blood cells, causing
anemia, white blood cells, causing leukopenia, and platelets, causing thrombocytopenia.
Another consequence of portal hypertension is that the endothelial cells lining the blood vessels
release more nitric oxide.
The reason behind this is unclear, but nitric oxide makes peripheral arteries dilate, so blood
pressure drops.
This stimulates the release of aldosterone, which tries to bring blood pressure back up by telling
the kidneys to retain more sodium and water.
In time, plasma volume expands so much, that fluid in blood vessels is more likely to get pushed
into tissues and across tissues into large open spaces like the peritoneal cavity.
The accumulation of fluid in the peritoneal cavity is called ascites.
As if that wasn’t enough, bacteria can also invade the peritoneal cavity, causing spontaneous
bacterial peritonitis.
So, the features of portal hypertension can be remembered as ABCDE: where “A” stands
for Ascites, “B” for Bleeding, “C” for Caput medusae, “D” for Diminished liver function, and
“E” for Enlarged spleen.
Now, causes of portal hypertension can be classified as prehepatic, intrahepatic or posthepatic,
depending on where the obstruction is.
The most common prehepatic cause is portal vein obstruction, like when there’s a thrombus
occluding the portal vein and blocking blood flow.
Intrahepatic causes include cirrhosis, schistosomiasis, which is when flatworms invade the liver,
and sarcoidosis, which is when inflammatory cells form lumps called granulomas inside the
liver.
Cirrhosis is by far the most common of the three.
Finally, posthepatic causes include right-sided heart failure, constrictive pericarditis, and Budd-
Chiari syndrome.
Both right-sided heart failure and constrictive pericarditis restrict the blood flow from the heart
to the lungs and to the rest of the body, causing blood to accumulate downwards - including into
the portal circulation.
And Budd–Chiari syndrome occurs when a thrombus, or a tumor, inside the hepatic veins that
obstructs hepatic venous flow towards the inferior vena cava.
Portal hypertension may be asymptomatic until complications occur.
Visible signs include a distended abdomen with ascites, and caput medusae, or visibly engorged
superficial abdominal veins.
GI bleeding secondary to esophageal varices can present with hematemesis, or vomiting blood;
or melena or hematochezia, when there’s blood in the stool.
With liver impairment, jaundice may occur.
And finally, with hepatic encephalopathy, there may be asterixis, which means
hand tremor when the wrist is extended, altered consciousness, lethargy, seizure, or coma.
The gold standard for determining if there is portal hypertension is obtaining a hepatic venous
pressure gradient measurement, where a catheter is inserted inside the inferior vena cava, and
then inside the portal vein to measure the difference between both pressures.
A liver ultrasound might be useful to detect nodules in case of cirrhosis.
CT scan or MRI help diagnose ascites, cirrhosis, splenomegaly, or vascular alterations
like inferior vena cava dilatation.
Labs including full blood count, liver enzymes, and serology can be useful to identify the cause.
And an upper GI endoscopy can identify esophageal varices in order to treat them appropriately.
Treatment is centered on preventing and treatment of complications.
Beta-blockers like propranolol can decrease portal venous pressure and prevent complications.
For ascites, diuretics and sodium restriction are indicated to reduce the fluid overload.
If esophageal varices bleed, a medication called octreotide, and procedures like balloon
tamponade, sclerotherapy and variceal ligation can be used.
To prevent bleeding from happening again, an interventional radiology technique called
transjugular intrahepatic portosystemic shunt or TIPS is the preferred procedure to
decrease hepatic portal pressure and prevent further complications.
With TIPS, a tube is inserted via a catheter to allow communication between the portal vein and
hepatic vein.

Summary
All right, as a quick recap… Portal hypertension is when the pressure in the hepatic portal
system is greater than 5 to 10 mmHg.
This happens when there’s an obstruction in the passage of blood from the portal vein towards
the vena cava.
So venous blood accumulates downward from the obstruction causing features
like ascites, esophageal varices and bleeding, caput medusae, diminished liver function and
an enlarged spleen.
The most common cause of portal hypertension is cirrhosis.
Diagnosis is done mainly by hepatic venous pressure gradient measurement.
Prevention of complications can be done with beta-blockers, and treatment options include
diuretics for ascites, and octreotide, balloon tamponade, sclerotherapy and variceal ligation for
bleeding esophageal varices.
To prevent bleeding from happening again, as well as further complications, a transjugular
intrahepatic portosystemic shunt - or TIPS - can be done.

Summary
Portal hypertension is hypertension in the hepatic portal system, which is composed of the portal
vein and its branches and tributaries. This can lead to serious complications, such as the
development of enlarged veins in the esophagus and stomach, called varices, which can rupture
and cause bleeding. It can also lead to ascites, an accumulation of fluid in the abdomen, and liver
failure. Treatment involves medications to reduce pressure in the portal vein, such as beta-
blockers like propranolol.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-
Hill Education / Medical (2018)
4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education /
Medical (2019)
5. "Portal hypertension: pathophysiology, diagnosis and management" Internal
Medicine Journal (2015)
6. "Pathophysiology of Portal Hypertension and Esophageal Varices" International
Journal of Hepatology (2012)

Cirrhosis
When cells are injured or damaged and die off, usually that dead tissue that was previously full
of living cells becomes fibrotic, meaning it becomes thickened with heaps and heaps of protein
and forms scar tissue.
So when your liver is constantly forced to process alcohol like in alcoholic liver disease, or
subject to a viral attack for a long time like in HBV, or anything else that causes a long-term or
chronic state of liver cell or hepatocyte destruction and inflammation, your liver can become
seriously scarred and damaged to the point where it’s no longer reversible, at which point it
becomes fibrotic and in the liver we call this process cirrhosis.
Because it’s usually irreversible, cirrhosis is often referred to as “end-stage” or “late-stage” liver
damage.
When liver cells are injured, they start to come together and form what are called regenerative
nodules. You can think of these as colonies of living liver cells. These are one of the classic signs
of cirrhosis and are why a cirrhotic liver is more bumpy as opposed to a smooth, healthy liver.
Also with cirrhotic liver tissue, you’ll see that in between these clumps of cells or nodules, is
fibrotic tissue and collagen.
Here’s a classic histology image of cirrhotic tissue, this clump of cells in the middle is the
regenerative nodule, and these blue stains surrounding it are the bands of protein from the
process of fibrosis.
If we zoom out a bit and look at it with the naked eye, we’ll again see these nodules, which have
fibrotic protein bands in between.
How do these bands of fibrotic tissue form though? Well fibrosis is a process mediated by
special cells called stellate cells, that sit between the sinusoid and hepatocyte, known as the
perisinusoidal space.
Here’s a pretty basic layout of the basic functional unit of the liver, you’ve got the portal
vein and hepatic artery that combine into a sinusoid, which then goes into the central vein, and
these are all lined with hepatocytes.
Along with these though you’ve also got a bile duct, and all three constitute a portal
triad/segitiga kiernan.
So the perisinusoidal space, which literally means “around the sinusoidal space”, and stellate
cells are about here. And usually in healthy tissue, these guys’ main function is to store vitamin
A and are otherwise considered quiescent, or sort of dormant.
When the hepatocytes are injured though, they secrete paracrine factors that “activates” and
changes the stellate cells.
When activated, the stellate cells lose vitamin A, proliferate, and start secreting transforming
growth factor beta1, or TGF-beta, which then causes them to produce collagen, which is the
main ingredient in extracellular matrix, fibrosis, and scar tissue.
As this fibrotic tissue builds up, it starts to compress the central veins and sinusoids.
It’s thought that in a healthy, normal state, these cells play key roles in the natural wound-healing
process, but when the liver cells are constantly injured, the stellate cells are constantly activated
and so they constantly produce collagen and factors that lead to fibrosis.
And this is when complications due to cirrhosis start to crop up.
As the central veins and sinusoids become compressed and push on the fluid inside, their
pressure starts to build up, leading to intrasinusoidal (or portal) hypertension, which is this higher
pressure in the portal veins.
Higher portal vein pressure means that fluid in blood vessels is more likely to get pushed into
tissues and across tissues into large open spaces like the peritoneal cavity.
That’s why cirrhosis leads to excess peritoneal fluid, a condition called ascites, and can result in
other complications like congestive splenomegaly and hypersplenism, where the spleen becomes
enlarged because all this fluid and blood can’t get into the liver, and backs up into the spleen.
In the same way, your circulatory system starts diverting blood away from the liver because of
the high liver pressures, this is known as a portosystemic shunt.
Blood flow follows the path of least resistance and shunts away from the portal system and
towards the systemic system of circulation.
Though not fully understood, these changes in portal flow ultimately trigger
renal vasoconstriction, so increased resistance in the renal circulation, which decreases blood
flow through the kidneys, leading to decreased filtration hepatorenal failure, where kidney
failure follows liver failure.
The fibrotic tissue, pressure buildup, and diversion of blood from the hepatic circulation
essentially reduces the number of functional sinusoidal veins, and the number of
functional portal triads in general.
As you have less and less of these basic liver functional units, your liver becomes less and less
able to do its job of detoxification.
When your liver isn’t detoxifying your blood, these toxins can get into the brain and start causing
mental deficits, a condition known as hepatic encephalopathy.
Although there are several neurotoxins that are thought to contribute to the development of these
mental changes, the best understood factor is ammonia in the blood, which is produced mainly in
the gastrointestinal tract; usually the liver plays a vital role in removing ammonia and stopping it
from going into the systemic circulation.
As more of these and other toxins get into the brain, patients might develop asterixis, where they
have tremoring or jerky hands when outstretched, and as even more toxins build up, eventually
patients can progress to a coma.
Also, since the liver plays a big role in metabolizing estrogen into inactive metabolites that can
be removed from the blood and excreted, patients can also experience complications due to
increased estrogen in the blood, like gynecomastia, spider angiomata, and palmar erythema.
And, since the liver usually conjugates bilirubin, increased unconjugated bilirubin in the blood
from a less-functional liver can lead to jaundice.
Another important job of the liver is producing albumin, so again, if the liver’s not functioning
right, you can have a decreased amount of albumin in the blood, or hypoalbuminemia.
Finally, the liver helps in making clotting factors or proteins that help coagulate your blood, so
when you aren’t producing these coagulation factors, you can develop issues related to your
ability to coagulate blood, which you need in order to stop blood loss after an injury.
To recap the general symptoms of cirrhosis, early on, with a small amount of scarring and
fibrosis, we call it compensated cirrhosis, meaning the liver can still do a lot of its job.
In this case, somebody with cirrhosis might not have any symptoms, or have nonspecific
symptoms like weight loss, weakness, or fatigue.
Later on, though, with extensive scarring, the liver progresses to decompensated cirrhosis, and
can’t function properly.
At this point many of the described symptoms start to develop, like jaundice and pruritus or itchy
skin, ascites, hepatic encephalopathy leading to confusion, and easy bruising from
low coagulation factors.
For diagnosis, the “gold standard” is a liver biopsy, taking a tiny sample of the liver tissue
examine under a microscope.
Common lab findings include elevated serum bilirubin, as well as elevated liver enzymes like
aspartate aminotransferase, (AST) and alanine aminotransferase (ALT), where AST is usually
more elevated than ALT, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase,
and thrombocytopenia, or low platelet count.
As to treatment, generally the scarring in cirrhosis is irreversible, so first of all it’s important to
prevent continued liver damage by identifying the underlying cause and treating that, for
example stopping alcohol consumption or antiviral treatment for those with hepatitis C. With
advanced cirrhosis, though, where the liver stops functioning, a liver transplant might be needed.

Cirrhosis: Clinical practice

Cirrhosis is when chronic inflammation and liver damage causes the liver to become fibrotic and
develop scar tissue.
At a cellular level, the hepatocytes become impaired and this leads to hepatic dysfunction
and portal hypertension.
Cirrhosis is usually irreversible, so it’s usually called “end-stage” or “late-stage” liver damage,
and often requires a liver transplant. However, in some cases, early treatment can slow down and
even reverse the cirrhosis.
Compensated cirrhosis is when there are enough healthy cells to make up for the damaged ones,
but minor complications like hemorrhoids can still occur.
Decompensated cirrhosis is when healthy cells can no longer keep up with the workload, causing
major complications like hepatic encephalopathy, ascites, and esophageal and gastric variceal
hemorrhage.
In compensated cirrhosis, although there aren’t any major complications, there may still be some
symptoms such as loss of appetite, fatigue, and muscle cramps. There may also be easy bruising
and excessive bleeding because there aren’t enough clotting factors produced by the liver.
Cirrhosis can also impair estrogen metabolism, causing amenorrhea and irregular menstrual
bleeding in females, and low libido and gynecomastia in males.
On physical exam, there may be hepatomegaly - where the liver can feel firm and nodular, but
when there’s a lot of scarring, the liver may be small so that it can’t be felt at all.
Another sign is spider angiomas- or spider nevi- which are swollen blood vessels just beneath the
skin surface- on the truck, face and upper limbs.
Palmar erythema- which is redness of the hands- can sometimes be seen.
There can also be hypertrophic osteoarthropathy- which is when there’s nail clubbing and
periostitis- which is inflammation around the small hand joints.
Sometimes, there are Dupuytren contracture, which is when one or more fingers are
permanently flexed.
Portal hypertension can lead to splenomegaly, along with caput medusae- which are distended
and engorged paraumbilical veins on the surface of the abdomen.
Finally, there may be minor complications such as hemorrhoids identified on a digital exam.
In terms of diagnosing cirrhosis, lab work includes a CBC- which most commonly
shows thrombocytopenia- especially if there’s also splenomegaly, but can also show anemia and
leukopenia.
Markers of liver injury are AST, ALT, alkaline phosphatase, and GGT and they’re usually
elevated.
Total and conjugated bilirubin are usually normal in compensated cirrhosis.
Finally, markers of liver function like albumin can decrease as cirrhosis progresses, and PT,
PTT, and INR- can increase as cirrhosis progresses.
In addition, Fibrosure or Fibrotest is done using alpha-2-macroglobulin, haptoglobin, total
gamma globulin, apolipoprotein A1, GGT, and total bilirubin to generate a score that
estimates liver fibrosis.
An abdominal ultrasound shows surface nodularity and increased echogenicity and sometimes
there’s atrophy in the right lobe and hypertrophy of the left and caudate lobe.
If there’s portal hypertension, then the diameter of the portal vein is over 13 millimeters.
There’s also ultrasound-based elastography- which measures tissue elasticity. Normal liver
elasticity ranges from 2.6 to 6.2 kilopascals and when it’s above 7 kilopascals, that means that
there’s significant fibrosis and when it’s above 11 kilopascals, that means there’s cirrhosis.
A liver biopsy is the gold standard for diagnosing cirrhosis and also finding the cause, but it’s not
always done, especially when other findings strongly suggest cirrhosis. If it’s done, a liver
biopsy will often show bridging fibrosis and irregular nodules of regenerating hepatocytes.
Individuals with cirrhosis should avoid alcohol, medications that are hepatotoxic, such
as acetaminophen and also herbal and dietary supplements, that can damage the liver like
germander. Individuals should also be vaccinated for hepatitis A and B if they’re not already
immune. Doses of certain medications, like tramadol which is an opioid pain medications, may
need to be adjusted to prevent further harm to the liver.
Individuals with cirrhosis should be monitored every 3 to 6 months using a CBC, markers of
liver injury and markers of liver dysfunction.
In addition, an ultrasound should be done and alpha fetoprotein levels can also be checked to
monitor for possible tumors, since cirrhotic individuals are at increased risk for
developing hepatocellular carcinoma.
Okay, now, with decompensated cirrhosis, there are major complications which may be triggered
by things like acute infections, alcohol intoxication, constipation, or even bouts of dehydration.
Treatment for these complications starts with resolving the triggering event - like treating the
infection or abstaining from alcohol.
One major complication of decompensated cirrhosis is jaundice - which can happen because the
liver is unable to conjugate bilirubin. Lab findings would show total bilirubin levels over 2
milligrams per deciliter.
Another complication is hepatic encephalopathy- and this happens because the liver is unable to
effectively remove toxins- like ammonia- from the blood. These toxins can build up and get into
the brain causing symptoms like insomnia or hypersomnia. As toxins accumulate, there can be
mood changes, along with confusion and even coma in some cases.
On physical exam, there may be asterixis- a flapping tremor of the hand that appears when the
wrist is extended- like a bird that’s flapping its wings.
Lab findings show high levels of ammonia, and it can be lowered using lactulose given orally or
through an enema. Lactulose is a non-absorbable sugar that decreases absorption of ammonia in
the intestines and prevents constipation.
If the individual doesn’t improve in 48 hours, then oral Rifaximin is given. That’s an antibiotic
that kills ammonia-producing bacteria in the intestines and also has anti-inflammatory proprietes.
Individuals with recurrent hepatic encephalopathy can be given ongoing treatment with lactulose.
Now, although portal hypertension can seen in compensated cirrhosis - as things worsen, it can
lead to major complications that are seen in decompensated cirrhosis.
Portal hypertension can cause peripheral edema as well as a build up of excess fluid in
the peritoneal cavity - resulting in ascites.
Ascites can cause abdominal distention, as well as shifting dullness on percussion and a positive
fluid wave test.
Additional lab work for ascites includes electrolytes in order to identify any imbalances,
especially hyponatremia.
An abdominal ultrasound can confirm the diagnosis- usually the fluid in ascites appears
anechoic.
Next, a paracentesis is done to collect ascitic fluid. The ascitic fluid is typically crystal clear, and
bloody ascitic fluid suggests a tumor.
A cell count and differential is also done and with normal ascitic fluid there are below
250 neutrophils. In addition, total protein levels are below 3 grams per deciliter, saying that the
fluid is a transudate- while an exudate has more than 3 grams per deciliter of protein.
Next, the ascitic fluid is tested for albumin to calculate the Serum-to-ascites albumin gradient- or
SAAG. A SAAG above 1.1, means that portal hypertension is present.
Because salt helps retain water, treatment of moderate ascites includes sodium restriction to 2
grams per day.
In addition, a combination of diuretics like spironolactone- a potassium sparing diuretic-
and furosemide- a loop diuretic- is commonly used to get rid of excess fluid. Individuals without
peripheral edema typically lose about 0.5 kilograms daily, and individuals with peripheral edema
lose about 1 kilogram daily. As the ascites resolves, the diuretics are tapered and then stopped.
If an individual develops hepatic encephalopathy or has severe hyponatremia- with sodium levels
below 120 milliequivalents per liter, then diuretic treatment is stopped and serial paracentesis is
done to reduce the ascites.
In severe hyponatremia, fluid intake is restricted to less than the urine volume.
Treatment of severe ascites is done using large volume paracentesis- where up to 5 liters of fluid
is taken out of the abdomen at one time without causing hypovolemia. When more than 5 liters
of fluid is taken out, albumin is given afterwards.
A major complication of ascites is spontaneous bacterial peritonitis- or SBP- which is an
infection of the ascitic fluid. It can cause severe abdominal pain, fever, and an altered mental
status.
A paracentesis of the ascitic fluid is done- and the fluid looks turbid or cloudy, the cell count is
over 250 neutrophils per millimeter square and total protein is above 1 gram per deciliter, and the
SAAG is above 1.1.
In addition, the glucose is usually above 50 milligrams per deciliter- which distinguishes SBP
from a secondary bacterial peritonitis, where glucose is below 50 milligrams per deciliter and the
LDH is below 225 international units per liter.
Cultures and cgram stains are also sent.
With SBP, there’s a single pathogen found and the common are Escherichia coli, Klebsiella
pneumoniae, and Streptococcus pneumoniae, whereas with secondary bacterial peritonitis,
multiple pathogens are usually involved. Empiric antibiotics for SBP are IV Cefotaxime.
Another major complication of portal hypertension is variceal hemorrhage- specifically bleeding
from dilated veins in the esophagus and stomach.
Esophageal and stomach variceal veins are usually seen on an upper endoscopy which is usually
done within 12 hours of the bleeding. During that procedure variceal ligation or endoscopic
sclerotherapy can be done to help stop the bleeding. In addition, IV octreotide, which is
a somatostatin analogue, is used to help decrease portal blood flow.
If there’s massive bleeding or if endoscopic therapy fails to stop the bleeding, then balloon
tamponade is done using a Blakemore tube. This applies direct pressure on the esophagus.
If endoscopic approaches fail, a transjugular intrahepatic portosystemic shunt or TIPS procedure
can be done- which creates a path between the portal and systemic circulation in order to lower
the portal pressure.
In moderately ill individuals, IV ciprofloxacin is given for a week to prevent an infection, and in
severely-ill individuals, IV ceftriaxone is given instead.
Given the risk of bleeding, it’s important to spot varices early on, so in compensated cirrhosis -
an upper endoscopy is done every 2 to 3 years and in decompensated cirrhosis, it’s done every
year.
Individuals with varices should have endoscopic variceal ligation done, and those at high risk
like individuals with decompensated cirrhosis should get prophylactic beta-blockers-
like propranolol- which reduce portal vein pressures.
Individuals with a history of ascites, or SBP, or variceal hemorrhage, are given trimethoprim-
sulfamethoxazole as antibiotic prophylaxis.
Two more complications - hepatorenal syndrome and hepatopulmonary syndrome - describe
failure of the liver and kidneys and failure of the liver and lungs, respectively. They occur
because portal hypertension causes arterial and capillary vasodilation which reduces systemic
vascular resistance and can damage the kidneys and lungs.
Okay, now let’s switch gears and talk about hepatocellular carcinoma, which is a primary liver
tumor that often occurs in cirrhosis.
In some cases, there’s a paraneoplastic syndrome with symptoms like hypoglycemia- because the
tumor consumes a lot of glucose, diarrhea- caused by vasoactive peptides that
increase intestinal secretion, and hypercalcemia- due to secretion of parathyroid- like hormone.
Lab findings can include high levels of alpha fetoprotein and if there’s a paraneoplastic
syndrome, there can be hypoglycemia and high levels of calcium. If there’s diarrhea, there may
be hyponatremia or hypokalemia.
An ultrasound would show a hypoechoic mass in the liver and an abdominal CT-scan can help
stage the tumor using the Tumor-Node-Metastasis system.
Finally, a liver biopsy can be done and that typically shows broad trabeculae and pseudoglands.
Common sites of metastasis include the lungs, intra-abdominal lymph nodes and bone.
Depending on the location and spread of the tumor, a partial hepatectomy or a liver transplant
may be done.
If the tumor cannot be surgically removed, then ablation and embolization or chemoradiation can
be done.
If lymph nodes were invaded or if there’s metastasis, then medications like sorafenib or
lenvatinib can be used to slow tumor growth and relieve the symptoms.
Now, let’s talk about the underlying causes of cirrhosis. First off, there’s chronic viral
hepatitis which is usually due to a hepatitis B or C infection that lasts for over 6 months.
With chronic hepatitis B, HBsAg and anti-HBc antibodies are positive, and with chronic
hepatitis C, anti-HCV antibodies are positive and there are elevated levels of HCV RNA.
Next, there’s alcoholic liver disease caused by drinking over 30 grams of alcohol per day- or
more than 3 beers daily, and nonalcoholic fatty liver disease or NAFLD -which is associated
with metabolic syndrome- which includes obesity, arterial hypertension, insulin resistance, and
dyslipidemia. Both of these lead to steatosis- which is the infiltration of liver cells with fat, and
steatohepatitis- which is when there’s fatty infiltration along with inflammation.
When NAFLD causes steatohepatitis, it’s called non-alcoholic steatohepatitis or NASH.
With alcoholic liver disease, lab findings can show anemia and an elevated MCV- suggesting
vitamin B12 or folate deficiency due to alcohol toxicity. The ESR can be elevated and AST to
ALT ratio is above 2.
With NAFLD induced hepatic steatosis and NASH, other causes of hepatic steatosis need to be
ruled out, like alcoholic liver disease and viral hepatitis.
Next, an ultrasound is done and the liver typically appears hyperechoic with both alcoholic and
non-alcoholic liver disease.
On an abdominal CT-scan, the liver composition is compared to the spleen. A fatty liver has an
attenuation that is at least 10 Hounsfield units lower than the spleen.
On a liver biopsy, in steatosis, there’s fat accumulation, and in steatohepatitis
there’s neutrophilic infiltration.
Treatment relies on alcohol abstinence and with NAFLD it requires management of metabolic
syndrome.
Hemochromatosis is a hereditary disorder caused by a mutation in the HFE gene which lead to
increased iron absorption. The excess iron gets deposited in the liver,
heart, pancreas and pituitary.
In advanced stages, individuals have a classic triad of cirrhosis, diabetes mellitus and skin
pigmentation - the latter two are lumped together in the term bronze diabetes.
Lab findings include a serum transferrin above 45%, and disease confirmation is done
with genetic testing. T
reatment consists of reducing iron load with phlebotomies that remove up to 500 milliliters of
blood weekly for 50 weeks, and after that every 2 to 4 months.
Autoimmune hepatitis is a condition where circulating antibodies attack liver cells.
Lab findings include an elevated total gamma globulin level, especially IgG, antinuclear
antibodies or ANA, anti-smooth muscle antibodies, anti-liver-kidney microsomal-1 antibodies,
and antimitochondrial antibodies.
Autoimmune hepatitis is often associated with other autoimmune conditions, like autoimmune
thyroiditis.
Initial treatment is typically done with oral glucocorticoids like prednisone and once there’s
remission- meaning that liver injury markers normalise and there are no
symptoms- prednisone or azathioprine can be used for maintenance therapy.
Primary sclerosing cholangitis is a progressive disease in which there’s inflammation, fibrosis,
and strictures of the medium and large ducts in the intra- and extra- hepatic parts of the biliary
tree. Sometimes, there's an elevated total gamma globulin level, especially IgM. Perinuclear
antineutrophil cytoplasmic antibodies- or p-ANCA- can also be high.
Next, an ultrasound is done and this shows bile duct wall thickening and focal bile duct dilations.
Diagnosis is confirmed by MRCP where the biliary ducts are beaded or have a “pruned tree”
appearance, meaning that there are multiple strictures.
If an ERCP is done, then a biopsy can be performed that shows onion skin fibrosis due to
periductal fibrosis.
Treatment is done using ursodeoxycholic acid- which is a bile acid- that stimulates hepatobiliary
secretion and protects hepatocytes from being destroyed by bile acids. The only treatment
for primary sclerosing cholangitis is a liver transplant.
Primary biliary cholangitis sometimes called primary biliary cirrhosis, is an autoimmune
condition in which the epithelial cells lining the intrahepatic biliary ducts- are gradually
destroyed. There can be distinctive skin changes like hyperpigmentation as well as lesions like
xanthomas and rashes that show dermatographism- which means that it looks like someone has
written or drawn on the skin.
Lab findings include elevated cholesterol levels, antimitochondrial antibodies which are the key
findings, and sometimes antinuclear antibodies are also present.
An ultrasound or MRCP are done to rule out an extrahepatic obstruction.
If a liver biopsy is done, it shows inflammation, abnormal connective tissue, or fibrosis in
the portal and periportal areas.
Treatment is done using ursodeoxycholic acid. The only curative treatment is a liver transplant.
Wilson disease is a genetic disorder that leads to excessive copper deposition in the liver, eyes,
and brain.
Neurological symptoms include dysarthria, ataxia, dystonia, tremor, and parkinsonism. There
can also be psychiatric symptoms like depression and personality changes.
An ocular slit-lamp examination shows Kayser- Fleischer rings - which are dark rings around
the iris.
Lab findings includes ceruloplasmin levels below 20 milligrams per deciliter - that’s the protein
that transports copper. In addition, a 24 hour urine copper test shows over 100 micrograms of
copper in the urine.
Treatment includes avoiding foods with a high copper content like nuts, chocolate, and
mushrooms. Treatment includes cheltators that can bind to excess copper like D-Penicillamine
and Trientine.
Alpha-1 antitrypsin deficiency is a genetic disorder that affects the lungs and the liver. In the
lungs, there’s excess protease activity that results in destruction of elastin, resulting
in emphysema. In the liver, the abnormal alpha-1 antitrypsin protein accumulates and causes
inflammation.
Lab findings include alpha-1 antitrypsin levels below 11 micromol per liter.
Next, isoelectric focusing can be done- this separates molecules based on their isoelectric point
and can identify different alpha-1 antitrypsin variants. PCR can be used to identify the different
alpha-1-antitrypsin variants.
Pulmonary treatment is done with inhaled bronchodilators- such as Salmeterol, and prevention
relies on avoiding smoke exposure. There is no specific treatment for the liver disease.

Summary
Finally! As a quick recap, cirrhosis can be compensated- in which the individual is asymptomatic
or presents nonspecific symptoms. A work up includes a CBC- that can show thrombocytopenia,
anemia, leukopenia, markers of liver injury, like AST, ALT, alkaline phosphatase, GGT which
are elevated, and total and conjugated bilirubin which can be normal. Markers of liver
function like albumin- can decrease as cirrhosis progresses - while PT, PPT, and INR- can
increase as cirrhosis progresses. An ultrasound is done next, along with FibroSure, ultrasound-
based elastography or a liver biopsy- which is the gold standard for diagnosing cirrhosis.
With decompensated cirrhosis, major complications are present. First,
there’s jaundice where total bilirubin levels are over 2 milligrams per deciliter.
With hepatic encephalopathy, there’s asterixis and high levels of ammonia. Treatment relies on
eliminating precipitating factors, lactulose, and rifaximin.
Another complication is severe portal hypertension which often leads to ascites- that’s usually
treated with sodium restriction and diuretic therapy, SBP- that’s treated with IV cefotaxime,
and esophageal and gastric variceal hemorrhage- that’s treated with endoscopic variceal ligation
or endoscopic sclerotherapy or TIPS and prevented with propranolol, hepatorenal
syndrome and hepatopulmonary syndrome.
One complication of cirrhosis overall is hepatocellular carcinoma, which can be monitored with
an ultrasound every 3 to 6 months. A CT-scan is done to confirm the diagnosis and stage the
condition using TNM system. Treatment depends on the extent and location of the tumor.

Cirrhosis: Pathology review

At the family medicine clinic, a 52- year- old male immigrant from Africa, named Jamar, came
in for a checkup for the first time in a decade. On questioning, he admits to an extensive history
of alcohol abuse. Physical examination reveals gynecomastia, palmar erythema and spider
angiomata, as well as a palpable spleen.
Next, a 70- year- old Caucasian female, named Eleanor, with a history of chronic hepatitis C
infection, is brought to the emergency department by paramedics due to altered mental status.
She is completely disoriented and unable to provide an adequate history. Neurologic examination
also reveals asterixis.
Lab tests of both show increased aspartate aminotransferase, or AST, and alanine
aminotransferase or ALT. There’s also decreased albumin and increased prothrombin time. The
difference is that Jamar has an AST level twice as high as ALT, in contrast with Eleanor, who
has an ALT higher than AST. Eleanor, in particular, also has high serum levels of ammonia.
Both Jamar and Eleanor have cirrhosis. This is when chronic inflammation damages the liver
causing it to become fibrotic. Normally, the liver is highly regenerative but scar tissue can
replace liver cells which prevents regeneration and when this goes on for too long, it reaches the
point where the damage is no longer reversible. If enough of the liver is replaced by scar tissue in
advanced cirrhosis, a liver transplant might be needed. . Now, if we zoom into a hepatic lobule,
we can see that it’s made of sheets of hepatocytes with sinusoids between them. The sinusoids
are made of branches of the portal vein and hepatic artery, and together with the bile duct, form
the portal triad which runs towards the central vein.
Now, there’s a space around each sinusoid, called the perisinusoidal space which contains
stellate cells. When the hepatocytes are injured, they cluster together and form regenerative
nodules. Here, they secrete paracrine factors that activate the stellate cells, which then
proliferate, and start secreting transforming growth factor beta1, or TGF-beta. This causes them
to produce collagen. The collagen builds up around the nodules and helps form scar tissue,
leading to fibrosis.
Okay, let’s look at some of the causes of cirrhosis. First off, there’s chronic viral hepatitis which
is usually due to a hepatitis B or C infection that lasts for over 6 months. Next, there’s alcoholic
liver disease caused by excessive alcohol consumption, and nonalcoholic fatty liver disease, or
NAFLD, caused by metabolic syndrome which consists of hypertension, hyperglycemia, insulin
resistance, and dyslipidemia. Now, alcohol metabolism needs alcohol dehydrogenase and
aldehyde dehydrogenase, which uses up NAD+. Beta oxidation in lipid metabolism also needs
this coenzyme, so when they’re used up, lipids accumulate inside hepatocytes.
Next, free oxygen species are also created during alcohol metabolism, and this could also
damage hepatocytes. In NAFLD, insulin resistance causes fat to build up in the hepatocytes, so
both kinds of liver disease lead to steatosis, which is the infiltration of liver cells with fat, and
steatohepatitis, which is when there’s fatty infiltration along with inflammation. Now, steatosis
and steatohepatitis are reversible, but when too much damage is done, they can lead
to cirrhosis and this is nonreversible. Then, there’s hemochromatosis, which is an autosomal
recessive disorder caused by a mutation in the HFE gene that leads to increased iron absorption
in the small intestine. Another cause is frequent transfusions, like when a person has thalassemia.
Excess iron gets deposited everywhere, but particularly in the liver, pancreas, heart, pituitary
gland, joints, and skin. On your exam, individuals will have a classic triad of cirrhosis, diabetes
mellitus, and skin hyperpigmentation, the latter two are lumped toget her with the term
bronze diabetes since the skin looks bronzed or tanned.
Treatment consists of reducing iron in the body with phlebotomy or with iron chelators like
deferasirox, deferoxamine, and deferiprone. Wilson disease is another autosomal recessive
disorder. This is caused by a mutation in hepatocyte copper-transporting ATPase which is
needed to move copper from the liver into bile for excretion, and it’s also needed to synthesize
ceruloplasmin, the copper storage and transport protein in the blood. So the mutation leads to
excessive copper buildup in the liver, and low ceruloplasmin level. Eventually, the copper
overflows into the blood and deposits in the brain and eyes. A typical case in your exam will
present an individual with cirrhosis and neurological symptoms like dysarthria, dystonia, tremor,
and parkinsonism or psychiatric symptoms like depression and personality changes. And another
high yield finding is Kayser- Fleischer ring, which is a dark ring around the iris due to copper
deposits in the cornea. Treatment includes cheltators that bind to excess copper, like
penicillamine or trientine.
Next, there’s alpha-1 antitrypsin deficiency, which is an autosomal codominant disorder, where
there’s insufficient alpha-1 antitrypsin. This protein normally inactivates neutrophil elastase, but
when there’s a deficiency, these elastases can damage the alveoli in the lungs, resulting
in emphysema. And in the liver, misfolded alpha-1 antitrypsin builds up, killing hepatocytes and
leading to cirrhosis. So, a test question will often present a young person
with cirrhosis and dyspnea without a history of smoking. Next, there’s autoimmune hepatitis,
where circulating antibodies attack liver cells. This is often associated with specific
autoantibodies, such as antinuclear antibodies, anti-smooth muscle antibodies, and anti-liver-
kidney microsomal-1 antibodies. Finally, cirrhosis can be caused by biliary diseases like primary
sclerosing cholangitis and primary biliary cholangitis. Both disorders cause damage to the biliary
system, leading to scarring of the bile ducts that prevent bile from draining.
The bile backs up into the liver, causing damage, and eventually cirrhosis. Key symptoms for
both include jaundice, pruritus, dark urine, clay-colored stool, and hepatosplenomegaly. Primary
sclerosing cholangitis or PSC, is a progressive disease in which there’s inflammation, fibrosis,
and strictures of the intra- and extra- hepatic parts of the biliary tree. This is classically described
as “onion- skin” fibrosis, because it looks a bit like an onion skin, with concentric rings of
fibrosis around the bile duct. It’s classically seen in middle- aged males with inflammatory
bowel disease. It’s also linked to cholangiocarcinoma and cancer of the gallbladder.
Now, in primary biliary cholangitis, or PBC, the epithelial cells lining the intrahepatic biliary
ducts are gradually destroyed, but the cause is unknown. It’s possibly autoimmune in nature
since it’s classically seen in middle- aged females with another autoimmune condition, like
autoimmune thyroiditis or rheumatoid arthritis. Since the liver plays a major role in cholesterol
metabolism, PBC can lead to hypercholesterolemia. This can manifest as xanthelasmas which
are cholesterol deposits that form skin nodules, typically around the eyes. Now, sometimes, the
exam will try to test you on cirrhosis by presenting its complications.
So, let’s start with portal hypertension. So, as the central veins and sinusoids become compressed
by scar tissue, their pressure starts to build up. Higher portal pressure means that fluid in blood
vessels is more likely to get squeezed out into tissues and then leak into large open spaces like
the peritoneal cavity. That’s how cirrhosis leads to excess peritoneal fluid, also known as ascites.
The classic patient with ascites will present with abdominal distention, as well as shifting
dullness on percussion. If abdominal distention is also accompanied by severe abdominal pain
and fever or chills, this might be a sign of spontaneous bacterial peritonitis.
This is an infection of ascitic fluid by a pathogen, most commonly a gram negative one,
like Escherichia coli, or Klebsiella pneumoniae, and, less commonly, gram positive,
like Streptococcus pneumoniae. It’s called spontaneous because there’s no obvious source of
infection like a ruptured bowel. An important thing to bare in mind here is that in a paracentesis
of the ascitic fluid, the cell count is over 250 neutrophils per millimeter square. It has a very
high mortality rate and is treated with a third generation cephalosporin, like cefotaxime. Okay,
with portal hypertension blood has a harder time getting into the liver from the GI tract, so it
backs up into the spleen, causing splenomegaly. It also backs up into the portosystemic
collateral veins on the anterior surface of the abdomen, causing caput medusae.
In the lower rectum, this leads to hemorrhoids, and in the lower end of the esophagus it leads
to esophageal varices. In fact, the only sign of portal hypertension could be esophageal
variceal bleeding, leading to hematemesis, or vomiting of blood, or melena, which is the passage
of black, tarry stools. The treatment for portal hypertension is transjugular intrahepatic
portosystemic shunts, or TIPS. This creates a shunt between the portal vein and hepatic vein so
blood from the intestines bypasses the liver and moves into systemic circulation. Two more
complications of portal hypertension are hepatorenal syndrome and hepatopulmonary
syndrome which describe failure of the liver and kidneys and failure of the liver and lungs.
Though not fully understood, they seem to occur because changes in portal flow trigger arterial
and capillary vasodilation which reduces systemic vascular resistance and can damage the
kidneys and lungs.
Now, other types of complications start to appear as functional liver tissue decreases. One of
them is the inability to remove toxins, like ammonia, from the blood. These toxins can build up
and harm tissues like the brain, causing hepatic encephalopathy. Anything that increases
ammonia production or reabsorption in the gut can be a trigger, like GI bleeding, constipation, or
infections. Decreased ammonia removal by the kidneys can also be a trigger, like when
there’s renal failure.
Finally, TIPS used to treat portal hypertension can also be a trigger since ammonium rich blood
from the intestines bypasses the liver completely. Hepatic encephalopathy presents with
symptoms like insomnia or hypersomnia, mood changes, along with confusion, and even coma in
some cases. For your exams, remember that the telltale sign is asterixis, a flapping tremor of the
hand that appears when the wrist is extended, like a bird that’s flapping its wings. A typical lab
finding is high levels of ammonia and it can be lowered using lactulose. This is a non-absorbable
sugar that decreases absorption of ammonia in the intestines. Rifaximin or neomycin can be also
used, which are antibiotics that kill ammonia- producing bacteria in the intestines.
Also, since the liver plays a big role in metabolizing estrogen into inactive metabolites,
increased estrogen in the blood can also lead to complications, like testicular atrophy, decreased
body hair and gynecomastia in male, as well as spider angiomas, which are swollen blood
vessels just beneath the skin surface, and palmar erythema, which is redness of the hands. And,
since the liver conjugates bilirubin, increased unconjugated bilirubin builds up in the blood
which leads to jaundice, or yellowing of the skin and sclera. Another important job of the liver is
producing albumin, so cirrhosis also causes low albumin levels in the blood,
or hypoalbuminemia. This causes peripheral edema, often seen in the lower limbs, since there’s
less oncotic pressure in the blood vessels and the fluid leaks out.
The liver also helps in making clotting factors, so, on your tests, a cirrhotic patient could also
present with easy bruising and excessive bleeding. Eventually, since the liver is in a constant
cycle of damage and repair, it raises the chances of genetic mutations, potentially leading to
carcinogenesis or development of hepatocellular carcinoma. This is the most common primary
malignant liver tumor in adults. A high- yield fact is that it’s associated with high levels of alpha
fetoprotein. For diagnosis of cirrhosis, the “gold standard” is a liver biopsy. But, for your exams,
there are many important findings that will act as clues to help identify the cause! In cirrhosis,
there’s usually indicators of liver cell damage, like elevated aspartate aminotransferase, or AST,
and alanine aminotransferase, or ALT. In most cases, ALT is higher than AST, except
for alcoholic liver disease, where the ratio of AST to ALT is typically higher than 2:1.
For alcoholic liver disease, remember that the histology will show Mallory bodies which are
damaged intermediate filaments that accumulate inside hepatocytes.
These are eosinophilic so they appear pink on H&E stain. In NAFLD, lipids build up
inside hepatocytes, causing them to swell up, which is called “ballooning.”
For hemochromatosis, look for high serum iron, ferritin, and transferrin, but low total iron
binding capacity.
Next, a liver biopsy with Prussian blue stain that detects iron is traditionally used, but this has
been replaced by MRI, which detects liver iron distribution without an invasive procedure.
In Wilson disease, look for Kayser- Fleischer ring with an ocular slit-lamp examination. Serum
ceruloplasmin level is low, while serum and urine copper are elevated. In alpha-1 antitrypsin
deficiency a liver biopsy will reveal globules of misfolded alpha-1 antitrypsin protein inside
the liver cells, and remember that these are Periodic Acid Schiff or PAS stain positive.
For your exams, remember that Primary sclerosing cholangitis is associated with elevated IgM
antibody levels and perinuclear antineutrophil cytoplasmic antibodies, or p-ANCAs. Perinuclear
means they are specific antibodies that target antigens around the nucleus of neutrophils. Also, in
a magnetic resonance cholangiopancreatography, or MRCP, the biliary ducts are beaded or have
a “pruned tree” appearance, meaning that there are multiple strictures. In contrast, primary
biliary cholangitis has increased antimitochondrial antibodies, and a normal MRCP. Indicators of
biliary injury, like elevated alkaline phosphatase or ALP and gamma- glutamyl transferase or
GGT are hints for primary sclerosing cholangitis or primary biliary cholangitis. Remember that
ALP can be also elevated in bone disease, in contrast with GGT, which is specific for biliary
diseases.
Next, indicators of reduced liver function include decreased serum albumin levels,
increased bilirubin levels and prothrombin time or INR. These are the best indicators of the
prognosis in a person with cirrhosis. Another common finding is also thrombocytopenia or low
platelet count, especially if there’s splenomegaly.
All right, time for a review! Cirrhosis is when there’s damage to the liver and healthy tissue is
replaced with scar tissue. Causes include chronic hepatitis B or hepatitis C infection, alcoholic
liver disease, non alcoholic liver disease, genetic disorders, like hemochromatosis, Wilson
disease, alpha-1 antitrypsin deficiency, as well as autoimmune hepatitis and biliary disorders,
like primary sclerosing cholangitis and primary biliary cholangitis. Over time, complications
develop. Portal hypertension can lead to ascites, splenomegaly, portosystemic collaterals,
hepatorenal or hepatopulmonary syndrome.
Decreased liver function can lead to hepatic encephalopathy,
increased estrogen, jaundice, edema and easy bruising. Diagnosis is done with a biopsy or
through lab and imaging tests. It’s important to identify and treat the cause of cirrhosis because
the only treatment for advanced cirrhosis is a liver transplant.
Okay, but let’s not forget about our cases. Jamar had the typical presentation of cirrhosis,
probably due to chronic alcohol consumption. This included signs of high estrogen levels,
specifically gynecomastia, spider angiomata and palmar erythema, as well as splenomegaly,
which is a sign of portal hypertension.
Meanwhile, Eleanor came in with altered mental status and asterixis, which alongside high
ammonia levels, should remind us of hepatic encephalopathy. This is a complication of cirrhosis,
probably secondary to her chronic hepatitis C infection. In both of them, blood tests showed
indicators of liver damage, meaning elevated AST and ALT, and decreased liver function,
meaning decreased albumin and increased prothrombin time.
The fact that Jamar has a ratio of AST to ALT higher than 2 is indicative of alcoholic liver
disease. And if a liver biopsy were to be done, it would show regenerative nodules with
intermediate bands of fibrosis. ...And that’s cirrhosis pathology in a nutshell.

Sources
1. "Fundamentals of Pathology" H.A. Sattar (2017)
2. "Robbins Basic Pathology" Elsevier (2017)
 3. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
4. "The Immunobiology and Pathophysiology of Primary Biliary Cirrhosis" Annual
Review of Pathology: Mechanisms of Disease (2013)
5. "Epidemiology of Alcoholic Liver Disease" Seminars in Liver Disease (2004)
6. "Pathogenesis, Diagnosis, and Treatment of Alcoholic Liver Disease" Mayo Clinic
Proceedings (2001)
7. "Current concepts in the assessment and treatment of Hepatic
Encephalopathy" QJM (2009)
8. "Oxidative Stress and Epigenetic Instability in Human
Hepatocarcinogenesis" Digestive Diseases (2013)
9. "Involvement of DNA Damage Response Pathways in Hepatocellular
Carcinoma" BioMed Research International (2014)
10. "Hereditary Hemochromatosis — A New Look at an Old Disease" New England
Journal of Medicine (2004)

Non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease is actually a spectrum of disease, going from least to most severe
—steatosis, steatohepatitis, fibrosis, and finally cirrhosis.
Nonalcoholic fatty liver disease results from fat deposition in the liver, which is unrelated
to alcohol or viral causes.
Typically, it affects individuals with metabolic syndrome, which includes a combination of three
of the following five diagnoses: obesity, hypertension, diabetes, hypertriglyceridemia,
and hyperlipidemia.
Given how common metabolic syndrome has become, it’s not surprising that the rate
of nonalcoholic fatty liver disease has also increased dramatically.
It’s a massive problem growing in lock-step with expanding waistlines, affecting about three
quarters of all obese individuals, including many children.
Although the exact mechanism of nonalcoholic fatty liver disease isn’t clear, insulin resistance
seems to play an important role.
Over time, insulin receptors on various tissues including the liver become less responsive
to insulin, and as a result the liver goes into a mode where it increases fat storage and
decreases fatty acid oxidation.
That means decreased secretion of lipids into the bloodstream, in the form of lipoproteins, and
increased synthesis and uptake of free fatty acids from the blood, a process called steatosis.
Steatosis causes fat droplets to form within hepatocytes, some of which become large enough to
cause the hepatocytes to swell up with fat and push the nuclei to the edge of the cell.
You can see this on a histopathology slide of the liver.
All of these white circles are large deposits of fat.
Zooming out and looking at the liver, you see widespread steatosis which makes the liver appear
large, soft, yellow, and greasy.
Over time, that fat in the hepatocytes is vulnerable to degradation.
Unsaturated fatty acids, or fatty acids that have at least one double bond in their carbon chain,
have hydrogen atoms that are especially vulnerable to initiators such as the reactive oxygen
species like the hydroxyl radical that have an unpaired electron.
In this example the hydroxyl radical pairs with the vulnerable lipid hydrogen to make water and
a fatty acid radical.
The fatty acid radical is unstable and reacts with non-radicals, including molecular oxygen and
undamaged fatty acids.
This goes on until one radical species reacts with another radical species, which terminates the
reaction.
This process damages lipid membranes leading to things like mitochondrial dysfunction and
eventually cell death.
Cell death generates inflammation, and together the process of steatosis and inflammation is
referred to as steatohepatitis.
In the absence of alcohol this is called nonalcoholic steatohepatitis or NASH.
In addition to bloated and dying hepatocytes, there might be additional histopathologic changes
like the presence of Mallory-Denk bodies which are tangles of intermediate filaments that can be
seen in the cytoplasm of hepatocytes.
The mechanism, though, for how these form remains unclear.
Hepatocyte damage also attracts neutrophils into the liver tissues.
And finally, chronic steatohepatitis can cause liver stellate cells to lay down fibrotic tissue
causing the disease to be classified as fibrosis.
As the process of fibrosis continues, the overall architecture of the liver changes, to the point
where the disease is classified as cirrhosis.
Even at the advanced stage of steatohepatitis, an individual might have no symptoms.
And when there are symptoms, they are often vague, like fatigue or malaise.
Once there is significant liver damage, though, there can be hepatomegaly or enlargement of the
liver, pain in the right upper quadrant of the abdomen, jaundice, and even an accumulation of
fluid in the peritoneal cavity called ascites.
Because hepatocytes are being destroyed, there can be an increase in liver enzymes like aspartate
transaminase (or AST) and to a greater extent, alanine transaminase (or ALT).
Classically, progression of steatosis to steatohepatitis and then to cirrhosis causes an increase in
the ALT and sometimes AST.
In contrast, alcoholic liver injury generally causes a big increase in AST and a more modest
increase in ALT giving a AST:ALT ratio generally greater than 2.
If nonalcoholic fatty liver disease is suspected, a diagnosis can be made with imaging studies
such as ultrasound, a CT scan, or an MRI to look for fatty infiltrates.
In addition, a biopsy of the liver can be done to confirm the diagnosis and assess the severity of
the disease.
Generally speaking, a liver with more than 5% fat content is considered abnormal.
Steatosis and to a lesser degree steatohepatitis is generally reversible by addressing the
underlying cause, although that’s generally not the case once fibrosis and cirrhosis have set in.
The goal is to reverse the factors that contribute to insulin resistance, primarily through a healthy
diet and an active lifestyle, as well as medications to control blood glucose levels if needed.

Summary
Alright, as a quick recap, nonalcoholic fatty liver disease happens when fat is deposited in the
liver, a process called steatosis.
Inflammation from steatosis can lead to steatohepatitis, and chronic steatohepatitis can lead to
fibrosis, and ultimately to cirrhosis.
This spectrum of disease is thought to be caused by insulin resistance, and depending on the
stage of disease, it can be reversed with careful attention to diet and exercise, as well as
medications to help control blood glucose levels.

Summary
Non-alcoholic fatty liver disease (NAFLD) is a condition in which excess fat is deposited in the
liver, leading to inflammation and scarring. NAFLD is a common liver disorder that affects
people who do not drink alcohol excessively. NAFLD commonly affects people with metabolic
syndrome, which includes a combination of three of the following five diagnoses:
obesity, hypertension, diabetes, hypertriglyceridemia, and hyperlipidemia.
Symptoms of NAFLD may be subtle or absent in the early stages of the disease. In advanced
stages, symptoms may include fatigue, abdominal pain, and jaundice. NAFLD can progress to a
more serious condition called non-alcoholic steatohepatitis (NASH), which can lead to liver
scarring and cirrhosis. Treatment for NAFLD may involve lifestyle changes such as weight
loss, regular exercise, and a healthy diet to help reduce fat in the liver and improve insulin
resistance.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
 2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-
Hill Education / Medical (2018)
4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw Hill
Professional (2019)
5. "The Role of Intestinal Bacteria Overgrowth in Obesity-Related Nonalcoholic Fatty
Liver Disease" Nutrients (2014)
6. "Non-alcoholic fatty liver disease" BMJ (2014)

Viral hepatitis: Pathology review

At your clinic, 44-year-old Colin comes to the office because of abdominal pain for 3 months.
He has not been to a physician in 10 years and has been using IV drugs since he was 17.
He does not drink alcohol and has no significant family history.
His temperature is 38.2°C or 100.76°F, pulse is 98/min, respirations are 19/min, and blood
pressure is 126/84 mmHg.
Physical examination shows a large distended abdomen, yellow sclera, palmar erythema, and
spider angioma on his abdomen and extremities.
Lab results reveal the following: Hepatitis A IgM antibody negative, Hepatitis B surface antigen
negative, Hepatitis B surface antibody positive, Hepatitis B core antibody negative, and HCV
antibody positive.
At the same time, a 32-year-old pregnant individual named Megan comes to the emergency
department because of vomiting and fever.
The patient worked as a global health nurse and her medical history is relevant for recent
traveling to Nepal.
Physical examination shows yellowing of the skin and sclera, right upper quadrant tenderness,
and hepatomegaly.
Her temperature is 38.5°C or 101.3°F, pulse is 97/min, respirations are 15/min, and blood
pressure is 120/75 mmHg.
Both Colin and Megan have viral hepatitis, which is inflammation of the
liver parenchyma caused by hepatitis viruses A, B, C, D, or E.
Based on the duration of symptoms, hepatitis can be acute, which lasts less than 6 months, or
chronic, which lasts more than 6 months.
Individuals with acute viral hepatitis typically present with fatigue, malaise, nausea, vomiting,
anorexia, low-grade fever, jaundice, dark urine, and right upper quadrant tenderness; whereas
individuals with chronic viral hepatitis can be asymptomatic or they can present with non-
specific symptoms such as malaise and fatigue.
Regardless of the virus that’s causing it, histopathology of viral hepatitis is characterized by two
main findings: first, there’s hepatocyte injury where the damaged hepatocytes swell up, and this
is called ballooning degeneration; second, there’s hepatocyte death and necrosis.
The dead cells are replaced by scar tissue which disrupts the normal architecture of hepatic
lobules.
If the damage is severe enough, dead hepatocytes can become confluent and form stripes that
connect zones of adjacent lobules, which is called bridging necrosis.
Other histopathological findings include Councilman, or apoptotic bodies, which are dying
eosinophilic hepatocytes surrounded by normal liver parenchyma.
Lastly, there’s panlobular mononuclear infiltration, where macrophages and lymphocytes move
into the lobules in order to contain the infection and clear out the debris.
Okay, so each lobule can be divided into 3 zones.
Zone I is closest to the portal triad, so it’s also called the periportal zone.
If we move towards the center, we have zone II, or the transitional zone, and closest to the
central vein, we have zone III, or pericentral zone.
A high yield concept to remember is that Viral hepatitis affects zone I first; Ischemic
injury and metabolic toxins, like those from alcohol and acetaminophen metabolism, affect zone
III first.
As far as laboratory findings go, viral hepatitis is associated with increased levels of serum
aspartate transaminase, or AST, and alanine aminotransferase, or ALT.
It’s important to note that in viral hepatitis, drug-induced liver injury, and ischemic hepatitis,
levels of serum ALT are higher than AST, in contrast to alcoholic hepatitis, where serum AST is
higher than ALT and the ratio is usually 1 to >1.5.
So remember, in virAL hepatitis, ALT is higher!
The exception is when there’s progression to advanced hepatic fibrosis and cirrhosis, the AST
will become higher than ALT.
Okay, now let’s focus on the specific viruses, starting with hepatitis A and hepatitis E viruses.
These viruses are naked viruses that do not rely on an envelope.
Hepatitis A virus, or HAV, is an RNA picornavirus which is transmitted by the fecal-oral route,
through ingestion of contaminated water or food, such as shellfish.
It’s the most common cause of acute viral hepatitis and populations at risk include travelers and
those in daycare centers.
The incubation period, which typically lasts for 30 days, can be followed by a silent, or
subclinical course, which is characterized by the absence of symptoms; or by the classic
presentation of acute viral hepatitis, along with hepatomegaly, and aversion to smoking.
Also, keep in mind that hepatitis A infection is a self-limiting disease that does not progress
to chronic hepatitis; therefore the prognosis is usually good and there’s no risk
of cirrhosis or hepatocellular carcinoma.
A high yield concept to know is that the anti-HAV IgM antibody is produced early in the
infection, so if detected, it means there’s an active infection.
The anti- HAV IgG antibody is the protective antibody produced later on, or even after the
infection has passed, and it suggests prior infection or vaccination.
Also, hepatitis A virus does not have a carrier state where infected individuals do not have
symptoms, but can spread the infection to others.
Treatment is supportive and generally, there’s complete recovery within 3-6 weeks.
Finally, hepatitis A vaccine, made from killed, or inactivated HAV, is indicated for people
traveling to, living, or working in endemic areas; individuals with chronic liver disease
or clotting-factor disorders; and men who have sex with other men.
On the other hand, passive immunization with immune globulin against HAV should be given to
individuals that were in close contact with an infected person.
The second type is hepatitis E virus, or HEV.
Hepatitis E virus is a single-stranded RNA virus that belongs to the hepevirus family.
It is transmitted by the fecal-oral route, such as undercooked seafood or contaminated water and
it can cause waterborne epidemics that are especially common in Asia, Africa, and the Middle
east.
Hepatitis E virus is characterized by its short incubation period and usually lasts for 6 weeks.
After the incubation period, individuals with hepatitis E virus infection typically present with the
classic presentation of acute viral hepatitis, and during this period they shed the virus in the stool.
Just like hepatitis A, hepatitis E infection is also a self-limiting disease that does not progress
to chronic hepatitis; therefore there’s no risk of hepatocellular carcinoma.
Also, you have to know that in pregnant individuals, this virus can cause fulminant hepatitis,
which is a life-threatening condition with severe liver function impairment.
As far as serology markers go, early stages of infection, while the person is still asymptomatic,
there’s increased HEV Antigen or HEV RNA.
When symptoms appear, there’s an increase in serum levels of ALT and AST because the liver
gets damaged, and this is the stage when anti-HEV IgM can be detected.
Remember that IgM indicate an active hepatitis infection!
On the other hand, anti-HEV IgG are produced during the latest stage and they signal recovery
from the infection.
Finally, the treatment for hepatitis E infection is supportive and there are currently no commonly
used vaccine.
Moving on to the third type, which is hepatitis B virus or HBV.
This virus belongs to the DNA hepadnavirus family.
On the surface of the mature virion, there’s a lipid envelope with hepatitis B surface antigen.
Within the envelope, there’s a hexagonal protein capsid, which consists of proteins
called hepatitis B core antigen or just core antigen.
Between the lipid envelope and capsid is a secretory hepatitis B e antigen.
Within the capsid, there’s a partially double-stranded viral DNA and DNA polymerase enzyme,
which has DNA- and RNA-dependent activity.
Now, once the virion enters the cell, the viral DNA is transferred into the nucleus of
the hepatocyte where DNA polymerase turns the partially double-stranded DNA into a fully
double-stranded circular DNA.
Next, the host RNA polymerase transcribes the newly formed DNA to make viral RNA, which is
sent into the cytoplasm of the cell where its used to synthesize viral proteins.
But that’s not all!
You have to know that the DNA polymerase then reverse transcribes the viral RNA into a new
partially double-stranded DNA molecule, and this will be packaged together with the newly
synthesized viral proteins to make a new virus.
Now, hepatitis B virus has several modes of transmission.
First, there’s parenteral transmission, or via blood; and individuals that are at risk include
intravenous drug users, healthcare workers exposed to blood and needle-stick accidents, patients
on dialysis, and blood transfusion recipients.
But remember, even though blood is the primary mode of transmission, hepatitis B virus can also
be detected in other bodily fluids such as saliva, tears, sweat, semen, and breast milk.
So the 2nd route is sexual transmission, and together with parenteral, they are categorized as
horizontal transmission.
The third type is perinatal transmission which is categorized as vertical transmission, and this is
when a mother transmit the infection to her infant either right before birth via the placenta, or
during and after birth via blood, body fluids, or breast milk.
So, once a person is infected, they will go through a long incubation period that can last from 30
to 180 days.
The incubation period is usually followed by a prodrome period which is characterized by
malaise, fever, arthralgias, lymphadenopathy, pruritus, and rash.
Now after the prodrome the individual can develop acute hepatitis with complete resolution.
On the other hand, some people will develop chronic hepatitis, with or without cirrhosis.
In this case, they might be in the carrier state where damage to the liver stops, but they can still
spread the infection to others.
Finally, they can also develop fulminant hepatitis, which is characterized by rapid and massive
necrosis of liver parenchyma and subsequent liver atrophy.
Okay, so a high yield concept is that in adults, the possibility to progress to chronic hepatitis is
less than 5%; in children, it is 20-30%; while in neonates this number goes up to 90%.
Therefore, a baby born to a mother with active hepatitis B infection has to receive anti-hepatitis
B immunoglobulin and the initial dose of the hepatitis B vaccine.
Hepatitis B vaccine is a subunit vaccine, meaning that it contains a hepatitis B surface antigen,
which stimulates the production of antibodies against this antigen.
Interferon alpha is used in the treatment of chronic hepatitis B infection.
Hepatitis B virus can also cause extrahepatic manifestations which can be subdivided
into: hematologic, such as aplastic anemia; renal, which include membranous
glomerulonephritis, which is more common, and membranoproliferative glomerulonephritis,
which is less common; and vascular, such as polyarteritis nodosa.
Now, histopathology of an individual with chronic hepatitis B infection shows a granular
eosinophilic “ground glass” appearance which is the hallmark of chronic hepatitis B infection.
This “Ground glass” appearance occurs when the cytoplasm of hepatocytes gets filled with bits
and pieces of hepatitis B viral proteins.
It’s important to note that the virus itself is not cytotoxic.
Instead, the liver is damaged by the response of cytotoxic T-cells to antigens that are presented
on infected hepatocytes, such as hepatitis B surface antigen and hepatitis B core antigen.
Now let’s move on to serological markers which are super high yield!
Let’s start with a hepatitis B surface antigen which indicates active hepatitis B infection;
and hepatitis B surfatzce antibody, which suggests recovery from infection or immunity due
to vaccination.
Next, there's hepatitis B core antigen which can only be detected after liver biopsy and if
positive, it indicates active viral replication.
On the other hand, hepatitis B core antibody can be IgM, which is associated with
recent hepatitis B infection, typically in the last 6 months; or IgG, which suggests resolved or
chronic infection.
Finally, the hepatitis B e antigen also suggests active viral replication.
Elevated levels of this antigen is closely linked to poor prognosis, and high transmissibility.
A high yield fact to remember is that this is especially true for vertical transmission!
On the other hand, antibody to hepatitis B e antigen is present after recovery from acute infection
and it is associated with low transmissibility.
Now let’s draw a graph of the serological markers in acute hepatitis B infection.
The vertical axis of the graph is the relative concentrations of serological markers; the horizontal
axis of the graph is time after exposure measured in months; and on the top are phases of
infection.
First, there’s the incubation period that lasts 2 months; which is followed by prodrome and acute
infection that lasts for 3 months.
The last phase is the recovery phase.
One month after exposure to the virus, hepatitis B surface antigen starts to rise and peaks when
the symptoms are most severe.
Soon after hepatitis B surface antigen rises, hepatitis B e antigen and viral DNA appear; and they
indicate that the person is highly infectious!
These markers are further followed by the appearance of IgM antibody to hepatitis B core
antigen.
In the next few months, these will go down and get replaced by IgG antibody.
For your exam, you have to know that the hepatitis B e antigen and viral DNA disappear before
the hepatitis B surface antigen.
Shortly after hepatitis B e antigen disappears, antibody to hepatitis B e antigen can be detected,
and at this stage, the person is no longer highly infectious.
After that, hepatitis B surface antigen will also disappear and the acute infection has passed.
Antibodies to hepatitis B surface antigen will go up sometime after.
These antibodies remain undetectable for several weeks and this period of infection, without
detectable hepatitis B surface antigen and antibodies to hepatitis B surface antigen, is referred to
as the window period.
This is high yield because it’s possible to miss the infection based on serological markers during
this period.
Once detectable, antibody to hepatitis B surface antigen rises and persists, providing
lifelong immunity.
Finally, we need to mention that at the end of the incubation period and during the acute phase of
the infection, a person will have elevated liver enzymes, especially ALT.
Also, you should not forget that if hepatitis B surface antigen persists after 6 months, the person
has progressed to chronic hepatitis B infection.
Okay, let’s summarize the serological markers during the phases of infection!
An individual with an acute hepatitis B infection has the following serologic markers: hepatitis
B surface antigen, and IgM antibody to hepatitis B core antigen.
Next, during the window period of hepatitis B infection, an individual is positive for hepatitis B e
antibody and IgM antibody to hepatitis B core antigen.
An individual with chronic hepatitis B infection and is high infectious will have hepatitis
B surface antigen, hepatitis B e antigen, and IgG antibody to hepatitis B core antigen.
On the other hand, if an individual has chronic hepatitis B infection and low infectivity he will
have hepatitis B surface antigen and IgG antibody to hepatitis B core antigen.
So remember, only individuals who have been infected with hepatitis B virus will be positive
for IgG to hepatitis B core antigen after clearing the infection or transitioning to chronic
infection.
Finally, during the recovery period of hepatitis B infection a person has the following serologic
markers: antibody to hepatitis B surface antigen, hepatitis B e antibody, and IgG
antibody to hepatitis B core antigen; while immunized individuals have only IgG
antibody to hepatitis B surface antigen since the other components are not in the vaccine.
Moving on to hepatitis D virus, or HDV.
This virus is a single-stranded RNA virus and is most commonly transmitted parenterally.
Less common modes of transmission include sexual and perinatal transmission.
For your exam, you have to know that hepatitis D virus requires the hepatitis B surface antigen to
enter and infect hepatocytes.
Therefore, the virus can be acquired either as a “coinfection” with hepatitis B virus, where both
infections happen at the same time, or as a “superinfection” of a chronic HBV carrier, where the
person is infected with HBV first, and then later with HDV.
It’s important to note that the superinfection of a chronic HBV carrier is associated with a worse
prognosis and increased risk of liver cirrhosis.
The incubation period is short and the clinical presentation of hepatitis D infection is similar
to hepatitis B infection.
Also, hepatitis D virus is associated with an increased risk of hepatocellular carcinoma.
Liver biopsy is similar to hepatitis B infection.
But, if serology reveals either IgM or IgG HDV antibodies, this suggests that a person has an
active infection since IgG is not considered to be a protective antibody in hepatitis D infection.
Finally, vaccination against hepatitis B virus also protects against hepatitis D virus, since it
needs hepatitis B surface antigen to infect hepatocytes.
The next one is hepatitis C virus, or HCV.
This virus belongs to the Flaviviridae family of viruses and it’s an enveloped single-stranded
RNA virus with icosahedral capsid symmetry.
A very high yield fact to remember is that it lacks 3′-5' exonuclease enzyme activity.
In other words, this virus isn’t capable of proofreading to correct errors made during the viral
replication.
Eventually, this leads to variations in the antigenic structure of its envelope proteins.
Now, there are six or more genotypes and multiple subgenotypes of hepatitis C virus due to
genetic mutations of the region that codes envelope proteins.
As a result, individuals with hepatitis C infection typically have several different subspecies of
the hepatitis C virus in their blood.
And due to the continuous formation of new mutant strains of the virus, the host's immune
system lags in the production of antibodies.
As a result, these individuals fail to develop an effective immune response against hepatitis C
virus.
Now, this virus is mainly transmitted parenterally and individuals that are at risk include
intravenous drug users, healthcare workers exposed to blood and needle-stick accidents, patients
on dialysis, and blood transfusion recipients.
Hepatitis C virus can also be transmitted sexually and perinatally, but these modes of
transmission are less common.
The long incubation period that lasts from 2 weeks to 6 months is followed by an acute
or chronic hepatitis C infection.
Acute infection can present as asymptomatic infection or mild hepatitis that typically resolves
within a few weeks.
But, for your exam, you have to know that the virus more commonly causes stable chronic
infection which can further progress to cirrhosis or hepatocellular carcinoma.
Hepatitis C virus can also cause extrahepatic manifestations which can be subdivided
into: hematologic, which include essential mixed cryoglobulinemia, immune
thrombocytopenia, autoimmune hemolytic anemia, and increased risk of B-cell non-Hodgkin
lymphoma; renal, like membranoproliferative glomerulonephritis, which is more common,
and membranous glomerulonephritis, which is less common; vascular, which include
leukocytoclastic vasculitis; dermatologic, such as sporadic porphyria cutanea tarda and lichen
planus; and finally, endocrine, which include increased risk of diabetes me llitus and
autoimmune hypothyroidism.
Just like in hepatitis B, hepatitis C does have a carrier state.
Now, the best screening test for hepatitis C infection is the HCV antibody test, which detects
antibodies to the hepatitis C virus, while the gold standard test for hepatitis C infection is the
HCV RNA test, which reveals the level of circulating virus.
Individuals with resolved hepatitis C infection are anti-HCV positive and HCV RNA negative; in
contrast to individuals with a chronic infection are anti-HCV positive and HCV RNA positive.
Also, individuals with a chronic infection have persistently elevated liver enzymes.
As far as histopathology goes, hepatitis C infection is associated with lymphoid aggregates and
focal areas of macrovesicular steatosis, which is characterized by one or more lipid droplets
within the cytoplasm that displace the nucleus to the periphery of the hepatocyte.
Another high yield topic is the treatment of HCV which includes several medications.
But, for your exam, you have to know that none of them is approved as a monotherapy!
Based on their mechanism of action, these medications are subdivided into several groups.
First, we have non-structural protein 5A inhibitors, which include ledipasvir and ombitasvir.
These medications inhibit the viral non-structural 5A phosphoprotein, thereby preventing the
replication of the viral RNA; their main side effects include headaches and diarrhea.
Moving on to non-structural protein 5B inhibitors, which include sofosbuvir and dasabuvir.
These medications act as chain terminators and inhibit the viral RNA-dependant RNA
polymerase, thereby preventing the replication of the viral RNA.
Common side effects of these medications include fatigue and headache.
Next, we have non-structural protein 3/4A inhibitors, which include simeprevir and grazoprevir.
These medications inhibit non-structural 3/4A protease and subsequently prevent viral
replication.
For your exam, you have to know that grazoprevir can cause photosensitivity reactions and rash;
while simeprevir can cause headaches and fatigue.
The last medication you should know for your exam is ribavirin, which works by inhibiting the
synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate
dehydrogenase.
Ribavirin is typically used as a supplementary medication of the therapy rather than the essential
medication.
Finally, hepatitis B and C infections can be treated with interferon-alpha.

Summary
All right, as a quick recap.
Viral hepatitis is defined as inflammation of the liver parenchyma and it is most commonly
caused by hepatitis viruses A, B, C, D, and E.
Now, let’s use this hepatitis worm to present the most common routes of transmission of each
virus: We write the letter A at the head, and then B, C, D, and finally, E at the tail.
The two ends, where the mouth and butt are, have fecal-oral route so that’s HAV and HEV.
Everything else in between, so HBV, HCV, and HDV, are most commonly
transmitted parenterally, but also sexually and perinatally.
Now, hepatitis A virus is an RNA picornavirus that has a short incubation period that typically
lasts for 30 days.
It can cause subclinical infection or acute hepatitis, but the overall prognosis is good and there’s
no risk for hepatocellular carcinoma.
Hepatitis B virus is a DNA hepadnavirus that has a long incubation period, from 30 to 180 days,
which is followed by a prodrome and “serum sickness-like” symptoms.
It can cause one of three syndromes: acute hepatitis with complete resolution, which is the most
common outcome; chronic hepatitis, with or without cirrhosis and hepatocellular carcinoma; or
fulminant hepatitis.
Hepatitis C virus is an RNA flavivirus with a long incubation period, from 2 weeks to 6 months.
It can cause acute hepatitis, which can present as asymptomatic infection or mild hepatitis; or
stable chronic hepatitis, which is more common and can progress to cirrhosis or hepatocellular
carcinoma.
Hepatitis D virus is an RNA deltavirus that requires the hepatitis B surface antigen to be
infectious; therefore the virus can be acquired either as a coinfection with hepatitis B virus or as
a more dangerous superinfection in a chronic HBV carrier.
Also, it is associated with an increased risk of hepatocellular carcinoma.
Finally, the hepatitis E virus is an RNA hepevirus with a short incubation period that usually
lasts for 6 weeks.
In most individuals, it causes self-limiting acute viral hepatitis and there’s no risk
for hepatocellular carcinoma.
However, in pregnant individuals, this virus can cause life-threatening fulminant hepatitis.
Now let’s go back to our case! Colin, who came to the office because of abdominal pain for 3
months, presented with a large distended abdomen, yellow sclera, palmar erythema, and spider
angioma on his abdomen and extremities.
The key to the diagnosis is in the lab results which revealed the following: Hepatitis A IgM
antibody negative, Hepatitis B surface antigen negative, Hepatitis B surface antibody
positive, Hepatitis B core antibody negative, and HCV antibody positive.
Now, since he has symptoms, we can narrow it down to either HCV or HBV infection, or maybe
both!
His history of IV drug use is a risk factor for both, so that’s no help.
However, the lack of Hepatitis B surface antigen means he doesn’t have an active infection and
the Hepatitis B surface antibody could be from a previous HBV infection that’s resolved, or he’s
been vaccinated against the virus.
So HCV infection is the most likely diagnosis.
On the other hand, Megan, who came to the emergency department because of vomiting and
fever, presented with yellowing of the skin and sclera, right upper quadrant tenderness, and
hepatomegaly.
She worked as a global health nurse and she recently traveled to Nepal, which is an endemic area
of HEV infections.
Although hepatitis E infection is primarily a self-limiting disease, pregnant individuals, like
Megan, can develop fulminant hepatitis.
We can confirm the diagnosis by testing for IgM and IgG HEV antibodies in the serum.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Rosen's Emergency Medicine - Concepts and Clinical Practice E-Book" Elsevier
Health Sciences (2013)
4. "Extrahepatic manifestations of chronic hepatitis C virus infection" Therapeutic
Advances in Infectious Disease (2015)
5. "Hepatitis C" Human Vaccines & Immunotherapeutics (2013)
6. "Hepatitis E" New England Journal of Medicine (2012)

Viral hepatitis: Clinical practice

Viral hepatitis is liver inflammation caused by a viral infection and it can either be acute or
chronic, and five important causes are hepatitis A, B, C, D and E.
Acute viral hepatitis lasts for less than six months and the individual has nausea, vomiting, and
right upper quadrant pain. Sometimes if there’s a high total bilirubin, it can lead to jaundice,
pruritus, dark urine, and clay- colored stools.
Chronic viral hepatitis lasts for more than six months and the individual can sometimes be
asymptomatic. Other times, chronic viral hepatitis can cause fever, fatigue, and loss of appetite,
as well as extrahepatic symptoms like arthralgias and skin rashes.
On the physical examination, with acute hepatitis, there’s typically hepatomegaly, but
with chronic hepatitis, the liver may feel normal on palpation, and if there’s cirrhosis, the lower
margin of the liver can feel irregular.
A diagnostic workup for viral hepatitis includes a CBC, AST, ALT, total
bilirubin and unconjugated bilirubin, alkaline phosphatase, and PT, PTT, INR.
Thrombocytopenia, prolonged PT and prolonged PTT as well as an elevated INR can be present
in both acute and chronic hepatitis.
In acute hepatitis, levels of AST, ALT are over 100 international units per liter and sometimes
the alkaline phosphatase and total bilirubin are elevated as well. If the total bilirubin is above 2
milligrams per deciliter, then an individual can appear jaundiced.
With chronic hepatitis, elevation of AST and ALT persists for more than six months but levels
don’t usually rise above 400 international units per liter. In addition, total bilirubin and alkaline
phosphatase levels can also be elevated.
During viral hepatitis, medications that are metabolized by the liver, like aspirin, or medications
that can damage the liver, like acetaminophen, should be used with caution, because they can
further damage the liver.
Okay, now let’s start with hepatitis A which only causes acute hepatitis. It’s caused
by contaminated food and water and often affects travelers.
In hepatitis A, serum anti-hepatitis A virus IgM antibodies are elevated for about 6 weeks , and
anti-hepatitis A IgG antibodies begin to rise a couple weeks after IgM antibodies and usually
persist for life.
So, if there are IgG antibodies and no IgM antibodies, that means that the person
was vaccinated for hepatitis A or had a prior infection and developed immunity.
Hepatitis A usually resolves within a few weeks, and the main treatment is giving fluids in case
of dehydration.
Hepatitis A can be prevented by vaccinating children, as well as adults that are about to travel in
countries with a high rate of hepatitis A infection. Two doses of the vaccine are given 6 months
apart.
Next up is Hepatitis E - which typically causes acute hepatitis, but can also cause chronic
hepatitis in immunocompromised individuals.
Like hepatitis A, it’s also caused by contaminated food and water, but it can also be transmitted
from mother to child during birth. Usually the symptoms are mild, but if it develops in
pregnancy, it can be severe and lead to acute liver failure.
In acute hepatitis E, anti-hepatitis E virus IgM are elevated for about 2 months and IgG
antibodies begin to rise around the same time as IgM antibodies, but they don’t persist for more
than a few years. HEV RNA - which is a marker of virus replication- is also checked in the stool
or in the serum to confirm the infection and levels are usually high.
With chronic hepatitis E, HEV RNA is detected in the serum or in the stool for more than six
months.
Acute hepatitis E usually resolves within a few weeks, and the main treatment is giving fluids in
case of dehydration. However, in acute liver failure, a liver transplant may be needed.
In immunocompromised individuals with chronic hepatitis E, treatment involves lowering the
doses of immunosuppressants and giving ribavirin for 12 weeks.
Next is hepatitis B which can cause acute hepatitis and chronic hepatitis. It’s caused by contact
with blood - like sharing needles or syringes, and contact with body fluids - like unprotected sex
and during passing from mother to child during labor and delivery.
Testing for hepatitis B requires sending serology.
First, there’s HBsAg and Anti-Hbs, which is the antibody to Hepatitis B surface antigen.
Usually, if one is positive, the other’s negative, sort of like yin and yang. One exception is if an
individual has never been exposed to the hepatitis B virus or vaccine in their life - in which case
they’re both negative.
Another exception is when a person has actually cleared the hepatitis B infection so the HBsAg
is gone, but levels of Anti-Hbs still haven’t risen high enough to be detected, so it appears to be
negative, even though technically there is Anti-Hbs floating around. That’s called the “window
period”.
But most of the time, if HBsAg is positive and Anti-Hbs is negative, that means - there’s an
acute or chronic hepatitis B infection.
And if HBsAg is negative and Anti-Hbs is positive, that means that an individual has been
immunized or has recovered from a natural infection - either way, they’re protected
from hepatitis B.
After looking at HBsAg and Anti-Hbs, the next step is to look at antibodies made against
HBcAg, which is hepatitis B core antigen.
There’s IgM-anti-HBc, which is IgM antibodies against hepatitis B core antigen, and there’s
total anti-HBc, which is total antibodies against hepatitis B core antigen, mostly made up of IgG
antibodies. Neither of these rises with the vaccine.
Now, in acute hepatitis, both the IgM-anti-HBc and the total anti-HBc become positive. But as
weeks go by, the IgM-anti-HBc becomes negative, while the total anti-HBc remains positive.
That happens if the person clears the hepatitis B infection, or if there’s chronic hepatitis - so it
really tells you about the passage of time.
Finally there’s HBeAg, which is hepatitis B e antigen - try saying that 3 times quickly. If it’s
positive then the virus is actively replicating, and that means that the person is highly infectious.
If it’s negative, it could be because the virus isn’t actively replicating or because there’s no virus
around at all.
There’s also HBV DNA PCR, or Hepatitis B virus DNA PCR that can be sent, and it usually
mirrors HBeAg but gives even more information.
High HBV DNA levels mean that the virus is actively replicating and highly infectious low HBV
DNA levels mean that the virus is around but not actively replicating, and having no detectable
HBV DNA means that there’s no virus.
Now let’s put these Hepatitis B serological markers into a table and go through some scenarios.
In someone that’s susceptible to hepatitis B and hasn’t been immunized, HBsAg, Anti-Hbs, IgM-
anti-HBc, total anti-HBc, HBeAg, and HBV DNA are all negative.
In someone that is immunized, Anti-Hbs becomes positive, while HBsAg is negative, and the
rest remain negative as well.
Now in someone with acute hepatitis B infection, HBsAg is positive and Anti-Hbs is negative,
and because it’s acute - IgM-anti-HBc and total anti-HBc are positive. Typically the virus is
actively replicating at this stage so HBeAg and HBV DNA levels are elevated as well.
After a number of weeks later, IgM-anti-HBc becomes negative, while total anti-HBc remains
positive for life.
Finally, if the infection gets brought under control to the point where the virus is no longer
actively replicating, then the HBeAg becomes negative and the HBV DNA levels fall, and anti-
HBe antibodies appear.
Finally there’s chronic hepatitis B infection, which has a few phases. The immune-tolerant phase
usually develops in individuals that were infected during birth, and it can last a few decades.
There’s minimal liver inflammation, so the ALT and AST may be normal or slightly elevated.
During this phase, HBsAg is positive and Anti-Hbs is negative, and because it’s chronic - IgM-
anti-HBc is negative, while total anti-HBc remains positive.
Typically the virus is actively replicating at this stage so HBeAg and HBV DNA levels are
elevated as well.
Then there’s the immune-active phase with positive HBeAg- which is when there’s more liver
inflammation so ALT and AST are elevated, and as a result the HBV DNA levels start to fall a
bit, but in other ways the labs are the same.
HBsAg is positive, Anti-Hbs is negative, IgM-anti-HBc is negative, and total anti-HBc remains
positive.
And the virus is still actively replicating so HBeAg is positive.
Next there’s, immune-active phase with negative HBeAg- which is when the ALT and AST
remain elevated, but the HBV DNA levels fall even lower, and the HBeAg becomes negative -
meaning that the individual is less infectious.
In other ways the other labs are the same. HBsAg is positive, Anti-Hbs is negative, IgM-anti-
HBc is negative, and total anti-HBc remains positive.
Next there’s the inactive chronic HBV phase- which is when the ALT and AST normalize and
HBV DNA levels fall even lower, and the HBeAg remains negative.
And as before the other labs are the same. HBsAg is positive, Anti-Hbs is negative, IgM-anti-
HBc is negative, and total anti-HBc remains positive.
Finally, when someone successfully clears the infection, Anti-Hbs becomes positive, while
HBsAg is negative, total anti-HBc remains positive as well, and the IgM-anti-HBc, HBeAg, and
HBV DNA are negative.
Now, an important complication of chronic hepatitis B is cirrhosis, which can lead
to hepatocellular carcinoma.
In fact, high titers of HVA DNA and HBsAg correlate with a higher likelihood of
developing cirrhosis. So every 6 months, an ultrasound is done and alpha fetoprotein levels can
also be checked to monitor for possible tumors.
Treatment of acute hepatitis B is mainly supportive, like giving fluids
and antiemetic medications like metoclopramide.
Treatment of chronic hepatitis B largely depends on the HBV DNA and ALT levels and whether
or not there’s cirrhosis.
Individuals without cirrhosis that have HBV DNA levels above 20,000 international units or IU
per milliliter and ALT levels above 2 times the upper limit of normal, are started on treatment.
If the HBV DNA levels are above 20,000 IU per milliliter but ALT is below the 2 times upper
limit cutoff, then ALT levels are monitored every 3 to 6 months and if it ever reaches that cutoff,
then treatment is started.
If HBV DNA levels are between 2,000 and 20,000 IU and levels of ALT are under 2 times the
upper limit of normal, then the labs are monitored every 1 to 3 months. If HBV-DNA remains
between 2,000 and 20,000 international units per milliliter for 6 months, then treatment is started.
If the HBV DNA levels are below 2,000 IU and levels of ALT are under 2 times the upper limit
of normal, then labs are monitored every 3 to 6 months. If ALT levels rise above 2 times the
upper limit of normal, then treatment is started.
Treatment options include Pegylated interferon- or PegIFN- which is an antiviral agent that’s
administered by subcutaneous injection once a week for 48 weeks.
Other options include nucleoside or nucleotide analogues - like Entecavir or Tenofovir which are
given orally until HBeAg becomes negative and then for one more year after that.
If HBeAg was initially negative and HBV DNA levels rise above 2000 IU and ALT levels rise
above 2 times the upper limit of normal then the treatment is restarted, to prevent HBeAg from
becoming positive. This time, PegIFN is used for a year and the nucleoside or nucleotide
analogues are used for several years.
Now treatment for chronic hepatitis B with cirrhosis. First, in individuals with compensated
cirrhosis, where there’s no jaundice or ascites- and HBV DNA is above 2,000 international units
per milliliter, Entecavir or Tenofovir is given indefinitely.
In individuals with compensated cirrhosis, and HBV DNA levels below 2,000 international units
per milliliter, Entecavir or Tenofovir is given only if ALT levels are elevated.
And in individuals with compensated cirrhosis, if HBV DNA levels are undetectable, then no
treatment is started.
In individuals with decompensated cirrhosis, where there is jaundice or ascites, Entecavir is
started, regardless of ALT and HBV DNA levels.
In individuals with decompensated cirrhosis, and undetectable levels of HBV DNA, a liver
transplant may be done.
Prevention of HBV infection is done by vaccination in infants and in adults that are not immune
to HBV infection and have a high-risk for developing it, such as healthcare personnel, injection
drugs users, and immunocompromised individuals. In newborns, three doses are given, the first
shortly after birth, the next at one month of age, and the last at 6 months. In adults, two doses are
given, one month apart.
Okay, next is hepatitis D which can cause acute or chronic hepatitis. It’s caused by hepatitis D
virus- or HDV- which is a defective virus that needs HBV to cause an infection, because HBsAg
makes up the outer envelope within which the HDV genome resides.
So like Hepatitis B, Hepatitis D, it’s transmitted through blood and body fluids.
Now, acute hepatitis D, can be due to a coinfection- meaning that both B and D viruses infect the
individual at the same time or a superinfection- meaning that hepatitis D infection occurs after
there’s a preexisting chronic hepatitis B infection.
Oftentimes, an acute hepatitis D infection doesn’t get cleared, and it turns into a chronic
hepatitis D infection.
Testing for hepatitis D requires confirmation of hepatitis B infection, as well as testing for
HDV IgM, which is IgM antibodies against hepatitis D, total HDV antibodies, which is total
antibodies against hepatitis D, mostly made up of IgG antibodies, serum HDV RNA, and HDAg
which usually remains positive only briefly.
In acute hepatitis D coinfection or superinfection, HDV IgM is elevated, and total HDV
antibodies may be negative if the IgG levels haven’t climbed very high.
HDV RNA is usually positive, and HDAg may be positive or negative because it disappears so
quickly.
Whereas with chronic HDV infection, HDV IgM is negative, total HDV antibodies are positive,
HDV RNA is positive, and HDAg is negative.
Treatment of hepatitis D is initiated in individuals that have elevated HDV RNA levels and
elevated AST and ALT levels.
Pegylated interferon alfa-2a or alfa-2b is given once a week for 12 months.
Prevention of hepatitis D is accomplished through hepatitis B vaccination.
Next is hepatitis C which is caused by hepatitis C virus and can cause acute or chronic hepatitis.
It’s caused by contact with blood - like sharing needles or syringes, and contact with body fluids
- like unprotected sex and during passing from mother to child during labor and delivery.
Hepatitis C can cause extrahepatic manifestations like cryoglobulinemia- which is where the
blood viscosity is high and causes headaches and confusion-, membranoproliferative
glomerulonephritis and dermatologic conditions, such as porphyria cutanea tarda which can
cause erosions and blisters.
The first step in diagnosis is to look for anti-HCV IgG antibodies. If they’re positive, then the
next step is to send HCV RNA PCR. If HCV RNA is not detected, it likely means that it was a
past infection that has now cleared. If HCV RNA is detected, then the individual has a hepatitis
C infection. If titers HCV RNA remains elevated for more than 6 months, then it’s considered
a chronic hepatitis C infection, otherwise it’s considered an acute hepatitis C infection.
Once the diagnosis is established, it’s helpful to calculate the APRI score - which is the AST
to platelet ratio index. It’s calculated by dividing the individual’s AST level by the normal value
of AST, and then dividing by the platelet count and multiplying by 100. This estimates the
degree of liver fibrosis. If the score is below 0.5, there’s minimal fibrosis, between 0.5 and 1.5 is
in- between, and above 1.5 means that there is significant fibrosis.
In individuals with cirrhosis, there is a high-risk for developing hepatocellular carcinoma, so an
ultrasound is done every 6 months, and alpha fetoprotein levels can also be checked to monitor
for possible tumors.
Treatment of hepatitis C in individuals without cirrhosis can be initiated using
either Sofosbuvir coupled with either velpatasvir or daclatasvir for 12 weeks or by using
Glecaprevir and pibrentasvir for 8 weeks.
In individuals with hepatitis C with compensated cirrhosis, Sofosbuvir and velpatasvir can be
used for 12 weeks or Glecaprevir and Pibrentasvir can be given for 12 weeks or Sofosbuvir and
daclatasvir can be given for 24 weeks.
In individuals with decompensated cirrhosis, sofosbuvir plus velpatasvir for 24 weeks
or sofosbuvir plus daclatasvir for 12 weeks can be used and some cases may require liver
transplantation.

Hepatitis medications
Anti-hepatitis medications are a group of antiviral agents used to treat viral hepatitis, which is the
inflammation of the liver caused by some sort of virus that targets and damages liver cells.
Now, viral hepatitis can be acute or chronic.
Acute hepatitis lasts for six months or less, and usually resolves on its own without any antiviral
treatment.
Chronic hepatitis lasts for more than six months, sometimes even for decades.
Anti-hepatitis medications are mainly used to treat chronic hepatitis and the two main viruses
are hepatitis B virus, or HBV, and hepatitis C virus, or HCV.
Alright, so, HCV is a single stranded RNA virus.
What this means is that HCV inject its RNA into the host’s cell and it can immediately use its
host’s ribosomes and translate the proteins needed to make more viruses, like capsomere proteins
and enzymes like RNA-dependent RNA polymerase.
This RNA-dependent RNA polymerase uses the viral RNA as a template, and uses
the hepatocyte’s nucleotides to transcribe a complementary strand of RNA, which is then used to
form new baby viruses!
HBV on the other hand is a double stranded DNA virus.
Once the DNA gets injected into a new cell, it enters the cell’s nucleus and is replicated by the
host cell’s machinery.
It’s also transcribed into several messenger RNAs and a pregenomic RNA, and then the
messenger RNAs are used to make capsomere proteins and enzymes like DNA polymerase.
DNA polymerase uses the pregenomic RNA to synthesize new copies of the viral DNA, which is
combined with the capsomere proteins to assemble new viruses.
With each type of virus, whether it’s RNA or DNA, it’s turning your own cells into virus making
factories and pumping out new viruses.
This process strains, damages and potentially kills the infected hepatocytes.
When these liver cells die, the liver gets inflamed and that’s called hepatitis.
The anti-hepatitis medications can be divided into two groups based on their mechanism of
action; nucleoside or nucleotide analogues and interferons.
Let’s start with the nucleoside and nucleotide analogues. This group includes nucleoside
analogues like ribavirin, entecavir and lamivudine; nucleotide analogues like adefovir, tenofovir,
and sofosbuvir.
However, entecavir, lamivudine, adefovir, and tenofovir are used to treat HBV infections
and ribavirin and sofosbuvir are used to treat HCV infections.
In both types of infected cells, the analogues are first phosphorylated by cellular enzymes into
either a diphosphate, or triphosphate form.
The phosphorylated forms are similar in structure to natural nucleotides present in the cells, so
we can think of them as fake nucleotide molecules.
Viral enzymes will try to use these fake nucleotide molecules when trying to synthesize new
nucleic acid.
In the HBV infected cell, this enzyme is HBV DNA polymerase, while in the HCV infected cell,
the target enzyme is RNA-dependent RNA polymerase.
Once these fake nucleotides are incorporated into the growing DNA or RNA, no
additional nucleotides can be added, and viral nucleic acid synthesis stops.
In addition to this, ribavirin also has another mechanism.
Ribavirin is initially phosphorylated to a monophosphate form, which inhibits the enzyme
inosine-5′-phosphate dehydrogenase.
Inosine-5′-phosphate dehydrogenase is an enzyme in the host cell, which converts inosine
monophosphate into xanthosine monophosphate, which then goes on to make
guanine nucleotides.
Ribavirin monophosphate resembles inosine monophosphate, and binds to its site on the enzyme.
This inhibits the inosine-5′-phosphate dehydrogenase, reducing the synthesis of
guanine nucleotides, which in turn reduces the synthesis of viral mRNA.
These nucleoside and nucleotide analogues are given per oral.
Adefovir and tenofovir are poorly absorbed when given orally, so adefovir is given in the form
of the prodrug, adefovir dipivoxil, and tenofovir is given in the form of tenofovir disoproxil.
These prodrugs are rapidly absorbed and converted into adefovir and tenofovir, respectively, in
the intestinal cells by an esterase enzyme.
Eventually nucleotide and nucleoside analogues are transported out into the blood, and carried to
the kidneys, where they are excreted via urine.
Ribavirin undergoes another extra step where it is first dephosphorylated by a phosphatase
present in the host cell’s nucleus.
This causes ribavirin to start accumulating within cells which lack a nucleus like the red blood
cells.
Now, nucleoside and nucleotide analogues commonly cause side effects like headache, nausea,
fatigue, and abdominal pain.
In addition, ribavirin can cause hemolytic anemia and hyperuricemia, or increase in uric acid
levels due to its accumulation within the red blood cells.
Ribavirin can also cause rash, itching, insomnia, cough, and also birth defects, when used in
pregnant women.
Ribavirin increases the efficacy of interferons when used together.
It can also interfere with the activity of other medications like HIV nucleoside reverse
transcriptase inhibitors like zidovudine.
Lamivudine can cause anorexia.
Keep in mind that HBV strains often develop resistance to lamivudine due to mutation in DNA
polymerase enzyme. This can cause the infection to return once the medication is stopped.
Next, at higher doses, adefovir can damage the kidneys, which causes proteinuria, or
increased protein in the urine; glycosuria, or increased glucose in urine; and azotemia, or
increased nitrogen-containing compounds like urea and creatinine in the blood.
The next group of anti-hepatitis medication are the interferons.
Interferons are cytokines, or signalling proteins, produced by virus infected cells and cancer cells
in the body, as a warning sign for the other healthy cells.
As their name implies, they interfere with processes like viral replication.
There are two types of Interferons: Type I and Type II.
Type I interferons include Interferon alpha and Interferon beta.
When surrounding hepatocytes detect these type I interferons, an alarm is raised and they try to
protect themselves by synthesizing proteins that degrade mRNA.
This blocks viruses from rapidly making copies of themselves, inhibit protein synthesis which
blocks viral proteins from being produced, and they increase expression of MHC molecules,
which makes it easier for cytotoxic CD8+ T cells and NK cells to do surveillance and kill them if
they’re infected.
Now, the only Type II Interferon is interferon gamma.
Like the type I interferons, interferon gamma also promotes an anti-viral state, but it also helps
activate macrophages and CD4+ helper T cells which then secrete their own interferon
gamma and IL-2.
In order to be used as a medication interferons are artificially synthesized using recombinant
DNA technology.
Interferons are either given as intramuscular or subcutaneous injection, which is typically given
thrice a week.
Sometimes interferons can be given in the form of pegylated interferon, which
is interferon plus polyethylene glycol, for example, pegylated interferon alfa, or pegINF-α.
Pegylated interferons are absorbed more slowly than plain interferons, so they require less
frequent dosing of about once per week, and also cause fewer side effects.
Currently only two types of interferons, IFNα2A and IFNα2B, are available for clinical use.
IFNα2A has a longer half-life than IFNα2B, meaning it stays in the blood longer.
Interferons are used in the treatment of both chronic HBV and chronic HCV infections.
IFNα2A, or IFNα2B, or their pegylated forms are used to treat chronic HCV infections either
alone or in combination with other antiviral medication like ribavirin. They are also used in the
treatment of chronic HBV infection.
In addition interferons are also used in the treatment of herpes virus infection, papillomavirus
infection, and Kaposi’s sarcoma occurring in HIV infections.
Side effects of IFN-α includes flu-like symptoms such as fever, malaise, nausea, and
vomiting; bone marrow suppression leading to neutropenia and thrombocytopenia; neurotoxicity
leading to sleepiness, depression, and behavioral disturbance; liver dysfunction leading to
elevated liver enzymes.
It can also cause alopecia, which is more common in children.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and
retain all these pharmacology facts! Since we’re talking about liver damage, let’s go to a bar
during the prohibition era.
Understandably, this bar is not busy and we have the Bartender, representing hepatitis B,
standing at one end, and his only Customer, representing hepatitis C, at the other end. Now this
bar is disguised as a pet shop to fool the cops so let’s put some animals in here to represent
the nucleotide and nucleoside analogues.
By the bartender, we have entecavir, an anteater, lamivudine, a lamb, adefovir, an aardvark,
and tenofovir, a tentacled octopus. These medications treat HBV infection.
By the customer representing HCV infection we have ribavirin, an angry rhino, and sofosbuvir, a
leather sofa that used to be a cow.
For side effects Ribavirin can cause hemolytic anemia, so let’s impale a large red blood cell on
the horn of the rhino. It’s also contraindicated during pregnancy so let’s have an angry pregnant
lady riding on its back. Adefovir causes renal damage so let’s have the aardvark eating a tasty
kidney that someone left on the ground.
Now two police officers busted into this bar to interfere with the good times, and they have the
letters A and B on their uniform for interferon alpha 2a and 2b. They are standing directly
between the bartender/petshop owner and the customer, since they can treat both types of viral
hepatitis.
For their side effects, one of them is holding a bone like a club for bone marrow suppression,
while the other is holding a damaged liver he found while looking for evidence. If we look at the
heads of the two officers, one is bald for alopecia, while the other has his brains showing to help
you remember interferons can cause neurotoxicity. The most common side effect is flu like
symptoms so let’s give them both runny noses and thermometers in their mouths.

Summary
All right, as a quick recap… Anti-hepatitis medications refers to a group of antivirals used in the
treatment of viral hepatitis.
They can be divided into two groups. The first is nucleoside or nucleotide analogues.
Ribavirin and sofosbuvir inhibits HCV RNA-dependent RNA polymerase.
Ribavirin also inhibits inosine-5′-phosphate dehydrogenase, which decreases synthesis of
guanine nucleotides.
Entecavir, lamivudine, adefovir, and tenofovir inhibits HBV DNA polymerase and are used to
treat chronic HBV infection.
Next we have the interferons like IFNα2A and IFNα2B, which stimulate the body’s cells to
synthesize proteins that degrades viral RNA and also surface proteins that alerts immune cells
like natural killer cells.

Summary
The medications for hepatitis can be divided into two broad categories: those that clear the virus
from the body (i.e. antivirals) and those that work to protect the liver from further damage (i.e.
hepatoprotectives).
Antiviral medications for hepatitis include pegylated interferon, ribavirin, and telbivudine. These
medications are typically used in combination with each other and are very effective at clearing
the virus from the body.
Hepatoprotective medications for hepatitis include milk thistle, ursodeoxycholic acid, and
vitamin E. These medications protect the liver from further damage and can be quite effective at
preventing or slowing the progression of liver disease.

Sources
1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th
Edition" McGraw-Hill Education / Medical (2018)
 2. "Rang and Dale's Pharmacology" Elsevier (2019)
3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th
Edition" McGraw-Hill Education / Medical (2017)
4. "Is Tenofovir Alafenamide Safer than Tenofovir Disoproxil Fumarate for the
Kidneys?" AIDS Rev (2016)
5. "Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with
Hepatitis C Virus" Antimicrobial Agents and Chemotherapy (2018)
6. "Review article: long-term safety of oral anti-viral treatment for chronic hepatitis
B" Alimentary Pharmacology & Therapeutics (2018)
7. "Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection" Annals of
Internal Medicine (2017)

Jaundice: Clinical practice

Jaundice -also called icterus- is the yellowish pigmentation of the skin and sclera- and appears
when total bilirubin levels exceed 2 mg/dL in adults.
Total hyperbilirubinemia can be predominantly due to unconjugated- or indirect bilirubin or it
can be due to conjugated-or direct bilirubin and it largely depends on where bilirubin
metabolism is disrupted.
So jaundice can be thought of as prehepatic, hepatocellular, or posthepatic.
A workup for jaundice includes total and conjugated bilirubin, AST, ALT, and alkaline
phosphatase, which are markers of liver injury.
In addition, albumin, PT, PTT, and INR which are markers of hepatocellular function are done.
If total bilirubin levels are elevated and conjugated bilirubin levels are normal and there’s no
other evidence of liver injury or liver dysfunction, then that means that there’s a high amount
of unconjugated bilirubin - and the jaundice is most likely due to a prehepatic cause. At that
point, additional labs can be sent, like a CBC, LDH, haptoglobin, and a blood smear.
Common prehepatic causes of excess unconjugated bilirubin include hemolytic
anemia and dyserythropoiesis- which is macrophages inappropriately destroy too many red blood
cells. These show anemia, an elevated LDH, a decreased haptoglobin, and can show schistocytes
on a blood smear.
Now, if the additional lab work comes back normal, then the cause of this jaundice may be
hepatocellular.
One example of this is Gilbert syndrome, which is a genetic condition that causes a decrease in
the enzyme uridine glucuronyl transferase. As a result, hepatocytes are less effective at
conjugating bilirubin. Individuals are usually asymptomatic, but when there’s a trigger like
fasting - adipocytes release a lot of unconjugated bilirubin and that can overwhelm
the hepatocytes.
Usually during an episode of jaundice, the unconjugated bilirubin doesn’t rise above 3
milligrams per deciliter and it resolves within 24 hours after resuming a normal diet.
Usually, laboratory tests repeatedly show normal results between jaundice episodes over 18
months. In some cases, the diagnosis can be confirmed with genetic testing.
There is no specific treatment required for Gilbert syndrome other than maintaining a normal
caloric intake.
Now, if total bilirubin levels are elevated and conjugated bilirubin levels are normal and there is
also evidence of liver injury, such as high AST and ALT levels, then it could be due to
medications such as rifampin and probenecid and the treatment is to stop taking those
medications.
Okay, now, if total bilirubin levels are high and conjugated bilirubin levels are high and there’s
no other evidence of liver injury or liver dysfunction, then the cause of jaundice may be
hepatocellular.
One example of this is Dubin-Johnson syndrome which is a benign genetic condition that causes
a decrease in bilirubin transport out of the hepatocyte. As a result, conjugated
bilirubin accumulates. Individuals present with mild jaundice, that’s usually noted only during
illnesses, pregnancy or after using certain medications, like oral contraceptives- because they
reduce bilirubin excretion and raise bilirubin levels. Serum total bilirubin levels are usually
between 2 and 5 milligrams per deciliter and almost half of this is made up of conjugated
bilirubin.
In order to diagnose Dubin-Johnson syndrome, we have to check the urinary coproporphyrin
excretion- which is normal in quantity, but not in quality.
Coproporphyrin comes from heme synthesis and has 4 isomers that are numbered from I to IV.
Normally, coproporphyrin I is excreted in the bile, and coproporphyrin III is excreted in the
urine. But, with Dubin-Johnson syndrome, a lot of coproporphyrin I gets excreted in the urine.
Although it’s not usually done, if a liver biopsy is done, the tissue appears black from a pigment
that’s similar to melanin. No specific treatment is required.
Another example is Rotor syndrome which is another benign genetic condition that causes
defects in proteins that normally transport bilirubin from the blood into the liver for storage and
excretion. The defective proteins lead to an accumulation of conjugated bilirubin. Individuals
usually have mild jaundice and the total bilirubin is usually high, but usually below 5 milligrams
per deciliter.
To differentiate Rotor syndrome from Dubin-Johnson syndrome, urinary coproporphyrin
excretion is measured and with Rotor syndrome, this is normal. Once again, no specific
treatment is required.
Now, if both total and conjugated bilirubin levels are high and there is also evidence of liver
injury, especially high levels of AST, ALT and no evidence of liver dysfunction, then jaundice is
still likely due to a hepatocellular cause, with a variety of possibilities.
At this point, an additional workup is done, like hepatitis B serologies, anti-HCV antibody
for hepatitis C, serum iron, transferrin and ferritin for hemochromatosis, ceruloplasmin
for Wilson disease, antinuclear anti-smooth muscle and anti-liver-kidney microsomal antibodies
for autoimmune hepatitis and antimitochondrial antibodies for primary biliary cholangitis.
An abdominal ultrasound is also done to identify liver steatosis, if alcoholic hepatitis or non-
alcoholic fatty liver disease is present.
If conjugated bilirubin levels are high - which will also lead to high levels of total bilirubin- and
there’s also evidence of liver injury, especially high alkaline phosphatase levels and no evidence
of liver dysfunction, then jaundice is most likely posthepatic and this is usually caused by
a biliary obstruction.
Associated symptoms include right upper quadrant pain, clay-colored stools- that’s
because conjugated bilirubin doesn’t get in the intestine and get turned into stercobilin -which
normally colors the stool- and dark urine. This happens because conjugated bilirubin builds up in
the blood and is excreted in the urine.
Okay, now, biliary obstructions are usually caused by stones and this happens
with choledocolithiasis and acute cholangitis, which is an infection behind the blockage. An
abdominal ultrasound is done and this shows dilated bile ducts.
With choledocolithiasis, magnetic resonance cholangiopancreatography is done to confirm the
diagnosis and then ERCP is done to remove the stones.
With acute cholangitis, ERCP is done immediately to locate and remove the stones.
Another cause is cholangiocarcinoma- which is a tumor of the bile ducts - that can either be
intrahepatic or extrahepatic.
Cholangiocarcinomas are usually asymptomatic, but they can cause right upper quadrant pain,
pruritus, and weight loss.
An additional workup includes tumor markers like C19-9 and CEA which can be elevated.
An abdominal ultrasound can show dilation of the biliary ducts, especially with an
extrahepatic cholangiocarcinoma.
Next, an MRI or MRCP is performed to confirm the diagnosis and also assess the extent of the
disease.
The main treatment is surgical resection of the tumor, but this is rarely curative, because
cholangiocarcinomas are often metastatic at diagnosis.
Treatment of an intrahepatic cholangiocarcinoma is a partial hepatectomy- where the part of the
liver involving the tumor is removed.
Treatment of an extrahepatic cholangiocarcinoma is more complicated because it requires
removal of part of the liver, the bile ducts, gallbladder and nearby lymph nodes.
When the tumor is really close to the pancreas, a Whipple procedure may also be necessary- this
is when part of the pancreas and small intestine is removed.
With unresectable tumors, chemotherapy and radiation therapy can be used.
Sometimes, the obstruction can be caused by primary sclerosing cholangitis- which is a
progressive liver disease where there’s inflammation, fibrosis, and strictures in both intra and
extrahepatic biliary ducts. To confirm the diagnosis, MRCP is done and the biliary ducts appear
beaded or have a “pruned tree” appearance, due to the presence of multiple strictures. The only
curative treatment is a liver transplant.
Finally, the biliary tract can be compressed from the outside by a tumor - most often a pancreatic
exocrine cancer.
Symptoms of pancreatic cancer include epigastric abdominal pain and weight loss.
Additional tests include blood tests for serum lipase and CA 19.9 levels and both can be
elevated.
Next, an abdominal ultrasound is done and this shows dilated bile ducts and sometimes the tumor
can be seen as a focal hypoechoic solid mass that has irregular margins.
An abdominal CT-scan can reveal an ill-defined mass within the pancreas.
If the diagnosis is unclear after imaging, then a percutaneous biopsy is done to confirm the
diagnosis.
Depending on the extent of involvement and the location of the tumor, a Whipple procedure or a
partial pancreatectomy can be done. That’s where part of the pancreas is removed.
If the tumor has spread to nearby blood vessels or if metastasis is present, then chemotherapy
and radiation therapy are typically given.

Summary
Alright, as a quick recap, jaundice appears when total bilirubin levels are above 2 milligrams per
decilitre in adults.
Workup for jaundice includes serum total and conjugated bilirubin, AST, ALT, alkaline
phosphatase, albumin, PT, PTT and INR.
If there’s isolated unconjugated hyperbilirubinemia, then jaundice can be prehepatic, in which
case additional workup including CBC, LDH, haptoglobin and a blood smear is done to rule
out hemolysis and dyserythropoiesis.
If labs come back normal, then jaundice may be hepatocellular and caused by Gilbert syndrome.
If there’s isolated unconjugated hyperbilirubinemia and high levels of AST and ALT, then
medications like rifampin or probenecid can be the cause, in which case treatment is stopping the
medication.
If total bilirubin and conjugated bilirubin levels are high, then jaundice can be hepatocellular and
caused by genetic syndromes, like Dubin-Johnson and Rotor syndrome.
If AST and ALT are high, then a large spectrum of liver conditions that lead to cirrhosis can be
the cause and additional workup includes hepatitis B serology, anti-HCV antibody for hepatitis
C, serum iron, transferrin and ferritin for hemochromatosis, ceruloplasmin for Wilson disease,
antinuclear anti-smooth muscle and anti-liver-kidney microsomal antibodies for autoimmune
hepatitis and antimitochondrial antibodies or AMA for primary biliary cholangitis and an
ultrasound for alcoholic and non-alcoholic liver disease.
If alkaline phosphatase levels are high, then jaundice is posthepatic and caused by an obstruction
of the biliary tree.
Obstructions are caused by stones- like with choledocolithiasis and acute cholangitis, liver
conditions like primary sclerosing cholangitis and tumors like cholangiocarcinomas or pancreatic
exocrine cancer.

Hepatitis B and Hepatitis D virus

Hepatitis B virus, or Hep B virus for short, is a member of the hepadnavirus family; hepatitis D
virus, or Hep D virus, is a deltavirus. They both cause hepatitis, or inflammation of the liver.
Even though they both cause hepatitis, hepatitis D virus cannot cause the disease by itself, and
needs hepatitis B virus to replicate.  
Both hep B and D viruses are enveloped, so they’re surrounded by a membrane. To make things
interesting, the membrane of both viruses contains hepatitis B viral proteins - specifically, they
both have a surface antigen called HBs. Beneath the membrane there is a protein shell called a
capsid, which has more antigens. HB core, or HBc, is in the capsid of hepatitis B. There is also
an HB envelope or HBe antigen for short, which is a variant of HBc but it’s not really part of the
virus. It’s secreted, and can be found in infected individuals' serum. Delta antigen or HDAg for
short is in the capsid of hepatitis D virus. 
Inside the capsid, there’s the viral genetic material. Now, hep B is a DNA virus, which means
that its capsid contains partial double-stranded circular DNA, which is made of a long and short
strand, so there is a part where the long strand is single stranded. And it also has DNA
polymerase, which is an enzyme with DNA- and RNA-dependent activity, meaning it can
convert DNA to RNA and vice versa. On the other hand, hep D is an RNA virus, so its capsid
contains single-stranded circular RNA in a rod-like folded structure, which is why host cell
enzymes can use it as double-stranded DNA.
The main source of hepatitis B virus is blood, but it can also be found in other bodily fluids like
milk, amniotic fluid, vaginal secretions and semen. So, routes of transmission include: sexual
contact; contaminated blood, either following transfusions or injections with contaminated
needles, the latter being more common in people who use intravenous drugs. The virus can also
be passed from an infected mother to the baby during childbirth. Rarely, during the pregnancy
the virus can pass through the placental barrier, which is a kind of a very thin wall that brings the
mother’s and fetus' blood very close, and allows them to exchange some substances like
oxygen, IgG antibodies, waste products and unfortunately certain microbes. More commonly the
virus can pass from an infected individual to the child during birth because of the close contact
between the individual's blood and secretions with the child. It is still not certain if C section can
protect against this kind of transmission. Hepatitis D virus spreads the same way, but it only
causes disease in individuals with an active hepatitis B infection.
Alright, now, both these viruses target the liver, which is made of functional units called hepatic
lobules. The main cells are called hepatocytes. They pick up and detoxify harmful substances
like drugs or alcohol; help maintain a normal blood glucose level; synthesize a variety of
important proteins, like albumin and coagulation factors; store certain vitamins and
some minerals; and convert cholesterol into bile salts, which, along with water and bilirubin,
make up the bile.
Hepatitis B virus enters the hepatocytes by fusing its membrane with the cell membrane and
releasing the capsid into the cell. The cell's polymerase elongates the shorter strand of the viral
DNA, so that it now forms a complete double-stranded DNA with the long strand. It then travels
to the nucleus. There, it is transcribed by the cell's transcription elements into multiple mRNAs,
which leave the nucleus and use the cell’s ribosomes to create viral proteins, like DNA
polymerase and viral antigens: HBs, HB core and HBe antigen. The largest mRNA is used by the
viral DNA polymerase to replicate viral DNA.  Viral antigens Hbs and Hb core are assembled
into new viral particles. Hbe, however, isn’t included in the viral particle, but leaves the cell and
can be found in the serum. The viral DNA is replicated and packaged into capsid at the same
time, which is why its replication is interrupted and the virus gets partial double-stranded DNA.
The capsid is then enveloped and released without damaging the cell, which is why the infection
can persist for a long time without causing liver damage. 
The damage actually comes from the body's immune system. T-cells find and eliminate
infected hepatocytes, which causes liver damage. B-cells react to the virus in the bloodstream
and secrete antibodies against hep B antigens. Bilirubin with bile salts is released from the
destroyed cells into the bloodstream and impregnates the tissue, causing jaundice, which is a
yellowish pigmentation of the skin, mucosa and whites of the eyes. The bile salts get into the
skin, and cause itching. The bilirubin from the blood is filtered by the kidneys and ends up in the
urine instead of the stool, making it dark, while the stool becomes pale.
An insufficient T-cell response, or, if large amounts of HBs antigen bind to neutralizing
antibodies, it can lead to chronic hepatitis. Acute hepatitis B becomes chronic in about 5 to 10%
of cases. In some cases, liver damage can progress to scarring, cirrhosis and liver
failure. Chronic hepatitis also increases the risk of liver cancer called hepatocellular carcinoma.
Hepatitis D virus enters the cell and the nucleus in the same way. However, it uses the host cell’s
RNA polymerase to copy itself and the cell's ribosomes to create delta antigens. Viral RNA is
packaged into the capsid, but in order to make a complete viral particle it must use HBs antigen
and get enveloped. It then leaves the cell.
Now, delta antigens are harmful to the cell and cause cell death and liver damage, so unlike hep
B, hep D damages the cells directly.
Hep D virus causes acute hepatitis in one of two ways. First, there’s co-infection with hep B,
when the two viruses infect the liver at the same time; second, there’s superinfection, which is
when hep D infects individuals with chronic hepatitis B, which is more severe. Hep D increases
the severity of the hep B infection. These individuals are more likely to develop fulminant
hepatitis, massive liver necrosis, and hepatic encephalopathy, when the brain function is affected.
Hep B has a long incubation period of 1-6 months, usually 2-3 months. About two-thirds of
affected individuals develop mild, asymptomatic acute hepatitis that is usually undetected.
Symptomatic hepatitis usually starts as a preicteric phase with fever, fatigue, body aches and
nausea. It lasts a few days to a week and is followed by the icteric phase, with jaundice and dark
urine. It usually lasts 1 to 2 weeks, after which the recovery phase happens. Very rarely, an
individual can develop fulminant hepatitis with liver failure, usually marked by sudden
fever, abdominal pain, vomiting, jaundice, confusion and even coma.
Symptoms of chronic hep B are typically similar to the acute hepatitis but milder. 
The diagnosis of hep B or B and D coinfection is based on the antigen and antibody findings in
the blood. HBs antigen is the first to appear and can be detected in the first 1-2 weeks after
exposure. HBe antigen appears shortly after but clears quickly. Shortly after its clearing, HBe
antibodies appear. Anti HB core IgM antibodies usually appear shortly before the symptoms,
followed by anti HB core IgG antibodies 1-2 weeks after. Anti HBs antibodies appear during
recovery. Hepatitis B DNA can be detected at any time during the disease. Now, in acute
hepatitis B infection, anti HB core IgM, HBs antigen, HBe antigen and viral DNA can be found.
HB core IgG is usually present, depending on the time of testing. In the recovery phase, also
called the window phase, only anti HB core IgM and anti HBe antibodies can be detected.
In chronic hepatitis B, anti HB core IgM is negative, while anti HB core IgG
antibodies and HBs antigen are present for longer than 6 months, and viral DNA can also be
detected. HBe antigen and antibody can be present as well. Anti HB core IgG antibody is the
marker of resolved hepatitis. Anti HBs and HBe antibodies can also be present, but no antigens,
anti HB core IgM or viral DNA are present. Serum alanine and aspartate aminotransferase (or
ALT and AST) are elevated during the active acute and chronic infection, but ALT is more
elevated than AST.
Finally, vaccinated individuals have only anti HBs antibodies present.
A liver biopsy can be done to confirm the diagnosis of chronic hepatitis B, and evaluate the
damage. It usually shows hepatocytes with granular cytoplasm called ground glass hepatocytes.
In severe cases, hepatitis B and D coinfection/superinfection can be suspected. The presence
of hepatitis D RNA, delta antigen or anti hepatitis D antibodies confirm the suspicion. 
Acute hepatitis B infection usually requires no treatment. Severe cases like fulminant hepatitis
and chronic hepatitis are treated with antiviral medication and immune system modulators
like interferon alpha and pegylated interferon. 
For hepatitis B, prevention is much more important. Screening of donated blood for hepatitis B is
done to prevent the spread of the virus. Individuals can avoid a lifestyle that puts them at risk of
infection, like unprotected sex and the use of intravenous drugs. Finally, high risk individuals
like babies of mothers with chronic hepatitis B, intravenous drug users, people who have
multiple sex partners, individuals on dialysis, health care providers, and so on, can
be vaccinated against the disease. However if the individual is exposed to the virus, hepatitis B
immune globulin can be given within a week after exposure to prevent the disease.
There is no specific treatment for hepatitis D. Because it is dependent on hepatitis B, treatment
and prevention of hepatitis B also protects from hepatitis D virus.
All right, as a quick recap…Hepatitis B virus is a DNA virus, transmitted by blood, sexually or
during birth that causes acute or chronic hepatitis by infecting liver cells, while the damage is
caused by the immune system. Initial symptoms of acute hepatitis include fever,
fatigue, body aches and nausea, after which the jaundice develops. Rarely, severe fulminant
hepatitis can develop. Chronic hepatitis has similar symptoms but is milder, and it increases the
risk of hepatocellular carcinoma. Diagnosis is based on clinical course and antigen and antibody
findings. It can be prevented by avoiding risky behavior and vaccination. Acute hepatitis usually
requires no treatment, but severe cases and chronic hepatitis can be treated by antiviral drugs
and interferons. Hepatitis D is an RNA virus transmitted similarly to hepatitis B virus. It can only
infect individuals with active hepatitis B infection and increases the severity and a chance of
fulminant hepatitis. It is diagnosed by antigen and antibody findings. No special treatment is
required, as treating and preventing hepatitis B treats hepatitis D as well.

Gastroesophageal reflux disease (GERD):

Clinical practice
The esophagus is a 25-30 centimeter long tube that food and liquids pass through, from
the pharynx to the stomach.
The esophageal wall is made of 4 layers: the inner mucosa, which is made of stratified squamous
epithelium, except at the lower esophageal sphincter, where it joins the gastric epithelium to
form the gastroesophageal junction; the submucosa, a muscular layer; and an outer layer called
adventitia.
At the top and bottom of the esophagus there are the upper and lower esophageal sphincters,
respectively. Both relax during swallowing to allow the passing of food or liquids, propelled by
peristaltic contractions.
Additionally, the lower esophageal sphincter is closed between meals to prevent acid reflux and
has a resting pressure of 10 to 45 millimeters of mercury.
When the lower esophageal sphincter pressure is lower than normal, gastric acid reaches
the esophagus and the pH of the esophagus drops from 7 to 4, and this is called acid reflux.
Some degree of acid reflux is normal, and it happens mostly after a meal, but it doesn’t
cause esophageal damage or associated symptoms.
Gastroesophageal reflux disease, or GERD, happens when the resting pressure of the lower
esophageal sphincter is below 10 millimeters of mercury, which allows the backflow of gastric
acid in the esophagus, causing esophageal lesions and symptoms that mostly happen at night.
GERD can be caused by a hiatal hernia, where the stomach and lower part of the esophagus slide
above the diaphragm and this usually happens in overweight, obese individuals. It can also occur
during pregnancy due to increased pressure in the abdomen from the growing fetus.
Other common causes are products that increase the production of gastric acid or decrease the
tone of the lower esophageal sphincter, like alcohol, spicy foods, caffeinated drinks including
coffee, tea, and soda, citrus fruits, tomatoes, and even peppermint!
With GERD, typical symptoms include heartburn and regurgitation. But, GERD can also cause
atypical symptoms such as retrosternal chest pain, dysphagia or difficulty swallowing, persistent
coughing, voice changes, halitosis or bad breath, dental erosions, ear or nose discomfort, or even
nocturnal asthma that is unresponsive to asthma therapy.
To help identify GERD as the cause of these atypical symptoms, a full workup can be done,
which includes an upper endoscopy with biopsy, esophageal manometry, and 24-hour pH-
monitoring.
Now, in addition, some individuals with GERD can have signs and symptoms that may be
worrisome for an esophageal cancer. These include unintended weight loss, iron deficiency
anemia, anorexia, odynophagia or painful swallowing, and upper gastrointestinal bleeding. In
these situations, to help identify GERD, upper endoscopy and biopsy can be done.
Finally, in some individuals with risk factors for Barrett’s esophagus, which is a premalignant
lesion, an upper endoscopy and biopsy may be done. These risk factors include male sex, white
race, age over 50 years, obesity, tobacco use, having a hiatal hernia, and having a first degree
relative with esophageal cancer.
An upper endoscopy with biopsy can detect various complications of GERD and it can rule out
malignancy.
The most common complication is reflux esophagitis, and on upper endoscopy there are signs of
erosion, even small ulcers. These lesions can be classified using the Los Angeles system or the
Savary-Miller system, both of which use a 1 to 4 grading scale, where grade 1 is
mild esophagitis and grade 4 is severe esophagitis.
A second complication is a peptic stricture, and on upper endoscopy there’s a narrowing of the
lumen, most often in the distal esophagus. These peptic strictures form when esophageal erosions
and ulcers heal and form fibrotic scars.
A third complication is Barrett’s esophagus, which is where metaplasia begins to develop. That’s
where stratified squamous epithelium of the distal esophagus is replaced
by metaplastic columnar epithelium. That’s the same cellular layer that’s found in
the intestine and when it forms in the esophagus it becomes more likely to have cancer develop
there. That’s why Barrett’s esophagus is considered a premalignant lesion.
In Barrett’s esophagus the upper endoscopy show a change in the epithelium that’s at least 1
centimeter above the gastroesophageal junction. A biopsy of that tissue confirms intestinal
metaplasia, which is characterized by goblet cells that secrete mucus.
Over time, the metaplastic cells of Barrett’s esophagus start to undergo genetic changes and they
become dysplastic. Meaning that the cells become bigger, pleomorphic, and being to proliferate
quickly.
Based on the rate of proliferation, the tissue is categorized as low-grade dysplasia or high-
grade dysplasia.
Biopsies typically show cytologic abnormalities like abnormally shaped cells with bigger nuclei
that are undergoing atypical mitosis.
With adenocarcinoma, the tissue has already mutated to the point where proliferation is
happening without regulation and the growing cell mass typically can break through normal
tissue boundaries and invade neighboring tissues.
In individuals with atypical symptoms, and a normal upper endoscopy, esophageal
manometry may be done next. This can help to identify functional esophageal disorders, such
as achalasia and diffuse esophageal spasm, and evaluate the peristaltic function of
the esophagus before a surgical intervention for GERD.
Manometry uses a pressure sensitive catheter that is inserted through the nose in
the esophagus so it can measure the effectiveness of the peristaltic contractions, as well as the
pressure in both upper and lower esophageal sphincters and with GERD, the pressure in the
lower esophageal sphincter is below 10 millimeters of mercury, showing that the lower
esophageal sphincter doesn’t close properly between meals and allows the backflow of gastric
acid.
Ambulatory 24-hour esophageal pH monitoring is used to confirm the diagnosis of GERD in
individuals with atypical symptoms or individuals that were unresponsive to medical therapy and
still have symptoms. This is a minimally invasive technique in which a flexible catheter with a
pH sensor is inserted through the nose and down into the distal esophagus. The outer part of
the catheter is connected to a monitor on an individual’s belt.
After 24 hours, the data is analyzed and a Demeester score is calculated based on how many
times the pH dropped below 4, the number of reflux episodes, and how long the longest reflux
episode lasted. A score above 14.7 is suggestive of GERD.
Treatment of GERD starts with lifestyle and dietary changes that include weight loss in
overweight and obese individuals. The goal is a Body Mass index between 18.5 to 25 kilograms
per square meter.
In addition, it’s ideal have the head of the bed elevated at least 6 inches to prevent nocturnal
GERD symptoms.
Also, it’s best to not eat within two hours of going to sleep, and eliminating foods that increase
gastric acid production.
In individuals with less than two episodes of acid reflux per week and no complications on upper
endoscopy - step up therapy is used.
Typically, the first medication used is a low dose histamine 2 receptor antagonist or H2RA
which decreases the production of gastric acid. Sometimes an additional medication like a
sodium alginate such as Sucralfate is used to help mucosal healing.
If the symptoms haven’t improved after 2 to 4 weeks of treatment, then the dose of H2RA is
increased for the next 2 to 4 weeks. After that, if symptoms are still present, then the H2RA is
discontinued and a proton pump inhibitor or PPI such as Omeprazole is started at a low dose for
another 2 to 4 weeks.
PPIs are generally more effective in decreasing gastric acid production, but are also generally
more expensive than H2RAs.
Once again, if symptoms are not controlled after 2 to 4 weeks of a PPI, then the dose of the PPI
is increased gradually.
If symptoms are controlled only with a high dose of PPIs, then a laparoscopic anti-reflux
procedure, called a Nissen’s fundoplication, may be done. That’s where the gastric fundus is
wrapped around the distal esophagus and stitched there, strengthening the lower esophageal
sphincter.
However, if symptoms disappear after medical therapy, then the treatment is discontinued to see
if the symptoms reappear. If the symptoms do recur, then medical therapy is reinitiated with the
medication and dosage that last controlled the symptoms.
In individuals with more than two episodes of acid reflux per week or erosive esophagitis, step-
down therapy is used. In this situation, treatment begins with a standard dose of a PPI for 8
weeks.
If symptoms disappear, the dose of PPI is gradually decreased. If PPIs were taken for more than
6 months, then the dose is decreased gradually and replaced by an H2RA.
If the symptoms do recur, then medical therapy is reinitiated with the medication and lowest
dosage that last controlled the symptoms.
For individuals diagnosed with erosive esophagitis that is severe, a repeat upper endoscopy
should be done after 8 weeks of medical therapy to see if there’s evidence of healing and to rule
out Barrett’s esophagus.
In individuals with Barrett’s esophagus, treatment begins with a standard dose of a PPI, and the
dose is increased until symptoms of GERD are controlled.
Barrett’s esophagus can develop into esophageal adenocarcinoma, so upper endoscopies with
biopsies are repeated depending on the results of the initial biopsy.
If the initial biopsy showed no dysplasia, then the upper endoscopy and biopsy is repeated after 3
to 5 years.
If the initial biopsy showed indefinite dysplasia, then the PPI dose is increased and the upper
endoscopy and biopsy is repeated after two months of medical therapy.
If the initial biopsy showed low grade dysplasia, localized high-grade dysplasia, or intramucosal
carcinoma, then the individual typically has an endoscopic resection of the esophageal mucosa
and submucosa and then radiofrequency ablation of the affected tissue.
Finally, in individuals with extensive high-grade dysplasia, an esophagectomy-which is the
surgical removal of the esophagus may be needed.
In individuals with esophageal adenocarcinoma, treatment depends on the stage of
the adenocarcinoma and this is assessed using computer tomography or magnetic resonance
imaging that can identify the local extent of the cancer and also the presence of metastasis.
These findings are then classified into the Tumor-Nodes-Metastasis or TNM system, which helps
to categorize tumors based on their size and growth pattern.
Based on the TNM system, adenocarcinoma has 5 stages, from 0 to 4, 0 meaning only the
epithelial wall of the esophagus is infiltrated and 4 meaning there are distant metastasis.
Usually, in the first 3 stages of adenocarcinoma - 0, 1, and 2, the tumor can be surgically or
endoscopically resected.
However, in the stage 3, the tumor is resectable only if it hasn’t invaded important structures,
such as the aorta, the trachea or the spine. If it has invaded those structures, then chemoradiation
therapy is indicated.
Stage 4 is also unresectable, and only chemoradiation is usually used.

Summary
Alright, as a quick recap, in GERD, an upper endoscopy is indicated in individuals with atypical
symptoms or alarm symptoms. It can also be helpful in detecting complications of GERD, such
as esophagitis, esophageal stricture, Barrett’s esophagus, and adenocarcinoma.
Esophageal manometry is indicated in individuals with retrosternal chest pain and dysphagia to
rule out functional disorders and ambulatory 24-hour pH monitoring is indicated to confirm the
diagnosis of GERD in individuals with atypical symptoms and unresponsive to treatment with
PPIs.
In individuals with less than two episodes per week, step up therapy is indicated and in
individuals with more than two episodes per week or erosive esophagitis, step down therapy is
indicated.
In individuals with Barrett’s esophagus and adenocarcinoma, treatment is indicated depending on
the grade of dysplasia and the TNM stage of adenocarcinoma.

Diabetes mellitus: Clinical practice

In diabetes mellitus, the body has trouble moving glucose from your blood into the cells –
so blood sugar levels are constantly high. Insulin stimulates the movement of glucose into the
cells, and glucagon stimulates the movement of glucose into the blood. In type I
diabetes the blood glucose stays high because of an autoimmune destruction of the pancreas,
which leads to low insulin levels. In type II diabetes, the body makes insulin, but the cells
are insulin resistant - meaning they don’t “respond” to insulin by taking glucose in.
Cells’ inability to use insulin translates in classical symptoms of diabetes like polyuria –
individuals pee a lot -, polydipsia – they drink a lot of water -, sometimes polyphagia – they eat a
lot – and unexplained weight loss. Both type I and type II diabetes get these symptoms –
however, with type I, the onset is usually abrupt and usually affects people under 30. With type
II, the symptoms gradually worsen over a few months, and individuals usually have risk factors
like being over 45 years old, having a first degree relative with type II diabetes mellitus, a body
mass index (BMI) over 25, a sedentary lifestyle, or cardiovascular disease, like hypertension.
Now, type II diabetes accounts for about 90% of the diabetes cases, so let’s start there.
Diagnosing type II diabetes relies on determining blood sugar levels using one of four tests. The
first, and most common test, is a fasting glucose test and it’s where the person doesn’t eat or
drink anything except water for 8 hours. Levels of 100 milligrams per deciliter to 125 milligrams
per deciliter indicates prediabetes and a level of 126 milligrams per deciliter or higher
indicates diabetes. Usually this test is done twice, and two results over 126 milligrams per
deciliter are sufficient to diagnose a person with diabetes. Second, we have the oral glucose
tolerance test, and it’s where a person is given 75 grams of glucose, and then blood samples are
taken at time intervals to figure out how well it’s being cleared from the blood. At the time
interval of 2 hours later, a level of 140 milligrams per deciliter to 199 milligrams per deciliter
indicates prediabetes, and a level of 200 or above indicates diabetes. However, these two tests
have one shortcoming - they only show what’s happening to blood glucose levels in that
particular moment in time, so we have no idea how long blood sugar levels have been high. This
is where our third test comes in - the HbA1c, which is the proportion of glycated hemoglobin in
the blood. When blood glucose levels stay high for too long, glucose begins to stick to proteins
that are floating around in the blood or in cells - like hemoglobin. HbA1c levels of 5.7% to 6.4%
indicate prediabetes, and 6.5% or higher indicates diabetes. Since red blood cells - and
hemoglobin - typically hang around in the blood for up to 4 months, this test reflects blood
glucose levels over the past few months. Finally, there’s our fourth test, called a non-fasting or
random glucose test, which can be done at any time. A red flag for diabetes is when this test
shows a blood glucose level of 200 milligrams per deciliter or higher in an individual that has
classic symptoms, like polyuria or polydipsia; or a hyperglycemic crisis.
Of these, fasting blood sugar and HbA1c levels can also be used to screen people for diabetes.
Guidelines recommend that screening begins at 45 in asymptomatic adults with no risk factors,
using either the fasting blood sugar or a HbA1c test; but screening can begin earlier if risk
factors are present. Specifically, individuals who are overweight or obese or have a family
history of diabetes mellitus can be screened starting at any age; as well as overweight or obese
individuals assigned female at birth who are planning a pregnancy. Additionally, individuals
with a personal history of gestational diabetes mellitus should have lifelong screening once every
three years. If screening is negative for both diabetes and prediabetes, one of those tests should
be repeated every 3 years. Alternatively, if prediabetes is detected, screening should be repeated
yearly.
Now, with type I diabetes, individuals typically present with sudden onset of polyuria,
polydipsia, polyphagia and unexplained weight loss, as well as high blood sugar. In order to
differentiate type I from type II diabetes, we need to look for autoantibodies directed at glutamic
acid decarboxylase - or GAD antibodies and islet cells - or ICA2 antibodies Finally, insulin
deficiency can be checked using C-peptide levels. C peptide is a molecule that’s cleaved off from
proinsulin when it’s converted to insulin, so low C-peptide levels reflect an insulin deficiency.
In both type I or type II diabetes it’s important to think about chronic diabetic complications.
Persistently high blood glucose levels can damage arterioles, primarily affecting the eyes, the
kidneys, and the nerves. In the eyes, diabetes can lead to retinopathy and evidence of that can be
seen on a fundoscopic exam that shows cotton wool spots or flame hemorrhages - and can
eventually cause diabetic retinopathy and blindness. In the kidneys, the afferent and efferent
arterioles, as well as the glomerulus itself can get damaged which can lead to diabetic
nephropathy. For this, a urine sample is used to screen for proteinuria, the presence of which
reflects small vessel damage. Finally, nerve damage causes a decrease in sensation in the toes
and fingers, sometimes called a stocking-glove distribution, as well as causing autonomic
nervous system dysfunction, affecting everything from sweating to passing gas. Finally, both the
poor blood supply and nerve damage, can lead to foot ulcers that don’t heal quickly and can get
pretty severe, even requiring amputation.
Now, in terms of treatment, there are three clinical scenarios - prediabetes, type II
diabetes and type I diabetes. For prediabetic individuals, the goal is to bring the HbA1c levels
below 5.7% - and to do this, recommendations are mainly lifestyle changes over a 16 week trial
period - like losing weight, sticking to a healthy diet, exercising and quitting smoking.
Specifically, we’re talking about losing 7% of total body weight over 16 weeks - which can be
done by decreasing caloric input by 500-1000 kilocalories per day, depending on starting weight,
and sticking to a diet rich in fruits and vegetables, and low in sugar-sweetened beverages and
processed sweets, and also low in saturated fats, like those found in meat and dairy products. So
less of the fast-food style soda, hamburgers, and fries, and more home cooked meals like roasted
vegetables over lentils and rice - which is also cheaper as well! Finally, exercising means
gradually increasing physical activity up to at least 30 minutes a day, at least 5 days a week -
brisk walking, jogging, swimming, going to the gym, you name it - it gets the blood flowing, it’s
good. In addition, sometimes Metformin, a biguanide, is started in these
individuals. Metformin works by making cells respond better to insulin - therefore decreasing
insulin resistance. Unfortunately, metformin can cause nausea and diarrhea, and can rarely
cause lactic acidosis, particularly in individuals with chronic kidney disease and severe heart
failure - so metformin is contraindicated in those settings. Metformin can also deplete vitamin
B12 levels, which can lead to anemia. So individuals on Metformin need to get B12 levels
checked and need supplementation if they’re low. They also need a complete blood count - or
CBC - with each evaluation, to track changes in hemoglobin and hematocrit.
For type II diabetes - the approach depends on HbA1c level. For HbA1c levels between 6.5%,
and 10% - the initial approach is the same as prediabetes - lifestyle changes
and Metformin. Metformin is available in 500, 850 and 1000 milligram tablets, and therapy
usually starts with a 500 mg tablet once daily with the evening meal. If well tolerated, a second
500 mg tablet can be added with breakfast. Doses can be increased by one tablet once every one
to two weeks, up to the usual effective dose of 1500-2000 milligrams per day. However, follow-
up is a bit more intensive here - so HbA1c levels are checked again every 3 months, and
generally speaking the goal is to keep the HbA1c below 7%.
If the HbA1c is still higher than 7% after 3 months of Metformin, a second antidiabetic
medication is usually used, and there are several options to choose from. Which one is best
depends on several individual factors - like whether or not the person is overweight, has chronic
kidney disease or severe heart failure, or atherosclerotic cardiovascular disease - defined as
coronary heart disease, cerebrovascular disease, or peripheral arterial disease presumed to be
of atherosclerotic origin. It’s also important to factor in the risk for hypoglycemia that some of
these medications pose.
Ok, so first, there are the sulfonylureas, like Glimepiride and Glipizide. These medications
increase the amount of insulin that the pancreas naturally releases, but they can
cause hypoglycemia as well as weight gain. As a result, individuals should take these
medications 30 minutes before a meal. Like metformin, sulfonylureas are also contraindicated in
individuals with chronic kidney disease. They may, however, be given to individuals with heart
failure.
Next up, are the thiazolidinediones, like pioglitazone, and they help reduce insulin resistance,
like Metformin, as well as hepatic gluconeogenesis - meaning they make the liver make less
glucose while fasting, overall lowering blood sugar. However, these medications can also cause
weight gain and are contraindicated in individuals with heart failure. On the flip side, studies
have shown that they could improve cardiovascular health in people
with atherosclerotic cardiovascular disease.
Next are the SGLT-2 inhibitors, like dapagliflozin, which inhibit a sodium-glucose cotransporter
in the kidneys, leading to increased urinary excretion of glucose, and lower blood glucose levels.
These drugs can help with weight loss, and they have also demonstrated beneficial effects on
cardiovascular health in people with atherosclerosis. However, they are contraindicated in people
with severe chronic kidney disease. Also, there is a minor risk for hypoglycemia, in case too
much glucose is lost in the urine.
Finally, there are two other classes of antidiabetic medication. These are glucagon-like peptide-1
or GLP-1 analogues, which are injected subcutaneously, and dipeptidil peptidase 4 or DPP-4
inhibitors, which are taken orally. GLP-1 is a hormone secreted by the gastrointestinal tract after
a meal, that decreases glucagon levels, and increases insulin production - causing blood sugar
levels to fall. DPP-4 is the enzyme that degrades GLP-1 in between meals. So GLP-1 analogues,
also called incretins, act like GLP-1 and lower blood sugar and cause weight loss - however, they
are contraindicated in severe chronic kidney disease. Examples
of incretins are Exenatide and Liraglutide. Liraglutide is specifically useful in people
with atherosclerotic cardiovascular disease and also for diabetic nephropathy, because it slows
progression of that disease. DPP-4 inhibitors, also called the gliptins, stop the degradation of
endogenous GLP-1 to keep blood sugar low, but they do come with a small risk
of hypoglycemia. They can’t be given in heart failure, but the good news is that they can be used
for individuals with severe chronic kidney disease.
So to wrap up quickly on these medications. The risk for hypoglycemia is high for sulfonylureas,
low for SGLT-2 inhibitors and DPP-4 inhibitors, and next to zero for the other medications. As
for the effect on weight, sulfonylureas and thiazolidinediones cause weight gain, GLP-1
analogues cause weight loss, and the rest have a neutral effect. People with severe chronic
kidney disease can be given thiazolidinediones, or DPP-4 inhibitors. For those with heart
failure, sulfonylureas, SGLT-2 inhibitors, and GLP-1 analogues are good options. Finally,
individuals with atherosclerotic cardiovascular disease might benefit from thiazolidinediones,
SGLT-2 inhibitors, and one particular GLP-1 analogue - Liraglutide.
Ok now, let’s go through an example. Let’s say a person with type II diabetes presents with an
HbA1c level of 8.5%. The first step would typically be lifestyle changes
and metformin treatment. 3 months later, if HbA1c level are still above 7%, then a second agent
is added - for instance, a sulfonylurea, like glipizide. However, if the person is severely
overweight, and has diabetic nephropathy, we might opt for a GLP-1 analogue, like Liraglutide,
instead of sulfonylurea to help with weight loss, and slow the progression of diabetic
nephropathy.
Ok now, if after 3 months of double therapy, so 6 months after the initial diagnosis, HbA1c is
still above 7%, then the recommendation is to add a third agent from the available antidiabetic
medications. Finally, if 3 more months pass, so 9 months after the initial diagnosis, HbA1c is
still above 7%, the recommendation is to initiate insulin treatment. Also, if the individual has an
initial HbA1c level higher than 10%, then the recommendation is to start insulin therapy directly,
just like in type I diabetes.
Now there are a few types of insulin, and they’re organized by their time to onset and how long
their effect lasts. Rapid acting insulins, like Lispro, Aspart or Glulisine act within 15 minutes,
and last for up to 5 hours. Short-acting insulins, like human regular insulin, act within 1 hour,
and last for up to 8 hours. Intermediate acting insulins, like NPH act within 2 hours, and last for
up to 18 hours. Finally, there’s long-acting insulins, like Detemir and Glargine insulins, that also
act within 2 hours, but last for up to 24 hours. And then, there are the premixed combinations of
these insulins. Most frequently, they’re a mix of a rapid acting insulin - like, say, ispro, with an
intermediate acting insulin like NPH. They come in preset concentrations - like 70/30, or 50/50,
where the first number is the concentration of NPH, and the second one, is the concentration of
the rapid insulin.
When insulin therapy is started, usually, a long acting insulin like Detemir or Glargine Is
introduced first, starting at 10 units right before bedtime. Doses are then adjusted depending on
the fasting blood glucose the next morning - which individuals can determine themselves, using
a glucometer - with a goal to keep fasting blood glucose between 80 and 130 milligrams per
deciliter. If fasting blood glucose is constantly higher than 130 milligrams per deciliter, basal
insulin doses should be gradually increased once or twice a week, until fasting blood glucose is
less than 130. Likewise, if fasting blood glucose is lower than 80 milligrams per deciliter, basal
insulin doses should be gradually decreased. If, after 3 months of using a long acting insulin,
HbA1c is still higher than 7%, then a rapid insulin can be added before the biggest meal of the
day. Eventually, one or two more doses of rapid insulin can be added throughout the day,
building up to an insulin therapy scheme called the basal bolus scheme.
Now, because type I diabetes is insulin dependent from the start, the basal-bolus scheme is also
the standard of care for type I diabetics.
So with basal-bolus, individuals administer one long acting insulin before bedtime, and a short
acting insulin 3 times a day, before breakfast, lunch, and dinner. This attempts to mimic the way
that the pancreas naturally releases insulin, but there’s a risk for hypoglycemia. To avoid that,
individuals measure their blood sugar before each insulin shot, and eat right afterwards. So a
typical day with the basal bolus scheme goes like this: wake up, measure blood sugar, take
rapid insulin, eat breakfast. Before lunch, measure blood sugar, take rapid insulin, eat lunch.
Before dinner, measure blood sugar, take rapid insulin, eat dinner. Finally, before bedtime,
measure blood sugar, and take a long acting insulin.
A simpler alternative to the basal-bolus scheme is to use two shots of premixed insulin per day -
one before breakfast, and one before dinner.
Finally, in a hospital setting a sliding scale regimen may be used - which is where the dose
of insulin is set according to how high blood sugar is. It’s possible to do this in a setting where
constant correction of blood sugar is possible - like giving a rapid insulin if blood sugar is too
high, and giving intravenous glucose if the blood sugar drops too low. However, this is not an
ideal choice in an outpatient setting, because it’s a reactive, rather than proactive regimen, and
there’s a risk for both hyper and hypoglycemia.
Now, let’s go over the diabetic emergencies, starting with hypoglycemia, which is when blood
sugar drops below 70 milligrams per deciliter, and can happen in both type I and type II diabetes.
It can happen if an oral antidiabetic medication or insulin dose is too high - or because the
individual took medication without eating much food. Other causes
of hypoglycemia are exercising too much and eating too little, as well as serious infections. With
mild hypoglycemia, early symptoms are weakness, hunger, shaking, and sweating, and it can be
corrected by eating or drinking something rich in rapidly absorbing carbohydrates - like juice,
sugar, or candy. Basically, all of the stuff you’re normally told to avoid are now life-savers! If
the hypoglycemia worsens, it can lead to confusion, loss of consciousness, seizures, or even
death. So in a severely hypoglycemic individual who’s lost consciousness, treatment
is intravenous glucose as fast as possible.
Ok now, another diabetic emergency, that occurs more frequently with type I diabetes, and can
sometimes even mark the onset of the disease, is diabetic ketoacidosis - or DKA. With DKA,
there’s high blood sugar - usually between 300 and 500 milligrams per deciliter, and a buildup of
ketones in the blood - ketonemia - and make their way into urine - ketonuria -, and there is also
acidosis, or a low blood PH. Clinically, individuals with DKA are dehydrated, and they can
develop Kussmaul respiration, which is a deep and labored breathing. Their breath also smells
sweet and fruity. Nausea, vomiting, and, in severe DKA, mental status changes and
acute cerebral edema can occur. In DKA, the blood sugar is high, the blood PH is low, and there
are ketones in the urine. Because of the acidosis, there’s hyperkalemia, and because ketoacids are
unmeasured anions, it results in a high anion gap.
Treatment of a DKA episode involves giving plenty of fluids, which helps
with dehydration, insulin which helps lower blood glucose levels, and replacement of
electrolytes, like potassium; all of which help to reverse the acidosis. In practice, the first step is
administering fluids at a rate of one liter of saline per hour. If blood pH is below
7, intravenous bicarbonate can be given to reverse the acidosis. Then, if the potassium is below
3.3 milliequivalents per liter, administer potassium before insulin, and then give a 10
unit insulin bolus when potassium levels are above 3.3. Then the person is started on a
continuous insulin infusion, while monitoring potassium levels and the anion gap. An hour or
two after the anion gap closes, IV insulin can be stopped. After that, administer a long
acting insulin, like Glargine or Detemir, subcutaneously, and keep them under observation.
A final complication which is specific to type II diabetes this time is a hyperosmolar
hyperglycemic state, or HHS. This is also a very high blood sugar situation - like, over 800
milligrams per deciliter high - which leads to a serum osmolarity of over 320 milliosmoles. This
can cause mental status changes ranging from confusion to coma, and severe dehydration.
There’s usually no acidosis, ketonuria, or anion gap with HHS, but sometimes the pH can drop a
bit, and ketone levels may rise just a tiny bit as well, so technically there is a bit of overlap
between DKA and HHS. Therefore, treatment of HHS is similar to DKA - giving the
person insulin and plenty of intravenous fluids - will slowly get everything back to normal.
Alright, as a quick recap. In type I diabetes, there’s an absolute insulin deficiency, and lab tests
will show high GAD and ICA-2 antibody titers, and low C-peptide levels. In type II diabetes,
there’s elevated blood glucose levels and a HbA1C above 6.5%. Most of the time, initial
treatment for type II diabetes is lifestyle changes with or without metformin, and the goal is to
get HbA1c below 7%, and additional medications can be added on to accomplish that. For
individuals with type II diabetes who aren’t able to get by on these additional medications and
for those with type I diabetes, insulin therapy is used. Typically insulin is given as a basal-bolus
scheme - that is, one long acting insulin before bedtime, and three rapid acting insulins before
each meal. A serious complication of antidiabetic treatment is hypoglycemia, which is
when blood sugar drops below 70 milligrams per deciliter, and it’s treated with either oral
or intravenous glucose, depending on the person’s consciousness. At the other end of the
spectrum, we’ve got the hyperglycemic complications of diabetes - diabetic ketoacidosis, more
frequent in type I, which is treated with intravenous fluids, insulin, and potassium,
and hyperosmolar hyperglycemic state, more frequent in type II, which is treated
with intravenous fluids and insulin.

Summary
Diabetes mellitus is a metabolic condition characterized by high blood sugar levels (glycemia).
The two types of diabetes mellitus are type 1 and type 2. Type 1 Diabetes Mellitus, also called
insulin-dependent diabetes, usually begins in childhood or adolescence. In this form of the
disease, an autoimmune process triggers the destruction of pancreatic beta cells responsible for
producing insulin, and thus the body produces little or no insulin. Insulin is a hormone that helps
the body to use sugar for energy.
Type 2 diabetes mellitus, also called non-insulin-dependent diabetes, usually begins in
adulthood. In this type, the body produces insulin but becomes resistant to it, meaning it cannot
use it effectively. Type 2 diabetes mellitus has a genetic component, and a sedentary lifestyle and
obesity significantly elevate its risk.

Systemic lupus erythematosus (SLE):

Clinical practice
Systemic Lupus Erythematosus, or lupus, is an autoimmune disease, where essentially any tissue
or organ can be the target of inflammation.
Often there are periods of illness, called flares, and periods of remission during which there are
few symptoms.
The diagnosis of lupus is made when 4 or more out of 11 criteria are met.
The first three have to do with the skin.
The first is a malar rash, sometimes just called a “butterfly rash”, which is a rash over
the cheeks that spares the nasolabial folds and appears after sun exposure.
Second is a discoid rash, which is chronic erythematous rash in sun-exposed areas like the arms
and legs that are plaque-like or patchy redness and can scar.
Third, is a general photosensitivity of the skin — essentially a catch-all category for other rashes
that happen to sun-exposed areas — typically only lasting a couple of days.
Lupus can also damage the inner membrane or mucosa of various tissues, so the fourth criteria
is ulcers in the mouth or nose.
The fifth criteria is serositis which is inflammation of the serosa, which is like the outer
membrane of an organ or tissue.
It can manifest as pleuritis, which is inflammation of the lining around the lungs and chest
cavity; as pericarditis, which is inflammation of the lining of the heart; or as peritonitis, which is
inflammation of the lining of the abdomen.
Now, in addition to pericarditis, it’s worth noting that lupus can also cause inflammation of
the myocardium, leading to myocarditis, or the endocardium, leading to Libman-Sacks
endocarditis, where clumps of fibrin and immune cells form vegetations on the mitral valve.
The sixth criteria is arthritis, and two or more joints have to get inflammed to meet the criteria.
The seventh criteria is evidence of kidney damage based on protein or cells in the urine.
It’s generally caused by lupus nephritis, which is a type of glomerulonephritis due to immune
complex deposition along the glomerular basement membrane.
Lupus nephritis can ultimately lead to end-stage kidney failure, which is the leading cause of
morbidity and mortality among individuals with lupus.
The eighth criteria is neuropsychiatric conditions like headaches, seizures, psychosis, and mood
disorders like depression.
The ninth criteria is having autoantibodies against blood components causing cell destruction,
and leading to conditions like anemia, thrombocytopenia, or leukopenia.
The final two criteria have to do with having specific antibodies in the blood.
The tenth criteria is having antinuclear antibody or ANA, which targets nuclear antigens.
Now a large proportion of patients with lupus have these, meaning this test is very sensitive, but
it isn’t very specific, because it can be found in other autoimmune diseases.
The eleventh criteria is having one of three other autoantibodies.
The first is anti-Smith, which is an antibody against small ribonucleoproteins.
The second is anti-dsDNA, which is against double stranded DNA and is often seen more during
flares, especially in individuals with kidney involvement.
These two are relatively specific for lupus.
The third type of antibody is antiphospholipid, which is actually an antibody that’s made against
proteins that are bound to phospholipids, and is less specific for lupus, meaning that it can pop
up in other situations.
There are three types of antiphospholipid antibodies.
The first is anticardiolipin, which can cause a false-positive test for syphilis since anticardiolipin
antibodies are sometimes involved in syphilis.
The other two antiphospholipid antibodies are lupus anticoagulant also called lupus antibody,
and anti-beta2 glycoprotein I.
Sometimes, because of these, patients with lupus develop an antiphospholipid syndrome, where
the antiphospholipid antibodies cause a hypercoagulable state, meaning they’re more prone to
developing clots and having complications like deep vein thrombosis, hepatic vein thrombosis,
and stroke.
Now, lupus can also cause additional symptoms that aren’t part of the diagnostic criteria.
Systemic symptoms include fever, fatigue, myalgia, unintentional weight loss,
and lymphadenopathy.
There can also be vasculitis, which can manifest as palpable purpura, petechiae, panniculitis,
skin ulcers, splinter hemorrhages, and livedo reticularis - which is where there’s a lace-like
purplish discoloration of the skin.
Another vascular condition that can occur in lupus is Raynaud’s phenomenon, which is where
arterial spasm causes reduced blood flow to the fingers.
It typically lasts for minutes, and the fingers turn white and then blue, often with numbness or
pain, and then as blood flow returns, the fingers turn red and burn.
Finally, lupus increases the likelihood of thromboembolic disease, specifically a blood clot can
form in a blood vessel and then breakaway to plug up a smaller vessel in another organ like the
lungs, brain, or kidneys.
Finally, lupus can cause activation of the complement system and during a flare it can cause
consumption of complement factors like C3 and C4. So in summation, if an individual meets the
diagnostic criteria, they may have many of these additional findings as well.
Next up, is laboratory testing.
That includes getting a complete blood count and differential, to look for leukopenia, anemia,
and thrombocytopenia; as well as a creatinine level which might reveal renal dysfunction.
In addition, it’s important to get antinuclear antibodies, anti-double-stranded DNA, anti-Smith,
and antiphospholipid antibodies, as well as an ESR and CRP to look for evidence of systemic
inflammation.
In addition, C3 and C4 levels, and a CH50, can be obtained to see if there’s an effect on
the complement system.
Now, because lupus nephritis is such a serious problem, a urinalysis should be done to check for
it and distinguish nephritic syndrome, which has faster evolution towards end-stage renal failure,
from nephrotic syndrome.
In nephritic syndrome, there’s a triad of hematuria, hypertension and azotemia with
subsequent renal failure.
Whereas in nephrotic syndrome there’s the pentad of edema, proteinuria, dyslipidemia, lipiduria,
and hypoalbuminemia.
More specific organ involvement may require additional studies.
For inflamed joints, plain radiographs can show joint deformities, and an ultrasound might detect
synovitis or joint effusions.
Chest X rays may be done for a suspected pleural effusion, interstitial lung disease, or cardiac
abnormalities, while echocardiography and an EKG can be done to look for evidence of cardiac
involvement - like pericarditis, myocarditis, and endocarditis.
An MRI may be needed to evaluate any neurologic deficits or cognitive dysfunction.
Finally, a biopsy of an involved organ, mainly the skin or kidneys, is often helpful in confirming
the disease or tracking its progression.
The key goals of therapy are to minimize both damage from the disease and toxicity from
medications.
So treatment is mainly aimed at preventing or limiting the severity of flares of the disease.
To help prevent flares means being careful to avoid triggers like sunlight, certain foods and
medications, and tobacco.
So individuals can avoid sunlight exposure with hats and long-sleeved clothes, avoid certain
foods, exercise regularly, quit smoking, use immunizations to prevent serious infections, avoid
medications like isoniazid, hydralazine, and procainamide, and carefully navigate pregnancy.
Treatment is based upon the severity of disease.
Individuals with mild lupus manifestations, which generally means only having skin, joint, and
mucosal involvement, are given hydroxychloroquine or chloroquine.
They sometimes also use nonsteroidal antiinflammatory drugs or NSAIDs and short courses of
low-dose glucocorticoids, meaning less than 7.5 mg of prednisone per day.
Individuals with moderate lupus involvement are defined as having significant but non-organ-
threatening disease, along with constitutional, cutaneous, musculoskeletal,
or hematologic manifestations.
These individuals usually respond to hydroxychloroquine or chloroquine plus short courses of up
to 15 mg of prednisone per day.
Finally, individuals with severe or life-threatening lupus manifestations with major organ
involvement, such as the kidneys and central nervous system, are usually treated in the hospital
with a short course of high doses of systemic glucocorticoids, meaning 1 to 2 mg per kilogram
per day of prednisone.
This can be supplemented with other immunosuppressive medications
like cyclophosphamide, azathioprine, or mycophenolate mofetil.
This initial therapy is followed by less intensive maintenance therapy with a lower dose
of glucocorticoids to keep them in remission.
Unfortunately, some individuals don’t respond to glucocorticoids or other immunosuppressive
agents.
In those cases, biologic medications can be tried like belimumab, a human monoclonal antibody
that inhibits the activation of B cells, or rituximab, a chimeric monoclonal antibody against
CD20, which is found on the surface of B cells, and triggers B cell death.

Summary
Alright, as a quick recap… Systemic lupus erythematosus is diagnosed when 4 out of 11 criteria
are met.
These are a malar rash; discoid rash; photosensitivity; oral or nasal ulcers; serositis; arthritis in
two joints; renal involvement; neuropsychiatric conditions; hematologic conditions like anemia,
leukopenia, and thrombocytopenia; antinuclear antibodies; or another type of autoantibody like
anti-double-stranded DNA, anti-Smith, or antiphospholipid antibodies.
To help prevent flares, individuals should avoid triggers.
Mild lupus is treated with hydroxychloroquine or chloroquine, with or without NSAIDs and
short-term low-dose glucocorticoids.
Moderate lupus is treated with hydroxychloroquine or chloroquine and short-
term glucocorticoids.
Finally, severe or life-threatening lupus is treated with short-term high-dose glucocorticoids with
or without other immunosuppressive medications like cyclophosphamide, azathioprine, or
mycophenolate mofetil.
Unresponsive cases may be treated with biologic medications like belimumab or rituximab.

Metabolic acidosis
With metabolic acidosis, “acidosis” refers to a process that lowers blood pH below 7.35, and
“metabolic” refers to the fact that it’s a problem caused by a decrease in the bicarbonate HCO3−
concentration in the blood.
Normally, blood pH depends on the balance or ratio between the concentration of bases, mainly
bicarbonate HCO3−, which increases the pH, and acids, mainly carbon dioxide CO2, which
decrease the pH.
The blood pH needs to be constantly between 7.35 and 7.45, and in addition the blood needs to
remain electrically neutral, which means that the total cations, or positively charged particles,
equals the total anions, or negatively charged particles.
Now, not all of the ions are easy or convenient to measure, so typically the dominant cation,
sodium Na+, which is typically around 137 mEq/L and the two dominant anions, chloride Cl−,
which is about 104 mEq/L, and bicarbonate HCO3−, which is around 24 mEq/L, are measured.
The rest are unmeasured. So just counting up these three ions, there’s usually a difference, or
“gap” between the sodium Na+ concentration and the sum of bicarbonate HCO3− and chloride
Cl− concentrations in the plasma, which is 137 minus 128 (104 plus 24) or 9 mEq/L.
This is known as the anion gap, and normally it ranges between 3 and 11 mEq/L. The anion
gap largely represents unmeasured anions like organic acids and negatively charged plasma
proteins, like albumin.
So, basically, metabolic acidosis arises either from the buildup of acid in our blood, which could
be because it’s produced or ingested in increased amounts, or because the body can’t get rid of it,
or from excessive bicarbonate HCO3− loss from the kidneys or gastrointestinal tract.
The main problem with all of this is that they lead to a primary decrease in the concentration of
bicarbonate HCO3− in the blood.
They can be broken down to two categories, based on whether the anion gap is high or normal.
So, the first category of metabolic acidosis is a high anion gap metabolic acidosis.
In this case, the bicarbonate HCO3− ion concentration decreases by binding of bicarbonate
HCO3− ions and protons H+, which results in the formation of H2CO3 carbonic acid, which
subsequently breaks down into carbon dioxide CO2 and water H2O.
These protons can come from organic acids which have accumulated in the blood, but they can
also come from increased production in our body.
One such example is lactic acidosis, which is where decreased oxygen delivery to the tissues
leads to increased anaerobic metabolism and the buildup of lactic acid.
Another example is diabetic ketoacidosis, which can occurs in uncontrolled diabetes mellitus,
where the lack of insulin forces cells to use fats as primary energy fuel instead of glucose.
Fats are then converted to ketoacids, such as acetoacetic acid and β-hydroxybutyric acid.
Another way acids can build up in our blood is due to an inability of the kidneys to throw them
away, although they are produced in normal amounts.
This can happen in cases of chronic renal failure, in which organic acids such as uric acid or
sulfur- containing amino acids can accumulate because they aren’t excreted normally.
In other cases, organic acids don’t come from inside our bodies at all, but, instead, they are
accidentally ingested.
These include oxalic acid which can build up after an accidental ingestion of ethylene glycol,
which is a common antifreeze, formic acid, which is a metabolite of methanol, a highly
toxic alcohol, or hippuric acid, which comes from toluene, which is found in paint and glue.
All of these organic acids have protons, and at a physiologic pH, these organic acids dissociate
into protons H+ and corresponding organic acid anions.
The protons H+ attach to bicarbonate HCO3− ions floating around, decreasing its plasma
concentration and shifting the pH towards the acidic range.
The key is that the plasma maintains its electroneutrality, because for each new negatively
charged organic acid anions, there’s one less bicarbonate HCO3− ion, and because the organic
acid anions are not part of the anion gap equation, the anion gap will be high.
In contrast, in other cases of metabolic acidosis, the decrease in bicarbonate HCO3− ions is
offset by the buildup of Cl- ions which are part of the anion gap equation, so the anion
gap remains normal.
The most common cause is severe diarrhea, where bicarbonate- rich intestinal and pancreatic
secretions rush through the gastrointestinal tract before they can be reabsorbed.
Another cause is type 2 renal tubular acidosis, which is the most common type of renal tubular
acidosis, and develops because the proximal convoluted tubule, a part of the nephron, is unable
to reabsorb bicarbonate HCO3−.
Other types of renal tubular acidosis also result in normal anion gap metabolic acidosis, but the
underlying mechanism is an inability to excrete protons H+ in the urine.
The excessive loss of bicarbonate HCO3− results in a low plasma bicarbonate HCO3−
concentration, which lowers the pH.
In response, the kidneys start reabsorbing more chloride Cl- anions, so for each bicarbonate
HCO3− ion that’s lost, there’s a new chloride Cl- anion.
This is why normal anion gap metabolic acidosis is sometimes called a
hyperchloremic metabolic acidosis.
Now, if there’s a decrease in the HCO3− concentration in the blood, threatening to decrease
blood pH, the body has a number of important mechanisms to help keep the pH in balance.
One of them is moving hydrogen ions out of the blood and into cells. To accomplish this, cells
usually need to exchange the hydrogen ion for a potassium ion, using a special ion transporter
located across the cell membrane.
So, in order to help compensate for an acidosis, hydrogen ions enter cells and potassium ions
leave the cells and enter the blood. This might help with the acidosis, but it results
in hyperkalemia.
In cases, though, when there’s a metabolic acidosis from excess organic acids, like lactic
acid and ketoacids, protons can enter cells with the organic anion rather than having to be
exchanged for potassium ions.
Another important regulatory mechanism involves the respiratory system, and begins
with chemoreceptors that are located in the walls of the carotid arteries and in the wall of
the aortic arch.
These chemoreceptors start to fire when the pH falls, and that notifies the respiratory centers in
the brainstem that they need to increase the respiratory rate and depth of breathing.
As the respiratory rate and depth of each breath increase, the minute ventilation increases - that’s
the volume of air that moves in and out of the lungs in a minute.
The increased ventilation, helps move more carbon dioxide CO2 out of the body, reducing
the PCO2 in the body, which increases the pH.
An additional mechanism, is that if metabolic acidosis is not caused by some renal problem, then
several days later, the kidneys usually correct the imbalance.
The kidneys excrete more hydrogen ions, while also, reabsorbing bicarbonate HCO3− so that it’s
not lost in the urine.
All right, as a quick recap, metabolic acidosis caused by a decreased bicarbonate HCO3−
concentration in the blood.
It can be classified into high anion gap cases, which are caused by the accumulation of organic
acids, either due to their increased production in the body, decreased excretion or exogenous
ingestion, and normal anion gap cases, which are caused directly by a loss of bicarbonate
HCO3−, as in diarrhea or type 2 renal tubular acidosis.

Chronic kidney disease

Chronic kidney disease is a broad term that includes subtle decreases in kidney function that
develop over a minimum of three months.
In contrast, acute kidney injury refers to any deterioration in kidney function that happens in less
than three months.
Now the kidney’s job is to regulate what’s in the blood, so they might remove waste, or make
sure electrolyte levels are steady, or regulate the overall amount of water, and even make
hormones - the kidneys do a lot of stuff!
Blood gets into the kidney through the renal artery, and once inside it goes gets into tiny clumps
of arterioles called glomeruli where it’s initially filtered, and the filtrate which is the stuff that
gets filtered out, moves into the renal tubule.
The rate at which this filtration takes place is known as glomerular filtration rate or GFR. In a
normal healthy person, this is somewhere around 100-120 milliliter of fluid filtered per minute
per 1.73 m2 of body surface area. The value is slightly less in women than men and it decreases
slowly in all of us as we grow older.
One of the most common causes of chronic kidney disease is hypertension.
In hypertension, the walls of arteries supplying the kidney begin to thicken in order to withstand
the pressure, and that results in a narrow lumen. A narrow lumen means less blood and oxygen
gets delivered to the kidney, resulting in ischemic injury to the nephron’s glomerulus.
Immune cells like macrophages and fat-laden macrophages called foam cells slip into the
damage glomerulus and start secreting growth factors like Transforming Growth Factor ß1 or
TGF-ß1.
These growth factors cause the mesangial cells to regress back to their more immature stem cell
state known as mesangioblasts and secrete extracellular structural matrix. This
excessive extracellular matrix leads to glomerulosclerosis, hardening and scarr, and diminishes
the nephron’s ability to filter the blood - over time leading to chronic kidney disease.
The most common cause of CKD is diabetes, excess glucose in the blood starts sticking to
proteins in the blood — a process called non-enzymatic glycation because no enzymes are
involved.
This process of glycation particularly affects the efferent arteriole and causes it to get stiff and
more narrow - a process called hyaline arteriosclerosis. This creates an obstruction that makes it
difficult for blood to leave the glomerulus, and increases pressure within the glomerulus leading
to hyperfiltration.
In response to this high-pressure state, the supportive mesangial cells secrete more and more
structural matrix expanding the size of the glomerulus.
Over many years, this process of glomerulosclerosis, once again, diminishes the nephron’s
ability to filter the blood and leads to chronic kidney disease.
Although diabetes and hypertension are responsible for the vast majority of CKD cases, there are
other systemic diseases like lupus and rheumatoid arthritis, can also cause glomerulosclerosis.
Other causes of chronic kidney disease include infections like HIV, as well as long-term use of
medications like NSAIDs, and toxins like the ones in tobacco.
Now, normally urea in the body gets excreted in the urine, but when there’s a
decreased glomerular filtration fate, less urea get filtered out, and therefore it accumulates in the
blood, a condition called azotemia, which can cause general symptoms like It nausea and a loss
of appetite.
As the toxin levels really build up, they can affect the functioning of the central nervous system -
causing encephalopathy. This results in asterixis, a tremor of the hand that kind of resembles a
bird flapping its wings and is best seen when the person attempts to extend their wrists.
Further accumulation of these toxins in the brain can even progress to coma and death.
The buildup of toxins can also cause pericarditis which is inflammation of the lining of the heart.
In addition, there can be increased tendency for bleeding, since excess urea in the blood
makes platelets less likely to stick to each other, and so there’s less clot formation.
Finally, in some cases, someone can develop uremic frost, where urea crystals can deposit in the
skin and they look like powdery snowflakes.
In addition to getting rid of waste, the kidneys play an important role in electrolyte balance.
Potassium levels are particularly important, and normally the kidney helps with potassium
excretion.
In chronic kidney disease, just like with urea, less potassium is excreted and more builds up in
the blood, and it leads to hyperkalemia, which is worrisome because it can cause cardiac
arrhythmias.
Another key role of the kidneys relates to balancing calcium levels. Normally, the kidney helps
to activate vitamin D which helps to increase absorption of calcium from the diet.
In chronic kidney disease, there’s less activated vitamin D, so less calcium is absorbed into the
blood, resulting in hypocalcemia - low calcium levels. As calcium levels in the
blood falls, parathyroid hormone is released, causing the bones to lose calcium. Over time, this
resorption of calcium from the bones leaves them weak and brittle, a condition known as renal
osteodystrophy.
The kidneys also release key hormones. For example, normally when the kidneys start sensing a
lower than normal amount of fluid getting filtered, they respond by releasing the hormone renin
to increase the blood pressure.
In chronic kidney disease, the falling glomerular filtration rate leads to more and more renin
secretion which leads to hypertension. Now, remember that hypertension is a cause of chronic
kidney disease itself, so this creates quite the vicious cycle.
The kidney also secretes the hormone erythropoietin which stimulates the production of red
blood cells from the bone marrow. In chronic kidney disease, erythropoietin levels fall and this
leads to lowered production of red blood cells, and ultimately anemia.
Ultimately the diagnosis of chronic kidney disease comes down to looking at changes in
the glomerular filtration rate over time. Chronic kidney disease might be suspected with a GFR
of less than 90 ml/min/1.73 m2 , and irreversible kidney damage might happen with a GFR
below 60 ml/min/1.73 m2.
To confirm the diagnosis a kidney biopsy can be done to look for changes like
glomerulosclerosis.
Treatment for chronic kidney disease often involves managing the underlying cause.
In severe situations, dialysis or a kidney transplant might be needed.

Chronic kidney disease: Clinical practice

Chronic kidney disease, or CKD, describes a decrease in kidney function with an estimated
glomerular filtration rate—or eGFR—below 60 milliliters per minute per 1.73 square meters,
that happens over a minimum of three months, regardless of the cause.
Now, if there’s already kidney damage- like with glomerular disease, tubulointerstitial disease,
vascular disease or congenital renal disease- but the eGFR is above 60 milliliters per minute per
1.73 square meters, then this is still CKD, because all these conditions progressively affect the
renal function and over time, without treatment, eGFR decreases.
Now, the causes of CKD can be split into three categories: prerenal, intrarenal, and postrenal
causes.
Prerenal CKD causes are due to a decrease in renal perfusion like in heart failure and cirrhosis.
Intrarenal CKD causes can be further classified into renal vascular disease, glomerular
disease and tubulointerstitial disease.
Renal vascular disease includes hypertension and renal artery stenosis.
Glomerular diseases include nephritic and nephrotic diseases.
And tubulointerstitial disease includes polycystic kidney disease.
Other causes of intrarenal CKD are nephrotoxic substances like lead and certain medications
like cisplatin.
Finally, there’s postrenal CKD, which is most commonly caused by prostate disease.
Also, repeated episodes of pyelonephritis can lead to CKD.
Diagnosing CKD usually requires having past measurements of the eGFR, albuminuria
or proteinuria and past urine dipstick and sediment examinations.
If that isn’t possible, the individual needs to have multiple assessments over a period of three
months to confirm that the problem is chronic.
That means getting a serum creatinine to calculate the eGFR, along with urinalysis- both by
dipstick and microscopy- to identify any abnormalities in the urine- such as hematuria and
checking the urine albumin levels.
Additionally, an abdominal ultrasound is done because CKD can cause the scarring which makes
the kidneys small and echogenic.
However, it depends on the cause, since some causes of CKD like diabetic nephropathy, leave
the kidneys normal-sized.
Now, based on eGFR, CKD is classified into five stages- called G-stages - measured in units of
milliliters per minute per 1.73 square meters. G1 is when eGFR is above 90, but there’s an
underlying kidney disease.
G2 is when eGFR is between 60 and 89, and this is considered mildly decreased kidney function.
G3a is when eGFR is between 45 and 59, and this is mildly to moderately decreased kidney
function.
G3b is when eGFR is between 30 and 44, and this is moderately to severely decreased kidney
function.
G4 is when eGFR is between 15 and 29, and this is severely decreased kidney function.
Finally, there’s G5, where eGFR is below 15, and this is end-stage renal disease or ESRD.
For individuals with stage G5 CKD, if they’re also on dialysis, a D is added to the G-stage, so
it’s called G5D.
Now, albuminuria or the albumin excretion rate has also been added to CKD staging and they’re
called the A-stages.
A1 is when the albumin excretion rate is less than 30 milligrams per day and this is normally to
mildly increased albuminuria.
A2 is when the albumin excretion rate is between 30 and 300 milligrams per day and this is
moderately increased albuminuria.
Finally, there’s A3 where the albumin excretion rate is over 300 milligrams per day and this is
severely increased albuminuria.
We use both these staging systems, because the higher the stage, the higher the risk of mortality
and progression of CKD is.
Individuals with CKD can develop signs and symptoms due to their decreased renal function,
such as edema and oliguria- meaning a urine output less than 400 milliliters per day, fatigue,
weakness, and anorexia.
Individuals with CKD may also have hypertension from sodium retention, increased activity of
the renin-angiotensin-aldosterone system, and secondary hyperparathyroidism.
Additionally, the individual may have symptoms from the underlying disease, such as
gross hematuria with IgA nephropathy or shortness of breath from heart failure.
CKD can also cause complications like anemia which may be due to the kidney’s making
insufficient erythropoietin.
In individuals that undergo hemodialysis, anemia can be caused by regular blood loss during
hemodialysis sessions.
Individuals with CKD are also prone to iron deficiency anemia for several reasons.
Some have a diet low in iron, blood loss during hemodialysis or impaired absorption of iron.
Another complication in CKD is mineral and bone disorder, sometimes called CKD-MBD for
short.
CKD-MBD includes metabolic changes that result in hyperphosphatemia and hypocalcemia,
skeletal abnormalities like bone fractures, and extraskeletal calcifications like coronary
artery calcifications.
CKD-MBD develops for a number of reasons. First, the kidneys can’t excrete phosphate, leading
to hyperphosphatemia and improper conversion of 25- hydroxyvitamin D to active 1,25
dihydroxyvitamin D or calcitriol which is the active form of vitamin D.
Low levels of calcitriol leads to hypocalcemia.
Hyperphosphatemia and hypocalcemia lead to increased levels of parathyroid hormone, which is
a type of secondary hyperparathyroidism and the parathyroids become bigger.
Sometimes, PTH can be the first one to increase, due to increased PTH gene expression, so
phosphate and calcium levels can remain normal for a long period of time.
Now, after a long period of time with secondary hyperparathyroidism, the
large hypertrophied parathyroids start secreting even more PTH, regardless of triggers
like hyperphosphatemia, hypocalcemia, or vitamin D deficiency. This is called tertiary
hyperparathyroidism. In this case, really high levels of PTH can lead to hypercalcemia.
Another complication is hyperkalemia, which can cause symptoms like palpitations,
paresthesias, and muscle weakness.
Finally, CKD can lead to metabolic acidosis which can lead to dyspnea or if it’s chronic, may be
asymptomatic.
Now, in individuals with ESRD there may be uremia- which is caused by the accumulation of
uremic toxins, including urea itself. Symptoms include nausea, vomiting, weight loss, fatigue,
and pruritus.
Another sign of uremia is bleeding and easy bruising, and that’s due to platelet dysfunction.
There’s also uremic pericarditis- which can cause chest-pain and on auscultation, there’s a
pericardial friction rub.
Next, there’s uremic neuropathy affecting the central and peripheral nervous system.
Clinically, there’s progressive encephalopathy - that causes confusion, asterixis, and myoclonus.
It can also cause distal symmetrical polyneuropathy and paresthesias. Finally, in severe cases it
can cause seizures and coma.
There can also be sexual dysfunction that presents with decreased libido and erectile
dysfunction in males and amenorrhea in females.
Further labwork consists of blood serum glucose and Hemoglobin A1C level is checked in
individuals with diabetes mellitus.
Individuals with CKD are at higher risk for cardiovascular disease, so cholesterol, triglycerides,
LDL, and HDL levels are also checked.
The most common finding in CKD is high triglyceride levels.
Electrolyte levels and an ABG are done to assess for metabolic acidosis.
Additionally, with ESRD, albumin levels are also checked and they’re usually low when there’s
malnutrition.
If the individual’s is at stage G3, then a CBC is checked because CKD can cause a normocytic
and normochromic anemia.
Additionally, serum iron, TIBC, and ferritin levels are also checked to assess for iron deficiency.
In iron deficiency, serum iron is low, TIBC is high, and ferritin is low.
Now, to evaluate CKD-MBD, phosphate, calcium, PTH, and vitamin D levels are checked.
Now, once the individual is at stage G3, PTH levels usually increase and vitamin D levels
decrease.
Calcium and phosphate levels can remain normal for a long time, typically until the individual
reaches stage G4, where there will be hyperphosphatemia and hypocalcemia.
This happens because high PTH gene expression leads to high PTH levels which in turn increase
phosphate excretion.
An abdominal ultrasound is usually done to check the size of the kidneys and to look for
evidence of hydronephrosis which can cause obstruction.
When PTH levels are high, a parathyroid ultrasound can be done to see if the parathyroid
glands are larger.
Treatment of CKD starts with stopping any nephrotoxic medications like NSAIDs and
aminoglycosides, and making sure the cause isn’t prerenal - in which case IV saline can be given
to restore the intravascular volume.
After that, the goal is to slow the progression of renal disease, rather than stopping it.
First, dietary recommendations include keeping the caloric intake between 30 and 35 kilocalories
per kilogram per day to help manage body weight, since a high BMI is a risk factor for
worsening renal function. That works out to just about 2300 kcal per day for a 70 kilogram adult.
Now, if the individual is not on dialysis, then protein restriction is recommended- 0.8 grams per
kilogram per day.
If the individual has hypertension or volume overload or proteinuria, then sodium restriction is
set at about 2 grams of sodium per day which is roughly one third of a tablespoon of salt daily.
Additionally, with volume overload, an oral loop diuretic- like furosemide is used.
If hypertension or volume overload or proteinuria aren’t present, then 2.3 grams of sodium per
day can be consumed.
Next, calcium intake should be below 1 gram per day to prevent tissue deposition.
Potassium intake is based on potassium levels, but generally speaking, when eGFR is below 30
milliliters per minute per 1.73 square meters, potassium intake is limited to a maximum amount
of 4 grams per day.
General measures include smoking cessation in all individuals with CKD, and having tight
glycemic control among individuals with diabetes mellitus.
Now, two factors that accelerate the progression of CKD are hypertension and proteinuria.
If there’s only proteinuria- meaning more than 1000 milligrams of protein lost per day, then
treatment with either an oral ACE inhibitor like enalapril or an oral ARB like losartan is
initiated.
Now, if there’s only arterial hypertension, then an ACE inhibitor or an ARB is started.
The goal is to get the systolic blood pressure below of 130 mm Hg but not below 110 mm Hg,
and the diastolic blood pressure below 80 mm Hg.
Now, if there’s both hypertension and edema, then an oral diuretic like furosemide is given as a
first choice.
Another risk factor is hyperlipidemia.
Now, when individuals are at stage G3, they should be started on a statin like atorvastatin, to
reduce the risk of cardiovascular disease.
If LDL levels are high, statin therapy is recommended until the level is below 70 milligrams per
deciliter.
If there’s hypertriglyceridemia- which is when triglycerides are above 200 milligrams per
deciliter, then weight loss and exercise are recommended.
Next, there’s treatment and prevention of complications which begin to appear in individuals at
stage G3.
In individuals with chronic metabolic acidosis, alkali therapy is used to keep the serum
bicarbonate between 23 to 27 milliequivalents per liter.
Between 0.5 and 1 milliequivalents per kilogram per day of oral sodium bicarbonate or oral
sodium citrate is given daily.
Treatment of anemia depends on the cause.
If there’s also iron deficiency, then oral iron supplements are given, which can be taken with
orange juice which is slightly acidic and can help absorption.
If oral iron isn’t effective, or the side effects can’t be tolerated, IV iron can be used instead.
Now, if hemoglobin levels are below 10 grams per deciliter and it’s not due to iron deficiency,
then treatment using subcutaneous erythropoiesis-stimulating agents-
like epoetin or darbepoetin is started.
Treatment of CKD-MBD starts with treating hyperphosphatemia, if present.
First, dietary phosphorus intake is restricted to 900 milligrams per day.
If dietary measures don’t lower phosphate levels, then noncalcium containing phosphate binders-
like oral Sevelamer- are used.
Hypocalcemia isn’t always treated, because vitamin D supplementation can lead
to hypercalcemia, which can further participate to extraskeletal calcifications.
However, if PTH levels above 195 picograms per milliliter and if there’s vitamin D
deficiency and hypocalcemia, then oral calcitriol or alfacalcidol is given.
In individuals at stage G5, meaning ESRD, renal replacement therapy is recommended and this
also helps prevent or treat uremia.
Generally, individuals at stage G4 are informed about renal replacement therapy options, which
include hemodialysis, peritoneal dialysis, and renal transplantation.
Typically these options are initiated when there’s any evidence of uremia.
Other indications for renal replacement therapy are volume overload refractory to
diuretics, hypertension refractory to antihypertensive medications,
persistent metabolic disturbances- like metabolic acidosis, hyperkalemia, hyperphosphatemia,
hypo or hypercalcemia that are refractory to medication, or refractory symptoms like nausea and
vomiting.
Generally, a kidney transplant is the best option for renal replacement but it’s not always
possible.
Absolute contraindications for a kidney transplant are active infections- like hepatitis B,
malignancies-like pancreatic cancer, active substance abuse, uncontrolled mental illness,
treatment nonadherence, or any other risk for a shortened life expectancy.
In these cases, hemodialysis or peritoneal dialysis can be tried instead.
In hemodialysis, there are three major types of vascular access that can be used.
First, there’s an AV fistula which is when an artery and vein are surgically ligated in the arm and
then strengthens over 6 months into a strong blood vessel.
Typically a person is referred for an AV fistula surgery when they’re at stage G4 and when
creatinine levels are above 4 milligrams per deciliter or when there’s a rapid decrease in renal
function.
The arm with an AV fistula shouldn’t be used for blood drawing or for blood pressure checks
and the individual shouldn’t sleep on that arm and carry anything over 5 pounds with that arm.
That’s because this can cause bleeding or an infection which can damage the AV fistula, making
it unusable for hemodialysis.
If an AV fistula can’t be surgically formed, then an AV graft made from polytetrafluoroethylene-
is placed between an artery and a vein from the arm. This can be done just six weeks prior to the
initiation of hemodialysis.
An AV graft isn’t always used, because there’s a higher risk for thrombosis or infection with this
approach.
In situations where hemodialysis needs to be initiated before 6 months, tunneled
hemodialysis catheters can sometimes be temporarily placed.
These are usually placed in the right jugular vein and the catheter is tunneled under the skin.
This is usually done when an individual needs hemodialysis and the AV fistula hasn’t matured
yet or when an individual is a poor candidate for an AV fistula- such as individuals
with congestive heart failure.
These aren’t usually used, because they can cause immediate complications like bleeding
or pneumothorax or long-term complications like thrombosis or central vein stenosis.
Finally, there’s peritoneal dialysis- which is when a peritoneal dialysis catheter is surgically
placed in the abdominal cavity and a dialysis solution flows through the catheter and into
the peritoneal cavity.
The fluid dwells in that space, and toxins and excess water diffuse across
the peritoneal membrane.
Generally, after a few hours, the fluid from the peritoneal space is drained through
the catheter and another dialysis solution is introduced in the peritoneal space.

Summary
Alright, as a quick recap, CKD has 5 stages based on eGFR, albuminuria and kidney damage-
which includes pre-existing conditions like glomerular disease, tubulointerstitial disease,
vascular disease or congenital renal disorders.
The higher the stage, the most likely progression of the renal disease is.
The individual may have edema, oliguria, and hypertension. For individuals at stage G3,
complications can develop like anemia, CKD-MBD- which
includes hyperphosphatemia, hypocalcemia, high PTH and vitamin D deficiency, hyperkalemia,
and metabolic acidosis.
With ESRD, there’s typically uremia which can cause uremic pericarditis, uremic bleeding, and
uremic neuropathy.
Lab work includes serum creatinine, BUN, urinalysis, albuminuria test, blood serum glucose,
HBa1C, cholesterol, triglycerides, LDL and HDL levels, electrolytes, and an ABG.
With ESRD, albumin levels should also be checked.
A CBC is done to check for anemia and Hb levels are under 12 grams per deciliter if present.
If there’s also iron deficiency, TIBC is high and ferritin is low.
For CKD-MBD, serum phosphate, serum calcium , along with PTH and vitamin D levels are
done.
In CKD, an abdominal ultrasound usually shows small kidneys.
The goal of treatment is to slow the progression of disease.
This can be done through dietary modifications, controlling hypertension-the goal being less than
130 over 80 mm Hg, and controlling proteinuria- to less than 1000 milligrams per day with ACE
inhibitors or ARBs.
If there’s hypertension and edema, then a loop diuretic is the first choice.
Individuals at stage G3 receive statins to reduce LDL levels to below 70 milligrams per deciliter.
If there’s hypertriglyceridemia, then lifestyle changes are recommended.
Treatment of volume overload is done with sodium restriction and an oral loop diuretic.
Hyperkalemia can be prevented through diet and avoiding medications that increase serum
potassium.
Chronic metabolic acidosis is treated with oral alkali therapy.
With anemia, if there’s also iron deficiency, then oral or iv iron is given.
If there’s no iron deficiency and hemoglobin levels are under 10 grams per deciliter,
then subcutaneous erythropoiesis-stimulating agents are given.
With hyperphosphatemia, dietary phosphorus intake is restricted and if this doesn’t work, oral
non-calcium containing phosphate binders are given.
If PTH levels are above 195 picograms per milliliter and if there’s vitamin D
deficiency and hypocalcemia, then treatment with oral calcitriol or alfacalcidol is given.
Renal replacement therapy is typically started with ESRD and options include renal
transplantation, hemodialysis, and peritoneal dialysis.

Renal failure: Pathology review

On the Nephrology ward, two people came in. The first one is 55 year old Matilda, who came in
with oliguria, fever and a rash on her arm. Matilda also has a history of taking NSAIDs for her
knee-pain. The second one is 34 year old George, which came in with oliguria, hypotension,
tachycardia and cold extremities. George says that he’s also been having diarrhea for a few days
now. BUN and creatinine levels were high for both of them.
Both Matilda and George have renal failure. Now, renal failure is when the kidneys aren’t
functioning properly. Before talking specifics, let’s remember some basic renal physiology. Now
the kidney’s job is to regulate what’s in the blood, so they might remove waste, or make
sure electrolyte levels are steady, or regulate the overall amount of water, and even make
hormones, such as erythropoietin, which stimulates red blood cell production. Okay, so blood
gets into the kidney through the renal artery, into tiny clumps of arterioles called glomeruli
where filtration happens. After filtration, the stuff that’s filtered out, called the filtrate, moves
into the renal tubules, where reabsorption and secretion of fluid and electrolytes happens. Along
with fluid and electrolytes, though, waste-containing compounds are also filtered, like urea and
creatinine, although some urea is actually reabsorbed back into the blood, whereas only a little
bit of creatinine is reabsorbed. In fact, in the blood, the normal ratio of blood urea nitrogen, or
BUN, to creatinine is between 5 and 20 to 1—meaning the blood carries 5 to 20 molecules of
urea for every one molecule of creatinine, and this is a pretty good way to assess kidney
function! So, when we want to check renal function, we look at BUN and creatinine levels and if
there’s something wrong, then levels of both BUN and creatinine will be high.
Now, back to renal failure. There are two types of renal failure: acute and chronic. Now, acute
renal failure is now called acute kidney injury. This is when the kidney isn’t functioning at 100%
and that decrease in function develops relatively quickly, typically over a few days. In this case,
the individual typically presents with oliguria, even anuria and levels of BUN and creatinine will
be high. Then there’s chronic kidney failure, which is now called chronic kidney disease. This is
when the kidney function gradually decreases over a minimum of three months. This is usually
caused by hypertension, diabetes mellitus, or congenital renal conditions.
Both acute and chronic renal failure has some pretty dire consequences. A lot of the things that
the kidneys normally excrete are now stuck in the body. First, H+ ion secretion is impaired and
this can lead to metabolic acidosis. Secondly, potassium excretion is also impaired and this can
lead to hyperkalemia. Now, in certain cases, such as heart failure, pulmonary
edema or hypertension, the kidney will retain more water and sodium, and so the individual can
present with peripheral or periorbital edema. Next, there’s uremia, which is caused by the
accumulation of uremic toxins, including urea itself. Symptoms include nausea and anorexia.
Another sign of uremia is bleeding and easy bruising, and that’s due to platelet dysfunction.
There’s also uremic pericarditis- which is the inflammation of the pericardium. Next, there’s
uremic neuropathy affecting the central and peripheral nervous system. Clinically, there’s
progressive encephalopathy - that causes asterixis, which is a tremor in the hand when the wrist
is extended, just like a bird flapping its wings. Finally, Renal failure can also increase lipid
synthesis in the liver, causing hyperlipidemia, especially hypertriglyceridemia.
Now, chronic kidney disease can lead to even more problems over a long period of time. If a
child is affected, it can lead to growth retardation and developmental delay, especially in
individuals that had to undergo dialysis. Another important fact for your exams is that there’s
also erythropoietin deficiency and this leads to anemia. Finally, there’s renal osteodystrophy.
This happens for a number of reasons and it’s important to memorize all of them. First, the
kidneys can’t excrete phosphate, leading to hyperphosphatemia. Next, the kidneys are needed to
convert 25- hydroxyvitamin D to active 1,25 dihydroxyvitamin D, or calcitriol, which is the
active form of vitamin D which helps with intestinal calcium reabsorption. As a result, there will
be hypocalcemia. Now, since there’s too much phosphate and too little calcium, this can affect
the bones and they can become thinner and more prone to
break. Hyperphosphatemia and hypocalcemia also triggers the parathyroid glands to release
more parathyroid hormone, a hormone that causes increased bone break down to release more
calcium. Finally, the extra phosphate in the blood can also bind to calcium and they can deposit
in various tissues, such as the vascular tissue.
Okay, now that we’ve gone over the general pathology, let’s look at some specific causes
of acute kidney injury. There are three types of acute kidney injury or AKI: prerenal
AKI, intrarenal AKI and postrenal AKI.
With prerenal AKI, the cause is decreased blood flow into the kidneys. Now, since less blood’s
going to the kidneys, this means that less blood is being filtered, so there’s a decrease in
the glomerular filtration rate, or GFR, which is how much blood, usually in mL, the kidneys
filter through their glomeruli per minute. If less blood is being filtered, that means less urea and
creatinine are filtered out, and more stays in the blood, so levels of BUN and creatinine will be
high. Also with less blood being filtered, the kidneys activate the renin-angiotensin system,
which causes aldosterone release by the adrenal glands. This hormone tells the kidneys to
reabsorb sodium. When sodium gets reabsorbed, water gets reabsorbed as well. Water and
sodium reabsorption is also tied to urea reabsorption, so in this situation, urea gets reabsorbed
and so even more urea gets into the blood, resulting in a BUN to creatinine ratio of greater than
20:1. Now, looking at the urine, more sodium is being retained, so the urine sodium is usually
less than 20 mEq/L. The ratio of sodium excreted to total sodium filtered, or FENa, is usually
less than 1%, and finally that urine is more concentrated because less water is excreted, so
typically the urine’s greater than 500 milliosmoles per kilogram.
Prerenal AKI can happen in hypovolemic states like an acute hemorrhage, gastrointestinal
losses- like with diarrhea and vomiting, renal losses- like with diuretics. All this can lead
to hypovolemic shock. In a hypovolemic states, the individual presents with
tachycardia, hypotension, reduced skin turgor, and cool extremities. Now, prerenal AKI can also
happen with hypervolemic states where there’s a low effective circulating volume. One example
is severe systolic heart failure leading to not enough blood getting pumped to the kidneys. When
this happens, it’s called cardiorenal syndrome. Finally, systemic vasodilation, like with sepsis,
can lead to prerenal AKI.
Next there’s intrinsic or intrarenal AKI, which is due to damage to the tubules, the glomerulus,
or the kidney interstitium, which is the space between tubules. In general, with intrarenal AKI,
there’s kidney damage, causing them to lose the ability to filter blood, and secrete or reabsorb
materials like normal. If urea isn’t reabsorbed, less urea stays in the blood relative to creatinine,
and the BUN to creatinine ratio falls to less than 20:1. Also, renal tubule cells can’t reabsorb
sodium, meaning the urine Na+ goes above 40 mEq/L, and the FENa goes above 2%, and finally
since water’s not being reabsorbed as much, urine osmolality falls below 350 mOsm/kg.
Okay, now, the most common cause of intrarenal AKI is acute tubular necrosis or ATN, which
causes damage to the tubules. Often ATN is due to ischemia from a prerenal acute kidney injury.
On your tests, make sure you don’t confuse this with prerenal AKI where there’s decreased
filtration of blood, but the kidneys are not damaged. In ATN, there’s severe ischemia leading to
the death of tubular cells. The proximal tubular cells and thick ascending limb cells are highly
susceptible to injury. That’s because these cells receive their blood from vasa recta which are
tiny capillaries located in the medulla of the kidney. In this particular zone, the blood flow is
relatively slow to allow for the countercurrent multiplication mechanism to work properly. The
other way tubules can be damaged is via nephrotoxins such as contrast dyes, aminoglycosides
antibiotics, cisplatin, heavy metals like lead, myoglobin from damaged muscles - like
in rhabdomyolysis, ethylene glycol or radiocontrast dye, and hemoglobinuria that’s usually
associated with hemolytic anemia. The proximal tubule cells are particularly susceptible to
nephro toxin injury.
Now, ATN usually has three stages. The first one is the inciting event or the trigger that causes
damage in the tubules. Next there’s a maintenance phase, also called the oliguric phase, which
usually lasts from 1 to 3 weeks. This is when the kidneys aren’t working and here there’s a risk
for developing electrolyte disturbances, like hyperkalemia, because potassium isn’t effectively
secreted, metabolic acidosis, because acid excretion is impaired and uremia, which is when there
are too many waste products retained. Finally, there’s the recovery phase, which is when the
kidneys start working, because the tubular cells begin a process of re-epitheliazation, meaning
new functional cells are born. As a result, creatinine and BUN levels fall, and there’s polyuria.
Also for your tests, remember that in this phase, there’s a risk for developing hypokalemia,
because too much potassium is excreted this time. There can be wasting of other electrolytes
or minerals as well. Remember for your exams that on microscopy, there are muddy brown
granular, epithelial cell casts, along with renal tubular epithelial cells.
Okay, moving onto another cause of intrarenal AKI, which is acute interstitial nephritis. This is
an inflammation of the renal interstitium over the course of days to weeks. It is thought to be a
type I or type IV hypersensitivity reaction, and is typically a response to a medication
like NSAIDs- in which case, it’s called analgesic nephropathy, penicillin, rifampin, proton pump
inhibitors and diuretics. After the cessation of the offending medication, symptoms of acute
interstitial nephritis typically resolve completely. In rare cases, the inflammation in
the interstitium can be caused by systemic infections, such as infections with Mycoplasma or by
autoimmune conditions, like Sjogren syndrome, sarcoidosis or systemic lupus erythematosus. It
can be asymptomatic, but for your exams, remember that it can also present symptoms like fever,
rash, hematuria, pyuria and costovertebral angle tenderness. With acute interstitial nephritis, the
blood count shows eosinophilia and the urine microscopy shows white cells, white cell casts, and
red blood cells.
Another type of intrarenal AKI is acute glomerulonephritis, which is when the glomeruli are
damaged by inflammation. Acute glomerulonephritis can be caused by rapidly progressive
glomerulonephritis, which is when inflammation in the glomerulus is so severe, that it breaks the
glomerular basement membrane and as a result, the kidney function decreases rapidly in a matter
of days to weeks. Another cause of acute glomerulonephritis is hemolytic-uremic syndrome,
which is caused by bacteria like E.coli O157:H7. For your exam, remember it’s characterised
by hemolytic anemia, thrombocytopenia, and acute kidney injury. Another clue is that the person
might have had bloody diarrhea for a few days prior to the oliguria.
Next up, there’s diffuse cortical necrosis, which is when there’s generalized cortical infarction of
both kidneys. This happens because of a combination of vasospasm and disseminated
intravascular coagulation, or DIC, where tiny thrombus block some of the arteries in the kidney
and so, the kidneys won’t get any blood in that area. This can be associated with obstetric
complications like abruptio placentae, where there’s massive blood loss, that can lead to both
vasospasm and DIC. It can also be associated with septic shock, which also causes DIC.
Okay, next, there’s renal papillary necrosis, where the renal papillae are damaged and tiny parts
of them can be eliminated in the urine, so there’s sloughing of the renal papillae. This is usually a
consequence of ischemia because the arteries supplying the renal papillae are tiny, so they’re
prone to obstruction. Now, renal papillary necrosis can be associated with sickle cell disease,
because the abnormal red blood cells can build up and obstruct the arteries that supply blood to
the renal papillae. It can also be due to acute pyelonephritis, because the inflammation can
obstruct those arteries. Another cause is the use of NSAIDs because they block the synthesis
of prostaglandins that keep afferent arteriole dilated. In other words, lack of
these prostaglandins causes vasoconstriction of the afferent arteriole and therefore
decreased glomerular filtration rate. So, when there’s reduced blood flow through the renal
artery, which is particularly common in the elderly and individuals with underlying heart, liver,
or kidney disease, vasoconstriction of afferent arteriole can lead to renal papillary necrosis.
Finally, diabetes mellitus can lead to papillary necrosis, due to the vascular damage it induces.
Let’s move on to postrenal AKI, which is caused by an obstruction in the outflow of urine from
the kidneys, which causes a buildup of urine that backs up into the kidney. Now, BUN to
creatinine ratio, FENa and urine sodium largely depend on if the tubules are working or not, so
for your tests, simply remember that these 3 parameters can vary. Just as with the others, less
water and fluid being reabsorbed causes the urine to be less concentrated, and urine
osmolality falls below 350 mOsm/kg.
Postrenal AKI is most frequently due to benign prostatic hyperplasia or prostatic cancer in a
male, both of which lead to compression of the urethra. This can lead to frequent urination but a
slow urinary stream and a low volume of urine excretion. Finally, there are kidney stones that
can get stuck in either ureter or in the urethra. Now, if only one ureter is obstructed, it’s called
unilateral obstruction, and the other kidney is working fine, then renal function is usually
preserved. But if both ureters are obstructed, it’s called bilateral obstruction.
Finally, let’s review! Consequences of renal failure includes metabolic acidosis, hyperkalemia,
sodium and water retention, hyperlipidemia and uremia for both acute and chronic kidney
failure. Chronic renal failure leads to growth retardation and developmental delay, along
with erythropoietin deficiency and renal osteodystrophy for chronic kidney disease. Okay,
now acute kidney injury can be prerenal, when there’s decreased blood flow to the kidneys. Labs
here show high levels of BUN and creatinine, BUN to creatinine ratio of greater than 20:1, urine
sodium is less than 20 mEq/L, FENa less than 1% and urine osmolality greater than 500
milliosmoles per kilogram. Intrarenal AKI is due to damage to the tubules, the glomerulus, or the
kidney interstitium. Labs show high levels of BUN and creatinine, BUN to creatinine ratio less
than 20:1, urine sodium above 40 mEq/L, FENa goes above 2%, and urine osmolality falls below
350 milliosmoles per kilogram. Causes of intrarenal AKI include ATN, acute interstitial
nephritis and acute glomerulonephritis. With postrenal AKI, there’s an obstruction in the outflow
of urine. Labs show urine osmolality below 350 mOsm/kg but the other values might vary
depending on if there’s damage to the kidneys themselves.
Now back to our cases. Matilda came in with oliguria, a fever and a rash on her arm and labs
showed that she had high levels of BUN and creatinine. Oh, and she is also taking NSAIDs.
Further lab work showed that she also had eosinophilia, BUN to creatinine ratio less than 20:1,
urine sodium above 40 mEq/L, FENa above 2%, urine osmolality below 350 milliosmoles per
kilogram. She also had pyuria and white cell casts. So we can say that Matilda has a case
of intrarenal AKI caused by interstitial nephritis which in turn is caused by NSAIDs, so this is
analgesic nephropathy. In this case, NSAIDs are stopped and the problem eventually resolved.
Next, there’s George that came in with oliguria, hypotension, tachycardia and cold extremities
and has also been having diarrhea for a few days. BUN and creatinine were high and further lab
work showed BUN to creatinine ratio greater than 20:1, urine sodium less than 20 mEq/L, FENa
less than 1% and urine osmolality greater than 500 milliosmoles per kilogram. So it’s a case
of prerenal AKI caused by diarrhea. We should hydrate him!!

Summary
Renal failure is a condition in which the kidneys are no longer able to function properly. There
are two main types of renal failure: acute renal failure and chronic renal failure. Acute renal
failure, also known as acute kidney injury (AKI), is when the kidney isn't functioning at 100%
and that decrease in function develops relatively quickly, typically over a few days. AKI is
commonly caused by anything that causes acute damage to the kidneys, such as infection, injury,
toxins, and certain medications. The symptoms include swelling, decreased urine output, and
changes in the color and smell of urine.
In chronic kidney failure, which is now called chronic kidney disease (CKD), kidney
function gradually decreases over a minimum of three months. CKD is most commonly caused
by chronic disorders like diabetes mellitus and hypertension. Other causes of CRF include
glomerulonephritis, polycystic kidney disease, and chronic obstructive uropathy. The symptoms
of CRF can include fatigue, anemia, and signs of fluid retention.

Sources
1. "Robbins Basic Pathology" Elsevier (2017)
2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 &
Vol.2)" McGraw-Hill Education / Medical (2018)
3. "Current Medical Diagnosis & Treatment 2009" McGraw-Hill Prof Med/Tech (2008)
4. "Radiology Illustrated: Uroradiology" Springer Science & Business Media (2011)
5. "Acute Kidney Injury Network: report of an initiative to improve outcomes in acute
kidney injury" Critical Care (2007)
6. "The future for diagnostic tests of acute kidney injury in critical care: evidence
synthesis, care pathway analysis and research prioritisation" Health Technology
Assessment (2018)
7. "Ultrasonography of the Kidney: A Pictorial Review" Diagnostics (2015)
8. "ANCA Glomerulonephritis and Vasculitis" Clinical Journal of the American Society
of Nephrology (2017)

Acute kidney injury: Clinical practice

With acute kidney injury, or AKI, there’s a decrease in kidney function that typically happens
over a few days.
This leads to the retention of urea and other nitrogenous waste products- such as ammonia and
uric acid and dysregulation of extracellular volume and electrolytes.
The most commonly used diagnostic criteria for AKI are the Kidney Disease: Improving Global
Outcomes or KDIGO guidelines.
The KDIGO guidelines define AKI as an increase in serum creatinine of at least 0.3 milligrams
per deciliter within 48 hours or as an increase in serum creatinine by 1.5 times the baseline serum
creatinine within the last 7 days or when the urine volume has been less than 0.5 milliliters per
kilogram per hour for six hours.
Based on these criteria, there are three stages of AKI, where stage 1 is mild and stage 3 is severe
AKI.
In stage 1 AKI, there’s an increase in serum creatinine to 1.5 to 1.9 times the baseline serum
creatinine or an increase in serum creatinine by 0.3 milligrams per deciliter or a decrease in urine
output to below 0.5 milligrams per kilogram per hour for 6 to 12 hours.
In stage 2 AKI, there’s an increase in serum creatinine to 2 to 2.9 times the baseline serum
creatinine or a decrease in urine output to less than 0.5 milligrams per kilogram per hour for
more than 12 hours.
In stage 3 AKI, there’s an increase in serum creatinine to 3 times the baseline serum creatinine or
an increase in serum creatinine to more than 4 milligrams per deciliter or a decrease in urine
output to less than 0.3 milligrams per kilogram per hour for more than 24 hours or anuria-
meaning less than 100 milliliters per day of urine- for more than 12 hours or where renal
replacement therapy has been initiated.
All individuals are classified according to whichever criteria places them in the most severe stage
of injury.
Once diagnosed, the causes of AKI can be split into prerenal, intrarenal, and post-renal causes.
In prerenal AKI, there’s decreased blood flow into the kidneys.
This can happen in hypovolemic states like an acute hemorrhage, gastrointestinal losses- like
with diarrhea and vomiting, renal losses- like with diuretics or osmotic diuresis in
hyperglycemia, dermal losses- like with burns and finally sequestration of fluid- also known as
third-spacing- like with acute pancreatitis or sepsis.
On the clinical examination, there’s tachycardia, hypotension, reduced skin turgor, and cool
extremities.
Now, prerenal AKI can also happen with hypervolemic states where there’s a low effective
circulating volume.
One example is severe systolic heart failure leading to pump failure, and when this happens, it’s
called cardiorenal syndrome. In this situation, there are signs of heart failure, like hypotension,
fatigue, dyspnea, and peripheral edema.
Another hypervolemic situation due to a low effective circulating volume
is hypoalbuminemia from decompensated liver disease. When that leads to AKI, it’s
called hepatorenal syndrome.
The individual has hypotension and signs of liver disease like splenomegaly, caput
medusae, ascites, and peripheral edema.
Additionally, some medications such as NSAIDs, ACE-inhibitors, ARBs, cyclosporine and
iodinated contrast can damage renal blood vessels - leading to ischemia and causing prerenal
AKI.
Next, there’s intrarenal AKI which is due to damage to the tubules, the glomerulus, or the
kidney interstitium, which is the space between tubules or vascular damage.
The most common cause of intrarenal AKI is acute tubular necrosis or ATN, which causes
damage to the tubules due to ischemia.
Often ATN is due to ischemia from a prerenal acute kidney injury.
The other way tubules can necrose is via nephrotoxins such as aminoglycosides
antibiotics, methotrexate, heavy metals like lead, myoglobin from damaged muscles - like
in rhabdomyolysis, ethylene glycol, radiocontrast dye, and uric acid. Typically, the individual
has been exposed to a nephrotoxin and has associated symptoms.
For example, if they’ve been exposed to ethylene-glycol, the individual might also be confused
and have dilated pupils, whereas if the cause is myoglobinuria - they may have had a
recent crush injury.
Another type of intrarenal AKI is glomerular disease, which is anything that damages the
glomeruli.
Glomerular disease can cause isolated gross hematuria- like immunoglobulin A nephropathy.
It can also cause signs of nephrotic syndrome, such as peripheral or periorbital edema,
even ascites- this can happen with membranous nephropathy or membranoproliferative
glomerulonephritis.
Labs here show proteinuria that’s above 3.5 grams per day, protein-to-creatinine ratio greater
than 3 grams per gram, hypoalbuminemia that’s typically less than 3.5 grams per deciliter
and hyperlipidemia, with levels of low-density lipoprotein or LDL above 130 milligrams per
deciliter and levels of triglycerides above 150 milligrams per deciliter.
On urinalysis, specifically microscopy, there is lipiduria, which is identified based on the
presence of fat droplets.
Or it can present signs of nephritic syndrome, such as arterial hypertension and peripheral
edema- this can happen with systemic Lupus erythematosus.
Labs here show moderate proteinuria- between 1 and 3 grams per day and on urinalysis, there are
more than 5 dysmorphic red blood cells per microliter and also red cell casts.
Finally, it can also present with signs and symptoms of a more severe systemic condition, such as
malaise, arthralgia and fever- like with Goodpasture disease.
Another cause of intrarenal AKI is acute interstitial nephritis, which is inflammation of
the interstitium over the course of days to weeks.
This is thought to be a type I or type IV hypersensitivity reaction, and is typically a response to a
medication like NSAIDs, penicillin, and diuretics, such as thiazide diuretics, like chlorothiazide.
Early symptoms include fever and rash.
Now, vascular damage can be caused by renal artery stenosis, which is when one or both renal
arteries are narrowed.
This can be caused by atherosclerosis in older individuals and by fibromuscular dysplasia, which
is a noninflammatory and nonatherosclerotic condition that usually affects the internal
carotids and renal arteries in younger individuals.
Symptoms include persistent arterial hypertension despite taking antihypertensive medications
and sometimes peripheral edema.
Finally, there’s postrenal AKI, which is due to an obstruction to the outflow of urine from the
kidneys which causes a buildup of urine and pressure that backs up into the kidney.
This is most frequently due to benign prostatic hyperplasia or prostatic cancer in a male, both of
which lead to compression of the urethra. This can lead to frequent urination but a slow urinary
stream.
Other causes include intra-abdominal tumors that compress the ureter- in which case the
individual can present with unintentional weight loss and fatigue.
Finally, there are kidney stones that can get stuck in either ureter or in the urethra.
Now, if only one ureter is obstructed, called unilateral obstruction, and the other kidney is
working fine, then renal function is usually preserved.
But if both ureters are obstructed- like when there are stones in both ureters, called bilateral
obstruction, or if the urethra gets blocked, then we’ve got a recipe for postrenal AKI.
With obstructive ureteral kidney stones, the individual has renal colic along with anuria if
both ureters are completely obstructed.
With urethral stones, the individual has pain in the urethra and anuria.
Now, additional labs include creatinine levels in order to calculate the estimated glomerular
filtration rate or eGFR, BUN, CBC, and electrolytes to check for hyperkalemia.
Hyperkalemia can develop because when the individual is oliguric, potassium isn’t effectively
removed from the blood.
Also, if the individual is hyperventilating, this can be a sign of metabolic acidosis, so an ABG is
also done.
AKI can lead to severe metabolic acidosis where the pH dips below 7.1, because acid excretion
is impaired when there’s a low eGFR.
Next, urinalysis- both dipstick and microscopic examination of the urine sediment and urine
sodium excretion are done to help calculate the fraction of sodium excreted to sodium filtered, or
FENa.
In prerenal AKI, the renin-angiotensin-aldosterone system is activated, leading to water and
sodium retention.
So the BUN to creatinine ratio is usually over 20:1, the urine osmolality is over 500 milliosmoles
per kilogram, the urine sodium excretion is less than 20 milliequivalents per liter, and the FENa
is less than 1%.
With intrarenal AKI, filtration, reabsorption, and secretion can all be affected.
As a result, the BUN to creatinine ratio is usually below 20:1.
Urinalysis results can vary based on the cause, but generally, the urine osmolality is below 500
milliosmoles per kilogram, because water isn’t as well retained.
In acute tubular necrosis, on microscopy, there are muddy brown granular, epithelial cell casts,
along with renal tubular epithelial cells.
In glomerulonephritis, there’s usually hematuria and proteinuria. Additionally, on microscopy,
there are dysmorphic red blood cells, and red blood cell casts.
In glomerulonephritis, an additional workup includes a 24 hour urine collection, serology, and a
kidney biopsy to identify the underlying cause.
In acute interstitial nephritis, the CBC shows eosinophilia. On the urine dipstick, there may
be hematuria, proteinuria, and pyuria. On microscopy, there are white cells, white cell casts, and
red blood cells.
With all types of intrarenal AKI, urine sodium excretion is typically above 40 milliequivalents
per liter and the FENa is above 1%, because sodium isn’t effectively reabsorbed.
Finally, there’s postrenal AKI.
If the obstruction damages the tubules, then reabsorption is affected, so the BUN to creatinine
ratio falls below 20:1 and the urine osmolality is below 500 milliosmoles per kilogram.
Urine sodium excretion is typically above 40 milliequivalents per liter and the FENa is above
1%, because sodium doesn’t get reabsorbed.
When the tubules are functioning, urea, water and sodium can be reabsorbed, so the BUN to
creatinine ratio is above 20, the urine osmolality is over 500 milliosmoles per kilogram, urine
sodium excretion is less than 20 milliequivalents per liter, and FENa is below 1%.
In both situations, on urinalysis, there can be hematuria. Sometimes, an obstruction can lead to
an infection, so there may also be pyuria.
An additional workup includes obtaining serum prostate specific antigen or PSA level which is
elevated with prostatic disease- both benign prostatic hyperplasia and prostatic cancer, as well as
imaging.
An abdominal ultrasound can help identify proximal ureter stones and hydronephrosis, and a
non-contrast CT-scan of the abdomen and pelvis can help identify abdominal tumors or stones
along the urinary tract, including the urethra.
AKI can lead to various complications such as volume overload, hyperkalemia, severe metabolic
acidosis with a pH that’s below 7.1, and signs of uremia like uremic pericarditis, where
the pericardial sac gets inflamed causing chest pain.
In this case, an echocardiogram is done and this typically shows a pericardial effusion.
Treatment relies on urgent dialysis or a temporizing measures until dialysis can be arranged.
Temporizing measures include administering IV diuretics- like furosemide when an individual is
fluid overloaded, administering IV bicarbonate when the pH is below 7.1 and administering IV
calcium gluconate, along with IV insulin plus glucose and IV furosemide when
there’s hyperkalemia with potassium levels above 5.5 milliequivalents per liter.
With any type of AKI, it’s important to identify and treat the underlying cause.
Now, with prerenal AKI and intrarenal AKI that’s caused by acute tubular
necrosis and interstitial nephritis, the goal is to carefully manage the body’s fluids while the
kidneys heal and recover.
With intrarenal AKI caused by glomerular disease, treatment relies on identifying and treating
the condition.
Finally, with postrenal AKI, treatment relies on identifying and removing the obstruction.
Now, there are some general principles that are taken into consideration with any type of AKI,
regardless of stage.
First, all nephrotoxic medication is discontinued and radiocontrast procedures are avoided, since
that can worsen the renal function.
Next, the individual’s hemodynamic status is monitored. If the individual has signs
of hypovolemia- like hypotension, then IV saline in given to restore intravascular volume.
Normally, that helps stabilize the blood pressure, but if an individual is persistently hypotensive,
then vasopressors like IV norepinephrine may be needed.
Now, on the flip side, if the individual is hypervolemic, then IV diuretics- such
as Furosemide are given.
In critically ill individuals, invasive hemodynamic monitoring is done using an arterial line,
central venous pressure and cardiac monitoring.
Serum creatinine levels and urinary output are usually monitored every few hours.
Blood glucose is also monitored because hyperglycemia can cause an osmotic diuresis- further
damaging the kidneys.
Additionally, with stage 2 AKI and stage 3 AKI, the dosage of medications should be adjusted
according to eGFR.

Summary
Alright, as a quick recap, AKI is diagnosed and staged based on creatinine levels and urine
output using the KDIGO criteria.
Prerenal AKI can be caused by either hypovolemia- like with acute hemorrhage, diarrhea,
diuretics or acute pancreatitis or hypervolemia- like with cardiorenal or hepatorenal syndrome.
Intrarenal AKI can be caused by acute tubular necrosis- which is either ischemic or caused by
nephrotoxins- like aminoglycosides, glomerulonephritis, acute interstitial nephritis- that can be
caused by the use of nephrotoxic medications and vascular damage-like with renal artery
stenosis.
Postrenal AKI can be caused by prostatic disease, intra abdominal tumors or kidney stones.
Additional lab work includes calculating eGFR, CBC, BUN, ABG, electrolytes, urinalysis, urine
sodium excretion and FENa.
In prerenal AKI, the BUN to creatinine ratio is greater than 20:1, urine osmolality is greater than
500 milliosmoles per kilogram, urine sodium excretion is less than 20 milliequivalents per liter,
and FENa is less than 1%.
With intrarenal AKI, the BUN to creatinine ratio is below 20:1 and the urine osmolality is below
500 milliosmoles per kilogram, urine sodium excretion is above 40 milliequivalents per liter and
FENa is above 1%.
When there’s acute tubular necrosis, microscopy shows muddy brown granular epithelial
cell casts and tubular epithelial cells.
When there’s glomerulonephritis, there’s also hematuria and proteinuria, along with dysmorphic
red blood cells.
When there’s acute interstitial nephritis, there’s eosinophilia, hematuria, pyuria, along with white
cells, white cell casts, and red blood cells.
With postrenal AKI, when the tubules aren’t working, BUN to creatinine ratio is below 20:1,
urine osmolality is below 500 milliosmoles per kilogram, urine sodium excretion is above 40
milliequivalents per liter and FENa is above 1%.
When the tubules are working, BUN to creatinine is above 20:1, urine osmolality is above 500
milliosmoles per kilogram, urine sodium excretion is less than 20 milliequivalents per liter and
FENa is below 1%.
Treatment of AKI is mainly about identifying and managing the underlying cause.
The indications for urgent dialysis are: volume overload, severe metabolic
acidosis, hyperkalemia, and signs of uremia.
Generally, all nephrotoxic medication is stopped and no contrast imaging is done or the dosage is
adjusted according to the renal function.
When there’s hypovolemia, IV saline is given, and after
that vasopressors like norepinephrine are used, if needed. When there’s hypervolemia,
IV furosemide is given.

Hyponatremia: Clinical practice

Hyponatremia means a lower than normal concentration of sodium in the blood, generally below
135 mEq/L.
However, since the concentration of sodium depends on both sodium and water levels in
the body, hyponatremia actually translates as too much water in the extracellular compartment.
Ok, now remember that total body water is distributed either in the intracellular compartment,
meaning inside the cells, or the extracellular compartment, meaning outside the cells.
Both the intracellular and extracellular compartments have the same amount of solutes dissolved
in that water - so the same osmolality, normally between 275 and 290 milliosmoles per kilogram.
Serum osmolality can be calculated using the formula: twice the concentration of sodium
measured in milliequivalents per liter, plus the serum concentration of glucose divided by 18,
measured in milligrams per deciliter, plus BUN, which stands for blood urea nitrogen, divided by
2.8, also in milligrams per deciliter - so if you remember one thing from this formula, it should
be that sodium is the major determinant of serum osmolality.
Ok, now just to make matters more interesting, some of these solutes, like sodium and glucose,
can’t freely cross cell membranes, so they generate an osmotic pressure inside the compartment.
This confers each compartment its tonicity - meaning how likely it is that compartment will draw
water out of the other one.
Normally, the intracellular and extracellular compartment are isotonic to each other - meaning,
they have the same concentration of osmotically active solutes.
However, small variations in solute concentrations, like having more sodium in the extracellular
compartment, can alter that equilibrium, so water moves across cell membranes in order to
restore the balance.
Water moves according to the rules of osmosis - or from the hypotonic compartment, where
there’s more water, to the hypertonic compartment, where there’s less water. And water does that
until the two compartments become once again isotonic.
That being said, hyponatremia, or low concentration of sodium in the extracellular fluid and
therefore the blood, can be caused by either losing more sodium than water, or gaining more
water than sodium - and it can develop acutely, over less than 48 hours, or chronically, over
more than 48 hours.
Depending on severity, hyponatremia can be classified as mild, when the serum sodium is
between 130 and 134 milliequivalents per liter, moderate, with the serum sodium is between 120
and 129 milliequivalents per liter, and severe, when the serum sodium is below 120
milliequivalents per liter.
Now, according to serum osmolality, hyponatremia can be split in three categories.
The first category is when there’s low serum osmolality, below 280 milliosmoles per kilogram,
and it confirms true hyponatremia.
True hyponatremia can be further divided into 3 subcategories of its own, depending
on body volume status.
The first subcategory is hypervolemic hyponatremia where there’s an enormous increase in total
body water with a less significant increase in total body sodium.
Typically this is seen in conditions like congestive heart failure, cirrhosis, or nephrotic
syndrome - which all present with edema.
The second subcategory is hypovolemic hyponatremia where there’s a small decrease in total
body water with a large decrease in total body sodium.
This can occur in conditions like diarrhea or vomiting, or in response to certain medications like
diuretics.
Another more nuanced condition is cerebral salt wasting which is when an intracranial
injury like meningitis disrupts the normal sympathetic nervous system stimulation of the kidneys
leading to disproportionate loss of sodium - and, along with it, water.
A third subcategory is euvolemic hyponatremia, or normal volume hypovolemia, which is where
there’s a normal body sodium with an increase in total body water - however, we call it
“euvolemic” because there’s no edema.
Euvolemic hyponatremia can be split into cases with dilute urine and concentrated urine.
Conditions that cause dilute urine include drinking too much water called polydipsia or beer
which is called potomania, as well as the “tea and toast” diet - which is literally what it sounds
like, hyponatremia in people who drink only tea and eat only toast.
The main condition that causes concentrated urine is syndrome of inappropriate antidiuretic
hormone secretion, or SIADH for short.
This can happen because of conditions that mess up the brain’s ability to regulate the release of
ADH, like strokes, hemorrhages or trauma, after surgery, and after treatment with some
medications, like mood stabilizers or antiepileptics.
Inappropriate ADH secretion can also happen in the context of tumors that secrete ADH, of
which small cell lung carcinoma is the most likely culprit.
Euvolemic hyponatremia with concentrated urine can also be seen in adrenal
insufficiency and hypothyroidism.
Ok, now, back to serum osmolality, we’ve got two more scenarios - normal and high. Normal
osmolality, between 280 and 285 milliosmoles per kilogram, point towards false hyponatremia,
or pseudohyponatremia.
This is where the body water and sodium levels are normal, but there’s an excessive amount
of lipids, like in hypertriglyceridemia, or proteins, like in multiple myeloma.
High levels of lipids and proteins affects the laboratory instruments that measure the sodium
concentration - making the instruments say the sodium concentration is too low, which is false.
So check serum lipids to rule out hypertriglyceridemia, as well as serum and urinary proteins - to
screen for multiple myeloma.
Finally, when serum osmolality is above 285 milliosmoles per kilogram, we call that hypertonic
hyponatremia.
This may sound paradoxical, but remember that other osmotically active solutes, can make the
extracellular compartment hypertonic, and this, in turn, causes water to shift from the
intracellular to the extracellular compartment.
Such osmotically active solutes may be the excess glucose in diabetic ketoacidosis, mannitol,
which is given in the treatment of cerebral edema, as well as glycine and sorbitol - which are
used for irrigation during procedures like transurethral resection of the prostate or bladder, or
laparoscopic surgery.
Ok, now, hyponatremia can cause symptoms like nausea, vomiting, and muscle cramps.
In severe hyponatremia, water moves within the brain cells, and they swell up, causing cerebral
edema. This can cause confusion, coma and even death.
It can also cause increased intracranial pressure which can squash the blood vessels heading in
and out of the brain causing ischemia, as well as possible brain herniation which can damage
respiratory centers in the brain and cause respiratory failure.
So, to find out the cause of hyponatremia, first we need to exclude pseudohyponatremia - by
checking serum osmolality, lipids and proteins, and hypertonic hyponatremia - by checking
serum osmolality, blood glucose levels and the history for recent use of mannitol, sorbitol or
glycine.
So if these causes are excluded and we’re left with a low osmolality, then we have to figure out
the cause of true, or hypotonic, hyponatremia. The first step is evaluating the volume status.
Individuals can be hypervolemic, hypovolemic, or euvolemic.
Hypervolemic individuals typically have edema, often around the ankles, as a result of renal
failure, decompensated heart failure, cirrhosis, or nephrotic syndrome.
We use urinary sodium to distinguish between renal causes - like renal failure, when urinary
sodium is greater than 20 milliequivalents per liter, and extrarenal causes, like heart
failure, cirrhosis and nephrotic syndrome, where urinary sodium is lower than 10
milliequivalents per liter.
With renal failure, the kidneys are not working properly and they lose sodium in the urine, hence
the urinary sodium above 20 milliequivalents per liter.
With extrarenal causes, the kidneys are perfectly capable of reabsorbing sodium, but the problem
is a low effective circulating volume.
This triggers the activation of the renin-angiotensin-aldosterone system, and aldosterone acts on
the distal convoluted tubule of the kidney, leading to sodium and water reabsorption, which is
why the urinary sodium is below 10 milliequivalents per liter.
Now just to clarify some things - bear in mind that while nephrotic syndrome reflects a kidney
ailment, it does not directly cause sodium waste, but rather loss of proteins in the urine, and the
result is a low effective circulating volume.
Heart failure and cirrhosis also cause a low circulating volume, which is why they’re all lumped
together.
Ok, now, at the other end of the spectrum we’ve got hypovolemic hyponatremia.
In this case, individuals may present with signs of dehydration, like orthostatic hypotension,
decreased skin turgor, dry mucous membranes and axillary dryness.
And we can differentiate between renal and extrarenal losses using the urinary sodium.
Renal losses are associated with urinary sodium greater than 40 milliequivalents per liter, and
this might happen because of diuretics, or cerebral salt wasting.
If it’s due to the use of diuretics, then stopping them may be enough to reverse hyponatremia.
Extrarenal losses are associated with urinary sodium lower than 25 milliequivalents per liter, as
well a low urine output - usually below 500 milliliters per day.
Common causes are gastrointestinal losses like vomiting or diarrhea, or third space losses, like
in pancreatitis, which can be confirmed by high serum amylase and lipase.
Finally, there’s euvolemic hyponatremia, which can also be split up based on the urine sodium
and osmolality.
Urine sodium is usually above 20 milliequivalents per liter, but osmolality varies depending on
ADH levels.
Think of urine osmolality as a sort of ADH “dipstick” - when ADH is not secreted, urine
osmolality is below 100 milliosmoles per kilogram, meaning the kidneys don’t retain water and
eliminate dilute urine.
When ADH is secreted, urine osmolality is above 100 milliosmoles per kilogram, meaning the
kidneys retain water and eliminate concentrated urine instead.
Now, for cases with dilute urine, there are three possible diagnoses: primary polydipsia, beer
drinkers’ potomania and the tea and toast diet.
Euvolemic hyponatremia with concentrated urine is a bit trickier - causes
include hypothyroidism, primary adrenal insufficiency and SIADH, with the last being a
diagnosis of exclusion.
So, with hypothyroidism, TSH levels are high, and free T4 levels are low.
In primary adrenal insufficiency, morning cortisol and aldosterone levels are low, and an ACTH
stimulation test can be done to confirm the diagnosis.
This means that ACTH is administered after measuring morning cortisol levels, and in healthy
individuals, the adrenals should produce more cortisol following ACTH administration.
In individuals with primary adrenal insufficiency, cortisol levels stay low after ACTH
administration.
If both the thyroid and the adrenals are working properly, SIADH is the most likely diagnosis.
Treatment recommendations for hyponatremia include general measures, like identifying and, if
possible, reversing the cause of hyponatremia, as well as fluid restriction - usually to less than
800 milliliters per day.
Bear in mind that fluid restriction in a hypovolemic individual is probably not the best idea - for
example, in cerebral salt wasting, you want to give intravenous fluids instead.
Additionally, hypertonic saline - or 3% sodium chloride -, with or without diuretics, can be given
in particular clinical scenarios.
For example, in individuals with heart failure and cirrhosis, loop diuretics like furosemide with
hypertonic saline can help.
Depending on the duration and severity of hyponatremia, additional recommendations are mostly
about whether or not to give hypertonic saline, and how much of it to give.
In acute, asymptomatic hyponatremia, when serum sodium is below 130 milliequivalents per
liter, it’s recommended to give a 50 milliliter bolus of hypertonic saline, infused over 10 minutes.
In acute, symptomatic hyponatremia, a 100 milliliter bolus of hypertonic saline is infused over
10 minutes, and 2 additional doses may further be given over the course of 30 minutes.
In chronic, asymptomatic hyponatremia, general measures like fluid restriction are usually
sufficient to correct the sodium - water balance.
Treatment of chronic, symptomatic hyponatremia, however, depends on whether or not there’s
associated intracranial pathology.
See, even with mild chronic hyponatremia, if the individual also has associated intracranial
pathology, like for example brain tumor, the risk of brain herniation increases.
So basically when there’s an increased risk of brain herniation it’s important to give a 100
milliliter bolus of hypertonic saline, infused over 10 minutes. After that, 2 more 100 milliliter
boluses may be given over 30 minutes.
In chronic, symptomatic hyponatremia, when sodium is less than 120 milliequivalents per liter,
but there’s no intracranial pathology, we go for a hypertonic saline drip - 3% sodium chloride - at
a rate of 15-30 milliliters per hour.
Finally, after administering hypertonic saline, serum sodium is rechecked once every one to two
hours.
The goal is to raise the serum sodium concentration by 4 to 6 milliequivalents per liter in the first
24 hours, but no more than 8 milliequivalents per liter per day - because of an increased risk
of osmotic demyelination, which is when the myelin sheath of neurons gets damaged in response
to overly rapid increases in serum sodium.
One final point to make before wrapping things up is the importance of differentiating between
SIADH and cerebral salt wasting - because biologically, they are very similar, but the fluid
restriction that helps in SIADH could do a lot of harm in cerebral salt wasting.
SIADH is associated with euvolemia, whereas cerebral salt wasting usually goes along
with hypovolemia - so far so good.
But sometimes the clinical signs of hypovolemia are very subtle and it’s hard to tell the
difference - so instead, it might be useful to determine the fractional excretion of uric acid in
urine.
If it’s above 11%, then the hyponatremia can be corrected by giving hypertonic saline, and then
remeasuring the fractional excretion of uric acid.
In SIADH, the value drops below 11% following correction, whereas in cerebral salt wasting the
value remains greater than 11%.

Summary
All right, as a quick recap… hyponatremia refers to a serum sodium concentration of less than
135 milliequivalents per liter.
True hyponatremia is associated with low serum osmolality, below 280 milliosmoles per
kilogram, and is further evaluated depending on volume status.
Hypervolemic hyponatremia presents with edema and can occur because of heart
failure, cirrhosis, or nephrotic syndrome, in which case urinary sodium will be less than 10
milliequivalents per liter, or because of kidney failure, and urinary sodium will be greater than
20 milliequivalents per liter.
Hypovolemic hyponatremia presents with signs of dehydration.
Renal losses are associated with urinary sodium greater than 40 milliequivalents per liter,
whereas extrarenal losses refer are associated with urinary sodium lower than 25 milliequivalents
per liter, and low urine output.
Finally, euvolemic hyponatremia can be associated with either low urine osmolality, like in
primary polydipsia or the tea and toast diet, or high urine osmolality - in
SIADH, hypothyroidism, or adrenal insufficiency.
Treatment of hyponatremia relies on general measures like fluid restriction and reversing the
cause.
Additionally, hypertonic saline or diuretics may be given depending on the duration, severity and
etiology of hyponatremia.

Kidney stones: Clinical practice

Kidney stones, also called nephrolithiasis, urolithiasis, or renal calculi, can form in the kidneys,
but also in the ureters, bladder, or the urethra.
They appear when solutes in the urine precipitate and crystalize. Depending on which solute
precipitates to form the stone, there can be calcium oxalate, calcium phosphate, uric acid,
cystine, and struvite stones.
Risk factors for developing kidney stones depend on their composition.
Risk factors for calcium oxalate stones include high urine calcium, high urine oxalate, low urine
citrate, and dietary factors include low calcium, low potassium, and low fluid intake, as well as a
high oxalate, and a high animal protein intake.
Calcium phosphate stones usually develop in individuals with renal tubular acidosis type I and II.
Uric acid stones can form when urine pH is persistently below 5.5, which can happen with
chronic diarrhea or conditions like gout, diabetes, and obesity.
Cystine stones occur in the setting of cystinuria - a genetic condition where too much cystine is
excreted.
Finally, struvite stones, also called staghorn calculi, are made up of magnesium ammonium
phosphate, and the main risk factor is a urinary tract infection with a bacterium that produces
urease - like Proteus and Klebsiella. These bacteria increase urine pH, making it a favorable
environment for magnesium ammonium phosphate to precipitate.
Sometimes, kidney stones can be asymptomatic and discovered incidentally during an ultrasound
or a CT-scan.
Other times a kidney stone can cause symptoms due to urinary obstruction and renal distention.
It can cause renal colic, which is when there’s acute pain that’s so intense that it requires IV pain
medication.
Passing a large stone through a narrow ureter has been compared to passing a
baby’s head through the vaginal canal! The difference is that you don’t have to raise and nurture
the stone once it passes.
In renal colic, the location of the pain depends on where the stone is located.
A stone in the renal pelvis or the proximal ureter causes unilateral flank pain and tenderness,
whereas a stone that’s located lower in the ureter causes unilateral flank pain that radiates to
the testicle or labia on the affected side.
In addition, there can also be macroscopic hematuria, nausea, and vomiting, and if the stone is in
the distal ureter, there may be dysuria and urgency as well.
If the blockage is severe, when there’s bilateral obstruction- like when there are stones in both
kidneys and they completely obstruct the flow of urine or when a person has only a single
functioning kidney - a solitary kidney - that gets obstructed, it can lead to signs of acute kidney
injury, like anuria- which is when there’s less than 100 milliliters of urine per day.
A struvite stone can be accompanied by a urinary tract infection- which causes symptoms like
fever, frequency, and urgency to urinate.
Lab studies include a basic metabolic panel, where blood urea nitrogen or BUN and serum
creatinine are done in order to check the renal function.
With acute kidney injury, serum creatinine is elevated.
Additionally, bloodwork and urinalysis may give clues as to the composition of the stone - low
serum bicarbonate and potassium levels may suggest an underlying renal tubular acidosis and a
calcium phosphate stone.
Serum calcium above 10 milligrams per deciliter suggests a calcium oxalate stone, whereas uric
acid levels above 6 milligrams per deciliter suggest a uric acid stone.
A urinalysis may show microscopic hematuria or, especially with struvite stones, there may be
signs of a urinary tract infection - like bacteriuria and positive leukocyte esterase.
On microscopy, if there are calcium oxalate crystals in the urinary sediment, this may point
towards a calcium oxalate stone.
Alternatively, with uric acid stones, uric acid crystals may be present.
When urine pH is above 7 and there are phosphate crystals in the urine, this suggests a calcium
phosphate stone or a struvite stone.
Finally, hexagonal cystine crystals are diagnostic for cystine stones.
The best way to see a kidney stone is by doing a non-contrast abdominal CT-scan, but in
pregnancy, an ultrasound is done instead.
Now, on a CT scan, the location and density of a stone can suggest its composition.
Calcium oxalate and calcium phosphate stones are radiopaque.
A struvite stone is also radiopaque, but not quite as dense as calcium stones and is usually large
and located in the renal pelvis.
Uric acid stones are lower density than both calcium and struvite stones.
Finally, a cystine stone is lucent and it’s barely seen on the CT-scan.
When an ultrasound is done, stones that are located in the renal pelvis and proximal ureter can be
seen. The stones are easily identified on the ultrasound, because they cast an acoustic shadow.
Additionally, indirect signs of obstruction may be seen on ultrasound - like hydronephrosis,
which is when the kidney are filled up with urine and swell up.
Sometimes, a kidney-ureter-bladder radiography or KUB radiography can be done and
radiopaque stones- like calcium oxalate and calcium phosphate stones and struvite stones that are
larger than 5 millimeters can be seen, but stones smaller than 5 millimeters or uric acid
stones and cystine stones are often missed.
Now treatment mostly depends on the location- specifically, whether the stone is in the renal
pelvis or in the ureter, size, and composition of the stones.
For individuals with acute renal colic, pain control is managed with an NSAID,
like indomethacin, or an opioid, like morphine.
During renal colic, IV hydration is avoided, unless the individual is dehydrated, because it can
worsen the pain.
In some cases, urgent decompression of the collecting system may also be necessary following
analgesia.
For example, when there’s bilateral obstruction caused by stones in both kidneys and acute
kidney injury, or when there’s obstruction of a solitary kidney, or if the individual presents with
signs of sepsis- like with a struvite stone that’s associated with a UTI or when
there’s hydronephrosis and a secondary bacterial kidney infection.
Decompression can be done with percutaneous nephrostomy - which is when a catheter is
inserted through the back or flank into the kidney in order to drain the urine.
Another option is ureteral stenting- which is when a cystourethroscopy is done. This is when a
flexible tube is inserted through the urethra in the bladder. Once in the bladder, the
affected ureter is identified and a guidewire is passed through the affected ureter and in the
kidney. A stent is then placed over the guidewire and pushed into the ureter, allowing the flow of
urine.
Now, if an individual’s symptoms are controlled and there are ureteral stones that are less than
10 millimeters, then initial management is observation and medical expulsive therapy or MET.
MET includes increased fluid intake - at least 2 liters per day, along with an NSAID, and
an antiemetic, like metoclopramide. In addition, an alpha-blocker, like tamsulosin, or a calcium
channel blocker, like nifedipine, may be used to help pass the stone.
This is done for about six weeks. During that time, if the individual has uncontrolled pain, fever,
nausea or vomiting or if the individual simply wants the stone removed, then a more aggressive
approach is taken based on stone location.
For proximal ureteral calculi, meaning stones located further up in the ureter, one option is
extracorporeal shock-wave lithotripsy or ESWL.
ESWL is a machine that uses high-energy sound waves that produce shock waves to
break kidney stones into smaller fragments which then can be passed in the urine.
If ESWL fails, then flexible ureteroscopy or URS can be done instead.
URS is also preferred during pregnancy. URS is done with an endoscope that’s passed through
the urethra, bladder, and finally into the ureter where it’s used to remove the stone.
For mid and distal ureteral calculi and for all ureteral calculi larger than 10 millimeters
regardless of their location, URS is done.
URS is also the treatment of choice when lab work and imaging studies suggest a cystine or uric
acid stone.
If URS fails, then percutaneous nephrolithotomy or PCNL is done.
PCNL is a minimally-invasive procedure where a small incision is made in the flank and then a
flexible nephroscope is inserted and the stone is removed through the working canal of the
nephroscope.
Other options include laparoscopic or open surgery.
Now, most stones that are under 5 millimeters pass spontaneously and individuals are advised to
drink at least 2 liters of fluids per day until the stone passes. Once it passes, they should retrieve
it and send it to the hospital laboratory to determine its composition.
Finally, there are renal stones.
For asymptomatic renal stones, active surveillance is done once a year using urinalysis,
creatinine and an abdominal ultrasound.
For symptomatic renal stones smaller than 20 millimeters, ESWL or URS can be done.
For symptomatic stones that are over 20 millimeters, PCNL is done.
For stones that are located in the lower pole calices and are under 10 millimeters, ESWL or URS
can be done.
For symptomatic stones that are located in the lower pole calices and are over 10 millimeters,
PCNL is done.
With struvite stones, urinary tract infections need to be treated with antibiotics.
Now, after retrieving a stone, its composition is analysed in order to determine what kind
of stone it was.
If the stone composition remains unknown, then after one to three months from the acute
episode, two 24-hour urine collections should be obtained to determine urine volume, pH, and
urinary excretion of calcium, uric acid, citrate, oxalate, sodium, potassium, and creatinine. This
helps identify risk factors for stone formation and prevent further stone episodes.
General measures include higher fluid intake- in order to produce at least 2 liters of urine per
day, less than one tablespoon of salt per day, less animal protein in the diet, less oxalate-
containing foods like french fries, dark chocolate, or black tea, and finally more fruits and
vegetables in order to raise the level of citrate in the urine.
If there’s high urine calcium, then a thiazide diuretic - like chlorthalidone is given to lower urine
calcium.
If there’s a high urine calcium, then the serum calcium is checked. If the serum calcium is high
as well, then there may be an underlying hyperparathyroidism.
If there’s high urine uric acid and general measures don’t lower the levels, then allopurinol is
given.
Finally, to prevent cystine stones, urinary alkalinization can be done with oral potassium citrate.
A follow-up with a 24-hour urine collection is done after 6 months of dietary and medical
therapy.

Summary
Alright, as a quick recap, the best test for identifying a kidney stone is a non-contrast CT-scan,
where calcium oxalate and calcium phosphate stones are radiopaque, struvites have a lower
density than calcium stones, and uric acid and cystine stones have an even lower density.
The ultrasound can identify renal stones or proximal ureter stones and hydronephrosis.
Acute renal colic is treated with NSAIDs or opioids.
If there are obstructive stones and there’s also fever or if there’s bilateral obstruction- like when
both kidneys have stones with high levels of creatinine or if there’s an obstruction on a solitary
kidney- specifically when there’s a single functional kidney, then percutaneous nephrostomy
or ureteral stenting is urgently done.
Most stones that are smaller than 5 millimeters pass spontaneously.
Ureteral stones that are smaller than 10 millimeters with controlled symptoms are initially
managed with MET- increased fluid intake, NSAID, an antiemetic, and an alpha-blocker for 6
weeks. If during this period, the individual has uncontrolled pain and fever, then options include
ESWL and URS for proximal ureteral stones.
URS is done for stones that are located in the mid and distal ureter and also for stones larger than
10 millimeters.
If URS fails, then PCNL, laparoscopic or open surgery is done.
Asymptomatic renal stones need active surveillance once a year using urinalysis, creatinine
levels and abdominal ultrasound.
Symptomatic renal stones under 20 millimeters are treated with ESWL or URS.
When they are above 20 millimeters, PCNL is done.
For lower pole calices stones under 10 millimeters, ESWL or URS is done, and for lower pole
calices stones over 10 millimeters, PCNL is done.
Stone composition needs to be determined in order to correct specific risk factors and to prevent
recurrence.

Advanced cardiac life support (ACLS):

Clinical practice
Advanced cardiac life support, or ACLS, is a structured way to respond to an unresponsive
person with cardiac arrhythmias and cardiac arrest.
ACLS can be done by an individual or by a team that’s led by a team leader.
When we suspect a person may be in need of assistance, the first thing we need to do is
determine their level of consciousness.
Talk loudly at them, rub their sternum, or apply pressure to their nail beds or ear lobes, while
simultaneously checking for absent or abnormal breathing.
If they're not responsive, check their carotid pulse for about 10 seconds. If there's no pulse, first
immediately activate the emergency response system to get more help and an AED or
defibrillator. Then, move on to the ACLS algorithm.
The first thing to do is cardiopulmonary resuscitation or CPR, which combines chest
compressions and artificial ventilation.
The big picture goal of CPR is to maintain blood flow to the brain while a patient is pulseless.
Because the patient’s heart is not functioning, the team is mechanically squeezing the heart to
ensure blood flows to the brain.
In a person over 8 years of age, chest compressions are done by placing the heel of one hand in
the center of the chest, then placing the other hand on top, interlocking the fingers, and without
flexing the elbows, pushing down on the chest to a depth of at least 5 centimeters or 2 inches -
which is about the same size as a closed fist lengthwise.
Compressions are done at a rate of about 100 compressions per minute, which you can remember
if you do them to the beat of “Staying alive” by the Bee Gees.
Additionally, the team attempts to artificially ventilate the patient so oxygen can enter the lungs
and carbon dioxide can leave the lungs.
Artificial ventilation includes a variety of ways to assist respiration for a person who isn’t
breathing or making sufficient respiratory effort on their own.
The options for ventilation usually involve a bag valve mask device to push air in.
A bag valve mask can be applied directly to the person’s mouth, or with an oral airway, a
supraglottic airway like a laryngeal mask airway or LMA, or an endotracheal tube.
Directly applying the bag valve mask is the simplest option, since it’s just positioned over the
nose and mouth of the patient, creating a tight seal so air does not escape around the sides of
the mask.
If the bag valve mask is ineffective or difficult to perform, for instance due to an air leak because
of an abnormally large face, then a supraglottic airway can be placed blindly into the airway
through the mouth by pushing towards the throat.
This is generally prefered over endotracheal tube intubation because it’s faster to perform, and
minimizes interruption of chest compressions.
Time and time again, researchers have shown that the most important part of ACLS is high-
quality, uninterrupted chest compressions followed by defibrillation in those who need it.
That’s why intubation is done only if the patient can’t be ventilated by other means.
Continuous capnography should be performed in addition to clinical assessment for both
confirming and monitoring correct tracheal tube placement, and for monitoring the quality of
CPR and the return of spontaneous circulation.
Capnography is a recording of the amount of expired CO2 coming out of the tube.
When ventilating a patient in cardiac arrest, 100% oxygen should be used.
In a person over 8 years of age, the rate of compressions and breaths should be 30:2 for both
single and 2 person CPR.
Finally, it’s important to have access with an intravenous - IV or intraosseous - IO - line in place
as soon as possible, so that it’s ready in case you need to start giving medications.
Compressions and ventilation are started immediately on patients without a pulse.
However, as soon as an AED or cardiac monitor or defibrillator is available, using it becomes the
most important step.
The ACLS team needs to troubleshoot the non-functioning heart by diagnosing the cardiac
rhythm and defibrillating if indicated.
Chest compressions should be paused briefly to apply and use the AED or cardiac monitor to
accurately assess the rhythm on the ECG and decide whether it’s a shockable rhythm
like ventricular fibrillation or VFib and pulseless ventricular tachycardia or VT - or a non-
shockable rhythm like asystole and pulseless electrical activity or PEA.
In ACLS, ECG interpretation is guided by three questions: is the rhythm fast or slow, are the
QRS complexes wide or narrow, and is the rhythm regular or irregular.
Rhythms where a defibrillator can be used to shock a patient - shockable rhythms - are ones that
are fast and have a wide QRS complex.
After that, VT is a regular rhythm, whereas VFib is an irregular rhythm.
If either VT or Vfib is found, defibrillation should be done as soon as possible.
Defibrillation with a synchronized shock is given when there’s a regular rhythm like in VT,
whereas an unsynchronized shock is given when there’s no regular rhythm like in VFib.
The initial dose of energy that the defibrillator delivers typically ranges between 120 to 200
Joules, but a maximal dose can be used even on the first attempt.
Immediately after delivering the shock, chest compressions must be resumed right away without
reassessing the rhythm.
After 2 minutes of chest compressions, there’s a new evaluation of the rhythm through ECG.
If the rhythm is still shockable, a second shock is given using the maximum available dose of
energy.
In addition, 1 milligram of epinephrine is given using the IV line.
All medications should be followed by a saline flush or by raising the patient’s arm to guarantee
that the medication travels all the way to the heart.
Once we start using epinephrine, it’s continuously given every 3 to 5 minutes while chest
compressions are being performed.
After 2 minutes of chest compressions or when there’s a rotation of the person doing CPR, the
rhythm is checked again.
If the rhythm is still shockable after a third defibrillation attempt, 300 mg of amiodarone may
be administered intravenously as well, with a repeat dose of 150 mg IV as indicated.
If amiodarone is unavailable, it may be replaced by 1 to 1.5 mg/kg of lidocaine given every 5 to
10 minutes.
Additionally, 2 grams of magnesium sulfate followed by a maintenance infusion of 1 to 2 grams
per hour may be used in case of polymorphic ventricular tachycardia consistent with torsade de
pointes, but it’s not recommended for routine use in ACLS.
This whole process is repeated for however long it’s needed, there’s no absolute standard.
Generally, it’s interrupted if there’s a clinical change in the patient - like breathing or
regaining consciousness.
Alternatively, it may be stopped if it looks like a patient won’t survive - like after 30 minutes of
unsuccessful resuscitation effort, or in patients with an end-tidal CO2 below 10 mmHg.
That’s because a low end-tidal CO2 following prolonged resuscitation - so over 20 minutes, is a
sign of absent circulation and a strong predictor of death.
End-tidal CO2 values are a function of CO2 production and venous return to the right heart
and pulmonary circulation. This is evaluated through capnography.
Now, moving on to non-shockable rhythms, the most frequent one is asystole, which is where
there’s a complete absence of electrical and mechanical cardiac activity.
The other one is pulseless electrical activity or PEA, which is a mix
of electrocardiographic rhythms which result in insufficient mechanical contraction of the heart
to produce a palpable pulse or measurable blood pressure.
PEA can be associated with any electrocardiographic rhythm, and actually, sinus rhythm is the
most frequent type of PEA.
To help identify potential reversible causes of PEA, review the H’s and T’s.
The H’s are Hypovolemia, Hypoxia, Hydrogen ion excess
(acidosis), Hypoglycemia, Hypokalemia, Hyperkalemia, and Hypothermia.
The T’s are Tension pneumothorax, Tamponade – Cardiac, Toxins, Thrombosis (pulmonary
embolus), and Thrombosis (myocardial infarction).
Once a non-shockable rhythm is diagnosed, 1 milligram of epinephrine is given right away and
then given every 3 to 5 minutes while CPR is performed.
After 2 minutes of CPR, the cardiac rhythm is reassessed - if it becomes shockable, defibrillation
may be done, otherwise CPR must be resumed for 2 minutes, and then the rhythm is reassessed.
This is repeated for however long it’s needed.
If a patient improves with ACLS, the immediate post-cardiac arrest treatment includes an
assessment using the ABCDE approach.
That stands for airways - checking if they’re patent, breathing - looking for signs of respiratory
distress, circulation - evaluating tissue perfusion and signs of bleeding, disability - using
the Glasgow Coma Scale, and exposure or examination - by doing a head-to-toe assessment and
getting the clinical history.
Additional, treatable underlying causes should be identified and managed as quickly as possible.
These include hypoxia, metabolic disorders, poisoning, hypovolemia, hypothermia, tension
pneumothorax, cardiac tamponade, and cardiac or pulmonary thrombosis.

Summary
All right, as a quick recap. In an unconscious patient, first you check for a pulse.
In a pulseless patient, you try to see if the patient speaks or moves.
Then, you check breathing.
ACLS begins in patients that are unresponsive and not breathing normally.
Resuscitation begins with chest compressions, attaching the defibrillator, placing monitors
and IV lines, and obtaining an ECG.
The ECG analysis will show either a shockable rhythm like ventricular fibrillation and
pulseless ventricular tachycardia - or non-shockable rhythm like asystole and pulseless electrical
activity.
A shockable rhythm, should get defibrillated as soon as possible, with IV medications given each
round.
In a non-shockable rhythm, epinephrine is given right away while CPR is performed.
ACLS is repeated for however long it’s needed.

Summary
ACLS is a set of clinical interventions that are designed to save the lives of people who are
experiencing cardiac arrest. The main aim of ACLS is to improve the chance of survival by
restoring a normal heart rhythm as quickly as possible.
The key components of ACLS include: 1) providing CPR (cardiopulmonary resuscitation) 2)
using an automated external defibrillator (AED) 3) giving oxygen therapy 4) using drugs to treat
arrhythmias (abnormal heart rhythms).
The ACLS guidelines are designed to help healthcare providers make rapid, informed decisions
about the best way to treat a person in cardiac arrest.
Some of the key interventions included in ACLS are: providing oxygen to the patient,
performing chest compressions, and using an automated external defibrillator (AED). Healthcare
providers may also use medications such as adrenaline and atropine to help support the patient's
heart function.

Hypertension: Clinical practice

Hypertension, or high blood pressure, affects over a billion people around the world.
Now, ‘normal’ systolic blood pressure is defined as less than 120 mmHg, and normal diastolic
pressure is less than 80 mmHg.
Elevated blood pressure is when systolic blood pressure is between 120 and 129 mmHg and less
than 80 mmHg on the diastolic side.
Stage 1 hypertension is between 130 and 139 mmHg on the systolic side, and between 80 and 89
mmHg on the diastolic side.
Stage 2 hypertension is defined as anything that is 140 mmHg or higher on the Systolic side and
90 mmHg or higher on the diastolic side.
Typically, both systolic and diastolic pressures tend to rise or fall together, but that’s not always
the case.
Sometimes, you can have systolic or diastolic hypertension, when one number is normal and the
other is really high. This is referred to as isolated systolic hypertension or isolated
diastolic hypertension.
There are two main types of blood pressure measurements - office blood pressure, which is taken
in a clinic, emergency department, or hospital, and an out-of-office blood pressure.
The out-of-office blood pressure is either a home blood pressure, which is taken by the patient at
home, or an ambulatory blood pressure monitoring or ABPM, which involves 24-hour
monitoring of blood pressure as the patients live their normal daily life, and while they sleep, to
see if the blood pressure falls at night compared to during the day. It uses a small digital blood
pressure machine that is attached to a belt around the body and it’s connected to a cuff around
the upper arm.
Ambulatory blood pressure monitoring is the best way to diagnose hypertension, but it’s not
always feasible, so it’s usually done when office and home blood pressure measurements are
really discordant from one another.
Now, the first step for an office blood pressure, is to make sure that the patient has rested for at
least five minutes and is positioned properly - sitting with their arms and back supported, and
their feet flat on the floor. And the measurement should be repeated at least twice.
Most of the time, blood pressure is taken in the brachial artery in the upper arm, because if the
pressure is high there, it’s probably high throughout the arteries.
And keep in mind that just being in the office can cause blood pressure to change.
In white coat hypertension - a person’s blood pressure rises, and in masked hypertension - a
person’s blood pressure falls.
So, the diagnosis of hypertension should be done by looking at both office and out-of-
office blood pressure measurements.
The second step is taking the patient’s history and physical examination.
Now, there are two main types of hypertension - primary or essential hypertension has no clearly
identifiable underlying reason, and secondary hypertension, which does have a specific,
identifiable underlying condition.
Primary hypertension is way more common, and it generally isn’t accompanied by symptoms.
It’s sometimes called a “silent killer”, because over time, pressure in the arteries silently creeps
up, and causes blood vessel damage which is a risk factor for serious problems, like myocardial
infarctions, aneurysms, and strokes.
Risk factors for primary hypertension include: old age, obesity, family history, a salt-heavy diet,
a sedentary lifestyle, heavy alcohol consumption, smoking, and race - for example, people of
african descent are more likely to develop hypertension.
And some of these risk factors can be improved with lifestyle changes that can help
reduce hypertension.
Now, secondary hypertension often is accompanied by a variety of symptoms associated with the
underlying cause.
In general, the younger the patient, the more likely it’s secondary hypertension.
For example, anything that limits the renal blood flow can cause hypertension, like
fibromuscular dysplasia, which generally affects young women, but also atherosclerosis in older
patients. Other examples include obstructive sleep apnea, atherosclerosis, vasculitis, or aortic
dissection, as well as pheochromocytoma, Cushing’s syndrome, and other endocrine disorders.
It’s also important to identify signs of end-organ damage, and whether the patient takes any
medications or exogenous substances that can worsen hypertension, sympathomimetic agents
like decongestants or even cocaine, cyclosporine or tacrolimus, sodium-containing antacids,
stimulants like amphetamines, atypical antipsychotics like clozapine, antidepressants, oral
contraceptives, erythropoietin, and even NSAIDS and liquorice - that delicious chewy black
candy!
A basal metabolic panel and electrocardiography should be performed to screen for secondary
forms of hypertension.
Management for hypertension is mainly based on the hypertension stage, risk of developing
cardiovascular events and organ damage, as well as taking into account any concomitant
diseases, such as diabetes or chronic kidney disease.
Lifestyle changes are crucial for all patients, especially in the long term, and include things
like quitting smoking, drinking alcohol in moderation, maintaining a healthy weight, reducing
dietary sodium, and staying physically active.
Not all patients with hypertension need antihypertensive drug therapy.
In fact, medication is generally suggested for only patients with out-of-office daytime blood
pressures higher than 135mm Hg systolic or higher than 85 mmHg diastolic, or an average
office blood pressure higher than 140/90 mmHg if out-of-office readings aren’t available. It’s
also recommended for patients with an out-of-office blood pressure higher than 130 mmHg
systolic or 80 mmHg diastolic or, if out-of-office readings are unavailable, or an average
office blood pressure higher than 130 mmHg systolic or 80 mmHg diastolic who also have other
features.
Specifically they need to have at least one of the following: cardiovascular disease, type 2
diabetes mellitus, chronic kidney disease, be over 65 years old, or have an elevated risk
of coronary artery disease.
On the flip side, it’s generally recommended not to give antihypertensive medication to patients
with stage 1 hypertension and are either over age 75 years old or have no organ damage.
There are four main classes of medications that are used to treat hypertension, ACE
inhibitors, Angiotensin Receptor Blockers or ARBs, thiazide diuretics, and long-acting calcium
channel blockers like dihydropyridine.
There is a lot of variability in terms of how individuals respond to different medications, so it’s
important to follow up to see how the medications are working.
Usually, therapy begins by choosing one medication.
Broadly speaking, ACE inhibitors are started in patients at high risk for coronary artery disease,
including those with a prior STEMI, heart failure, asymptomatic left
ventricular dysfunction, diabetes, and chronic kidney disease.
A common side effect of ACE inhibitors is chronic cough, so ARBs are often started in patients
who don’t tolerate ACE inhibitors, mostly because of cough.
Thiazide diuretics and calcium channel blockers show very similar efficacy to ACE inhibitors,
and they’re first line therapy in patients of african descent. But diuretics have a lot
of metabolic effects, so they can’t be given to patients with high blood glucose
and cholesterol levels.
The blood pressure goal while on medications varies based on the initial blood pressure, age, and
other health conditions.
But, in general, it’s ideal to have an out-of-office blood pressure below 135/85 mmHg and an
office blood pressure below 140/90 mmHg.
If the blood pressure isn’t improving within a month, then the dose is usually increased or a
second medication from a different class is often started.
Some combinations are useful, while others aren’t. ACE inhibitors and ARBs should not be
combined; and instead either can be combined with a thiazide diuretic or a calcium channel
blocker.
In some cases, diuretics may be combined with beta blockers.
If blood pressure is not kept under control after combining two medications, then an ACE
inhibitor or ARB should be combined with both a thiazide diuretic and a calcium channel
blocker.
If a thiazide diuretic isn’t well tolerated or is contraindicated - for instance in patients
with metabolic conditions - then a mineralocorticoid receptor antagonist
like spironolactone or eplerenone can be used instead. And if those medications also can’t be
used because it isn’t well tolerated or is contraindicated, then a beta blocker can be used.
If the blood pressure isn’t controlled with a combination of three antihypertensive medications,
including a diuretic, then it’s considered drug-resistant hypertension.
Oftentimes, patients with hypertension feel pretty well and forget to take
their hypertension medications. That’s why regimens of daily pills have got better medication
adherence as compared to twice daily pills.
In fact, when there’s a patient with drug-resistant hypertension, it’s important to confirm that
they are actually taking the medication.
Finally, if the blood pressure gets really high, really fast, it’s called a hypertensive crisis.
In hypertensive crisis, either the systolic pressure is greater than 180 mmHg or the diastolic
pressure is greater than 120 mmHg.
Hypertensive crisis can be further split into hypertensive urgency and hypertensive emergency.
With hypertensive urgency, there hasn’t yet been damage to end organs like the brain, kidneys,
heart, and lungs.
In hypertensive emergency, there is damage to end organs, and patients can have symptoms like
confusion, drowsiness, chest pain, and dyspnea.
The most common cause of hypertensive crisis is not taking antihypertensive medications, but it
can also be due to causes of secondary hypertension like renovascular
disease, pheochromocytoma, hyperaldosteronism, and erythropoietin intake.
For treatment, it’s important to gradually reduce the blood pressure over 1 to 2 days, to make
sure that the brain never gets underperfused.
Treatment of a hypertensive urgency is done with oral medications like ACE inhibitors.
On the other hand, in a hypertensive emergency, the goal is to lower the mean arterial pressure
by 20% within the first hour, and treatment is given intravenously with medications like beta
blockers, calcium channel blockers, and vasodilators like nitroprusside or nitroglycerin.