Conjugated vs. unconjugated hyperbilirubinemia

Today, we talked about the things that cause an elevation in serum bilirubin (hyperbilirubinemia). We also talked about how it’s useful to know whether the patient has an elevation in conjugated or unconjugated bilirubin (because that helps you narrow down the possible causes). Here’s a question and explanation to get you thinking about this a bit more.

While examining the gums of a 25 year old patient, a yellowish discoloration of the oral mucosa and sclera is noted.  Laboratory tests show a significant increase in unconjugated bilirubin.  Which of the following disorders is most likely the cause of this patient’s abnormalities?

A. A stone in the bile duct
B. Carcinoma of the head of the pancreas
C. Pancreatic pseudocyst
D. Sickle cell disease
E. Hepatocellular carcinoma

Let’s review a little before we get to the question.

Bilirubin is a breakdown product of heme (which, in turn is part of the hemoglobin molecule that is in red blood cells). It is a yellow pigment that is responsible for the yellow color of bruises, and the yellowish discoloration of jaundice.

When old red cells pass through the spleen, macrophages eat them up and break down the heme into unconjugated bilirubin (which is not water soluble). The unconjugated bilirubin is then sent to the liver, which conjugates the bilirubin with glucuronic acid, making it soluble in water. Most of this conjugated bilirubin goes into the bile and out into the small intestine. (An interesting aside: some of the conjugated bilirubin remains in the large intestine and is metabolized into urobilinogen, then sterobilinogen, which gives the feces its brown color! Now you know.)

So: if you have an increase in serum bilirubin, it could be either because you’re making too much bilirubin (usually due to an increase in red cell breakdown) or because you are having a hard time properly removing bilirubin from the system (either your bile ducts are blocked, or there is a liver problem, like cirrhosis, hepatitis, or an inherited problem with bilirubin processing).

The lab reports the total bilirubin, and also the percent that is conjugated (this is usually called the “direct” bilirubin). You can easily figure out, then, how much unconjugated bilirubin you have (it’s just the total bilirubin minus the direct bilirubin).

If you have a lot of bilirubin around and it is mostly unconjugated, that means that it hasn’t been through the liver yet – so either you’ve got a situation where you’ve got a ton of heme being broken down (and it’s exceeding the pace of liver conjugation), or there’s something wrong with the conjugating capacity of the liver (for example, the patient has hepatitis and it’s interfering with the liver’s ability to conjugate bilirubin).

If you have a lot of bilirubin around and it’s mostly conjugated, that means it’s been through the conjugation process in the liver – so there’s something preventing the secretion of bilirubin into the bile (for example, there’s something blocking the bile duct, or the patient has hepatitis and it’s interfering with bilirubin excretion), and the bilirubin is backing up into the blood.

Back to our question. Let’s go through each answer and see what kind of hyperbilirubinemia these disorders would cause.

A. A stone in the bile duct – if big enough, a stone here could block the excretion of bilirubin into the bile. The bilirubin would already be conjugated, so this would be a conjugated bilirubinemia.

B. Carcinoma of the head of pancreas – this could also cause biliary obstruction, similar to A. (An important aside: it’s nice when pancreatic carcinomas announce themselves this way, because it may allow for earlier detection of the tumor. Unfortunately, this is uncommon. Pancreatic adenocarcinoma is usually silent until the tumor is very large and possibly metastatic.)

C. Pancreatic pseudocyst – same idea as A and B.

D. Sickle cell disease – Sickle cell anemia is a type of hemolytic anemia. Hemolytic anemias can cause unconjugated bilirubinemia if the hemolysis is massive enough. If it’s just a low level of hemolysis, the liver can often keep up, in which case you’d excrete the conjugated bilirubin normally (through the poopy).

E. Hepatocellular carcinoma – this would fall into the category of blocking excretion of bilirubin. The bilirubin would already be conjugated – so this would be a conjugated hyperbilirubinemia.

So: since A, B, C and E produce only conjugated hyperbilirubinemia, the answer is D, sickle cell disease.

Quiz 1 and 2

I posted the scores for quiz 1 on Canvas just now. I added a point to everyone’s score for that question about community-acquired pneumonia that was miskeyed. Please take a look and make sure that your score looks right!

Also – tomorrow we’ll have quiz 2 at the beginning of the hour, and then a short lecture on Upper GI Pathology. Quiz 2 will cover everything we’ve done since quiz 1, which means Respiratory Pathology (slides 46-63) and Renal Pathology.

Let me know if you have any questions!

Quiz 1 coverage

Just a quick note about what quiz 1 will cover.

In class today, we went through most of the Respiratory Pathology lecture (we did slides 1-45) – but we did not talk about lung cancer (slides 46-63).

So on Monday (9/26), we’ll begin with quiz 1, which will cover everything we’ve done so far (all the lectures from 9/7-9/21). Then we’ll finish off the rest of Respiratory Pathology (slides 46-63).

All of this is listed on our lectures page.

Please let me know if you have any questions!

Which direction does blood flow through the ductus arteriosus?

Here’s a great question from last year that helps sort out the issue of which way blood flows through the ductus arteriosus.

Q. I just had a quick question for you. Our notes say that a ductus arteriosus allows flow from the pulmonary artery to the aorta, which I knew. However, they also say that it’s a left to right shunt, and that it can become right to left. This confuses me, since from what I know, flow would be going from right (pulmonary artery) to left (aorta).

A. When we talk about the ductus allowing flow from the pulmonary artery (right) to aorta (left), we’re talking about intrauterine flow through the ductus. Before birth, the pressure on the right side of the heart is greater than the pressure on the left – so blood flows from pulmonary artery to aorta (through the ductus).

After birth, though, the pressure on the left becomes greater than the pressure on the right. In most babies, the ductus closes (probably in response to the new levels of oxygen in the blood). In some babies it remains patent, in which case flow would now be from the aorta (left; higher pressure) to the pulmonary artery (right; lower pressure).

If the ductus is widely patent, then after a while, that left to right shunt can put enough pressure on the lungs that they react by closing down vessels, effectively making it more difficult to push blood through. Now the right heart has to work really hard to push blood through the lungs – and it can get to the point where the right heart is actually bigger and stronger than the left, making the shunt reverse and go from pulmonary artery (right; higher pressure) to aorta (left; lower pressure).

Serum markers of myocardial infarction

I wrote a little post on some of the more important serum markers you can use to see if someone has had a myocardial infarction.

The two most commonly used markers these days are troponins and CK (creatine kinase). Each as their own special features that make it good for diagnosing certain kinds of MIs.

You don’t have to know these in detail (although I have seen questions in dental decks…so perhaps it is a good review for boards). We have enough to cover in class without getting into too much detail.

Basically, when your cells die, they release the stuff that was inside, and you can detect that stuff in the serum. Often you’re detecting enzymes of some sort. Depending on the amount of that particular marker, and the time elapsed between injury and testing, you can get some kind of idea of whether many cells have undergone irreversible cell damage.

What’s the difference between aneurysm, thrombosis, and stenosis?

I got this really great question from one of you, and it got me thinking about how important it is to have really clear definitions of pathologic conditions. These three conditions – aneurysm, thrombosis, and stenosis – are totally different things. And yet they can sometimes co-occur, or one can cause another – so it can become confusing!

I’m so glad this person asked this question, because it gives me a chance to clarify these terms for everyone. Here’s the question.

I was reviewing the Blood Vessel Pathology lecture notes from this past week and was having a bit of trouble differentiating between aneurysm, thrombosis and stenosis. I’ve written what I believe to be the differences, but would you mind giving me some feedback on if this is correct? 

“An aneurysm is when a clot occurs, widening the blood vessel to unhealthy proportions due to high blood pressure and or atherosclerosis, and it may rupture with no warning signs, leading to internal bleeding. The difference between aneurysm and thrombosis is that aneurysm causes damage to the lining wall of the blood vessel. Thrombosis is clotting of a blood vessel without damage to the walls. Stenosis is narrowing of the artery to cause clotting, and it comes with the warning sign of severe chest pain.”

Great question!! You’re on the right track – but there are some things in your statement that aren’t quite right – so I’ll give you my definitions and then comment on what you wrote.

Aneurysm

An aneurysm is an abnormal widening (or dilation, or outpouching) of a blood vessel. It’s focal in nature, which means that it’s just in one place; you can point to where it is (it’s not like the entire vessel is just a little bit wider). Here’s the image from slide 26, rearranged a bit and with an arrow pointing to the aneurysm:

Screen Shot 2022-09-10 at 5.52.31 PM.png

Aneurysms can be caused by lots of things (like trauma and atherosclerosis), or they can be congenital. Sometimes aneurysms just sit there and never cause any problems. But sometimes they get larger and larger, and the vessel wall weakens to the point where it eventually ruptures. 

Thrombosis

A thrombosis (or thrombus) is an abnormal blood clot. It’s not just a normal little blood clot formed to repair a hole in a vessel – it’s a blood clot that’s been made when it isn’t needed. The most common place for a thrombus is in the deep veins of the legs – but you can form a thrombus anywhere in the body. 

It’s not good to have a thrombus for a few reasons: 

  • If it’s big enough, the thrombus can block blood flow through the vessel, and the tissues fed by that vessel can be damaged or even die as a result.
  • Thrombi can weaken and damage the vessel wall, leading to other problems (like aneurysms, or even rupture of the vessel if it gets weak enough).

Here’s a related term: embolus. An embolus is a blood clot that’s floating in the blood (maybe it broke off from a thrombus in the leg, or maybe it formed on its own somewhere). The point is that it is mobile, and it’s going to move with the blood until it gets to a vessel that’s too small for it to pass through, and it will lodge there. If the embolus is tiny, you may not notice anything clinically. But if the embolus is big enough to block off an important vessel (say, one of the vessels in the brain), that means that the tissue fed by that blood vessel won’t get blood, and it will die.

Stenosis

Stenosis just means “narrowing.” It can be used to describe abnormal narrowing of lots of different structures in the body (like heart valves and the spine). When a blood vessel is stenotic, that means its lumen is smaller than normal.

There are many possible causes of stenosis in vessels. Here are some common ones: atherosclerosis (formation of plaques that take up space and narrow the lumen), thrombosis (formation of an abnormal clot that takes up space within the vessel lumen), and vasculitis (inflammation of the vessel).

Like the other abnormalities we talked about above, stenosis can be asymptomatic if it is mild. But if a vessel is very stenotic (for example, if the vessel lumen is only 20% of its normal diameter), that can impair blood flow enough to cause serioproblems to the tissue downstream. This is particularly a problem if the vessel feeds the heart or the brain; in these places, restriction of blood flow can cause severe symptoms (or even death).

Why these things are confusing

These three conditions are distinct and separate entities – but they can occur together, and they can also occur sequentially – and this can be confusing. For example, if you have a thrombus in a vessel, that can weaken the vessel wall enough to cause an aneurysm. Or you can have a thrombus that simply sits there and takes up space in the vessel lumen, causing stenosis of the vessel. 

We talked about another confusing example in class: a “false aneurysm.” This happens when you have a big hole in a blood vessel, and blood pours out of the hole, forming a hematoma (a collection of blood) on the outside of the vessel. This is a crazy thing – usually when you get a hole in a vessel, blood just pours out, and it’s bad. But if you have enough connective tissue around the vessel, it can sometimes prevent the blood from going anywhere – and so the blood just pools in one place (this is called a hematoma), and eventually (if the connective tissue holds), the hematoma will turn into a blood clot.

Here’s the image of a false aneurysm from slide 26:

Screen Shot 2022-09-10 at 6.27.56 PM.png

Back to the statement part of the question – my comments are in blue.  

An aneurysm is when a clot occurs, widening the blood vessel to unhealthy proportions due to high blood pressure and or atherosclerosis, and it may rupture with no warning signs, leading to internal bleeding. You’re correct in saying that an aneurysm is a widening of a blood vessel that may be caused by high blood pressure or atherosclerosis, and that it may rupture. And it’s true that aneurysms can be caused by abnormal blood clots (thrombosis) – but just to clarify – not all aneurysms are caused by clots. The main point is that an aneurysm is an abnormal widening of a blood vessel – and there are many potential causes. The difference between aneurysm and thrombosis is that aneurysm causes damage to the lining wall of the blood vessel. Thrombosis is clotting of a blood vessel without damage to the walls. No; the difference between aneurysm and thrombosis is that an aneurysm is an abnormal dilation/widening of a blood vessel, whereas a thrombosis is a blood clot that forms within a blood vessel. Both aneurysms and thromboses can damage the vessel wall. Stenosis is narrowing of the artery Yes! to cause clotting Not exactly. Stenosis is just the narrowing of a vessel lumen; it doesn’t necessarily cause the formation of a blood clot. However, thrombosis (abnormal clotting) can lead to stenosis (narrowing of the vessel lumen)! This is where you have to be really strict about your definitions, otherwise it gets confusing! and it comes with the warning sign of severe chest pain Sometimes! If the stenotic vessel is one that supplies the heart, and if the stenosis is moderately severe (meaning that the lumen is narrowed enough to decrease the amount of blood that can flow through the vessel), then the patient will experience chest pain (because there’s less blood flow to the heart than usual). This is a warning sign – it tells you that the tissue isn’t getting quite enough blood flow, and you better go see a cardiologist and get those vessels looked at. However, if the stenosis is really severe (like if the lumen is only 10% of its normal diameter), then almost no blood is getting through, and that may be enough to actually cause tissue death (myocardial infarction, or heart attack). In this case, the chest pain the patient experiences isn’t just a warning sign – it’s a sign that the tissue is actually dying right now.

Welcome to Systemic Pathology!

I am so excited to be back in the classroom with you guys I can hardly contain myself! It was so nice to see your beautiful shining faces yesterday.

I’d like to give you a quick summary of how this course will work. We talked about this yesterday, but it’s nice to have it all written down in one place. So here goes.

Content. In General Pathology, we talked about the ways things can go wrong in the body (injury, infection, immune dysfunction, neoplasia) and also the general mechanisms the body uses to fix these problems (tissue repair, inflammation, immune responses). This created a nice little brick foundation for your pathology house!

In Systemic Pathology, we’re going to add floors and rooms to the house. The course is organized into organ systems (cardiovascular, respiratory, etc.), and in each system, we’ll cover the abnormalities and diseases that are most relevant for you for your future practice (and for boards).

Format. This course has the same components as General Path:

  • Lectures: Lots of lectures. All of our lectures will be recorded, and I’ll post the recordings on our lectures page as soon as I get them (usually the same day as the lecture).
  • Quizzes: We’ll do these in class, using Kahoot. You’ll be able to talk with each other and use your notes, like you did in General Path.
  • Exam reviews: Same thing: in-class Kahoots. Only with exam reviews, there are prizes for first, second, and third place. Maybe the prizes will be coffee cards…maybe they’ll be cookies…who knows?!
  • Exams: We’ll use ExamSoft, and you’ll have the entire exam day to take the exam.

Grades. We’ll have three quizzes, and four exams. At the end of the course, I’ll add all your quiz and exam points together (no weighting of exams or anything) to give you a final score for the course. Grades will be determined as follows:

  • A = final scores greater than or equal to 90% of total course points
  • B = scores between 80% and 90% of total course points
  • C = scores between 70% and 80% of total course points

Also, I just want to remind you that I’m still your “mom.” Dental school is fun and interesting…but it is also really hard and overwhelming. You need to take care of yourself.  So I’ll be checking in with you from time to time to see how you’re doing, and to remind you that I am here for you. If you need to vent, or want advice, or just need to know that you’re not alone, email me. We can stick with email, or we can meet in person. Whatever feels best to you. I mean it. You are not alone.