Pathology Student

I received a bunch of great questions from a student in my pathology course, and thought I’d share them with you. I think reading about things in in question/answer format helps the material stick in your head. These particular questions are about congenital heart defects.

Q. Can VSD and PDA also lead to the same pulmonary problems as ASD since they are all left to right shunts?
A. Yes! Any left-to-right shunt, if it is big enough, can eventually put enough pressure on the right side of the circulation that the lungs respond by constricting vessels and laying down fibrotic tissue, leading to pulmonary hypertension. Eventually, if pressures on the right side exceed those on the left, the shunt reverses, becoming a right-to-left shunt.

Q. What is the effect/outcome of the overriding aorta in Tetralogy of Fallot?
A. The main problem in Tetralogy of Fallot is the pulmonary outflow obstruction – that really determines the extent and severity of the clinical picture. The overriding aorta doesn’t contribute much. It does allow unoxygenated blood to flow directly into the aorta, which doesn’t help matters. There already is a ventricular septal defect, which allows mixing of blood, so the overriding aorta would just exacerbate that mixing, making it even easier for blood to bypass the lungs and go straight to the peripheral circulation. Which manifests as cyanosis.

Q. Can you surgically repair transposition of the great arteries?
A. Yes. Patients with TGA usually have some sort of shunt as well (like a VSD) – and depending on the degree of shunting, they may be fairly stable for a little while. However, most of the time, the transposition is repaired surgically within weeks of birth.

Q. Is mitral valve prolapse an insufficiency since it cannot close properly?
A. Yes – that’s exactly right. Insufficiency means the valve can’t close properly; stenosis means it can’t open properly. In mitral valve prolapse, the leaflets are floppy, and they don’t come together like they should, so during diastole, blood regurgitates into the left atrium.

Congenital heart diseases are abnormalities of the heart and/or great vessels present at birth. They are not all that uncommon: 1% of live births in this country has a congenital heart defect! The clinical spectrum is broad. Some congenital heart diseases cause death in the perinatal period; others are so mild that there are only minimal symptoms, even in adulthood.

Something happens in embryogenesis at the time of heart development (weeks 3-8) – but the actual cause can be traced only 10% of the time. Of the known causes, infections (like rubella) and genetic disorders (like trisomy 13) are the most common.

You can divide congenital heart defects into two broad groups: those that cause shunts (abnormal communication between chambers or vessels) and those that cause obstructions (narrowed chambers, valves, or major vessels). Shunts are more common than obstructions; the more common of these are atrial septal defects, ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. The most common obstruction is aortic coarctation. Let’s take a really quick look at these defects.

Atrial septal defects
In this type of congenital heart disease, there is a hole between the two atria. Initially, this causes a left-to-right shunt. Left to right shunts, in general, are pretty well tolerated, and that’s the case for ASD too. However, over time, especially if the defect is large, pulmonary vessels can become annoyed by all that extra blood volume they are exposed to – and the pressure in the lungs goes up (due to vessel constriction and fibrous tissue deposition). So the pressure on the right side goes up, and eventually it can even exceed the pressure on the left, leading to a reversal of the shunt. This is called Eisenmenger Syndrome. This is not a good thing, because it can lead to heart failure, irreversible pulmonary vascular disease, and paradoxical embolism (where blood clots from the heart go to the systemic, rather than pulmonary, circulation).

Ventricular septal defect
This is the most common congenital cardiac anomaly, and it’s just what the name says: a hole between the two ventricles. Small VSDs are generally asymptomatic; large VSD cause big left-to-right shunt, which may become right-to-left (as described above). Most close spontaneously in childhood.

Patent ductus arteriosus
The ductus arteriosus is a normal connection between the pulmonary artery and the aorta that exists in fetal life to allow most of the blood to bypass the unoxygenated lungs (this helps the left ventricle get stronger). The ductus normally closes spontaneously by day 1 or 2 of life; if it remains open, then you can get a left to right shunt. Most of the time PDAs are asymptomatic, but if they big enough, they can eventually lead to Eisenmenger syndrome.

Tetralogy of Fallot
This defect is an example (the most common example) of a right-to-left shunt. Right-to-left shunts in general present with cyanosis at birth, because poorly-oxygenated blood from the right heart gets mixed into the arterial circulation. Patients can get clubbing of the fingertips and erythrocytosis as a result. Tetralogy of Fallot has four features: VSD, obstruction to the right ventricular outflow tract, an aorta that overrides the VSD, and right ventricular hypertrophy. Even untreated, though, many patients survive into adult life. It all depends on the severity of the pulmonary outflow obstruction.

Aortic coarctation
“Coarctation” means “narrowing” – so aortic coarctation means narrowing of the aorta. There are two forms: infantile (in which the narrowing occurs proximal to the ductus arteriosus) and adult (in which the narrowing occurs distal to the ligamentum arteriosum). In the infantile form, there is delivery of poorly-oxygenated blood through the ductus, which leads to cyanosis in the lower half of body. The femoral pulses are generally weaker than those of the upper extremities. This is a severe abnormality; these babies need intervention or they may not survive neonatal period. The adult form is usually asymptomatic, and the disease may go unrecognized into adult life. When there are symptoms, they consist of upper extremity hypertension (due to poor perfusion of kidneys) but weak pulses and lower blood pressure in lower extremities.

Image credit: qthomasbower (http://www.flickr.com/photos/qthomasbower/3470650293/), under cc license.

Atherosclerosis is responsible for half the deaths in the US today! If you get it in your coronary arteries, you’re at risk for myocardial infarction; if it’s in your carotid arteries, you’re at risk for stroke. And lest you think this is something you don’t need to worry about until you’re old, you should know that this process starts very, very early in life – somewhere during childhood – and you just can’t tell you have it until you suddenly start getting nasty symptoms (doctors call this the “clinical horizon,” which sounds strangely picturesque). Scary.

There are lots of risk factors for getting atherosclerosis. They are divided into two groups: major risk factors (which are known for sure to cause atherosclerosis) and lesser or uncertain risk factors (which have less of an effect, or are as yet unproven). Let’s take a look at both groups.

Major risk factors

Some of the major risk factors for atherosclerosis you are simply stuck with, and there is not a thing you can do about them. These include:

• increasing age (atherosclerosis is more common as people get older)
• gender (At younger ages, males are more at risk. Premenopausal women are relatively protected; after menopause the risk in women increases and eventually exceeds the risk in males.)
• family history
• genetic abnormalities (lots of these probably exist; many aren’t fully understood).

The good news is that there are several major risk factors that you can potentially do something about. These include:

• Hyperlipidemia (best thing to do is have a high level of HDL cholesterol, which actually scavenges lipids and removes them from atherosclerotic plaques, and a low level of LDL, which is the “bad” cholesterol that makes up part of the plaques.
• Hypertension (there’s no one right number, but it should be at least below 140 systolic and 90 diastolic)
• Cigarette smoking (smoking potentiates the other risk factors)
• Diabetes (patients with diabetes mellitus have an increased amount of atherosclerosis at a younger age)
• C-reactive protein level (this is a serum marker of inflammation; the higher the level, the greater the risk for atherosclerosis)

Lesser or uncertain risk factors

Then there are a bunch of other things that may be related to an increased risk, but the data is not yet conclusive. These include:

• Obesity
• Physical inactivity
• Stress
• Postmenopausal estrogen deficiency
• High carbohydrate intake
• Lipoprotein (a) (an altered form of LDL that seems to be independently associated with increased risk of atherosclerosis)
• Trans-fat intake
• Chlamydia pneumoniae infection (Chlamydia pneumoniae and other bugs have been detected in plaques but not in normal arteries, and there are increased antibody titers to C. pneumoniae in patients with more severe atherosclerosis. But a causal link hasn’t been established.)

So: don’t smoke; eat well (not too many carbs, no trans fats), exercise, and maintain a healthy weight; keep your blood pressure and lipids within the normal range; if you have diabetes, work to keep it as controlled as possible; don’t get Chlamydia pneumoniae. Oh, and don’t get all worried about it – stress is another potential risk factor!

Image credit: Hamed Masoumi (http://www.flickr.com/photos/hamedmasoumi/2266654041/), under cc license.

Hemolytic disease of the newborn (HDN) is a disease in which there is hemolysis in a newborn or fetus caused by blood-group incompatibility between mother and child.

There are a bunch of related terms:

• Immune hydrops (Hydrops means accumulation of edema fluid in the fetus during intrauterine growth. It is not specific to HDN, but can occur in many different fetal conditions including cardiovascular conditions, chromosomal disorders like Down syndrome, non-immune fetal anemia, twin-twin transfusion, infections, tumors, and metabolic disorders. Whew.)
• Hydrops fetalis (When the accumulation of fluid – from whatever cause – is severe and generalized, it is called hydrops fetalis.)
• Erythroblastosis fetalis (Erythroblastosis means that early red cell precursors are showing up in the peripheral blood. This can happen in any severe anemia, not just HDN.)

Mechanism of HDN

1. Fetus inherits blood group antigens (usually Rh D antigen or ABO antigens) from the father that are foreign to the mother.
2. Fetal blood gets into mom’s circulation (either during last trimester of pregnancy, when cytotrophoblast is no longer present, or during childbirth).
3. Mom makes antibodies to these blood group antigens.
4. Antibodies cross the placenta, attack baby’s red cells, causing hemolytic anemia and its consequences.

The consequences of hemolysis are numerous. One such consequence is extramedullary hematopoiesis. If the anemia is mild, extramedullary hematopoiesis in the liver and spleen may produce enough red cells to maintain normal numbers.

Other consequences are not so happy. If the anemia is severe, the heart and liver may suffer hypoxic injury, resulting in circulatory and hepatic failure. Liver failure causes decreased protein levels (proteins are synthesized in the liver) and a reduction in oncotic pressure in the circulation. Heart failure causes an increase in venous pressure (blood is backing up behind the failing heart). If severe enough, the combination of reduced oncotic pressure and increased venous pressure leads to generalized edema and ascites, a condition called hydrops fetalis, which can be fatal. Lesser degrees of edema can also occur.

If hemolysis is severe, jaundice can occur due to accumulation of unconjugated bilirubin. Unconjugated bilirubin is water insoluble; it binds to lipids in the brain (the blood-brain barrier in the fetus is poorly developed), causing serious damage to the CNS, termed kernicterus. The affected brain is enlarged, edematous, and yellow.

Rh-mediated HDN

Rh-mediated HDN most often involves the D antigen (sometimes it involves E or c; rarely it involves e or C). The baby inherits the D antigen from father, and mom is D negative (same as saying “Rh negative”). Fetal blood gets into mom’s circulation (through trauma, ruptures in the placenta during pregnancy, medical procedures carried out during pregnancy that breech the uterine wall, or childbirth). As a result, mom makes anti-D antibodies (the amount of antibody made depends on dose of antigen received from baby! Mom only makes anti-Rh antibodies when the she has received more than 0.5- 1 mL of Rh + cells.). Just like any other developing antibody, IgM appears first, and IgG appears later. This is important because IgG can cross the placenta, but IgM can’t. So HDN is uncommon in a first pregnancy. But if the mom gets pregnant again, and the fetus inherits D again, mom will now make IgG antibodies, and HDN can happen then.

Rh-mediated HDN is diagnosed using a direct antiglobulin test (DAT). This test will be positive in the baby (baby’s cells are coated with mom’s antibodies). An indirect antiglobulin test  will be positive in mother (though if the mother has received Rhogam at 28 weeks – keep reading – the IAT will be artificially positive!). Administration of anti-D antibody (Rhogam) at 28 weeks and again within 72 hours of delivery to Rh-negative moms prevents HDN in the current pregnancy (and, if mom has not produced anti-D yet, protects future pregnancies too) by coating any circulating D+ fetal red cells before mom is able to make any anti-D antibodies! The incidence of Rh-mediated HDN has gone way down since Rhogam was developed.

In order to determine the appropriate dose of Rhogam to give the mom, you have to quantify the amount of fetomaternal hemorrhage. This is done using either the Kleihauer-Betke test or an immunophenotyping assay. We’ll discuss these tests in our next post.

ABO-mediated HDN

ABO incompatibility occurs in 20-25% of pregnancies…but laboratory evidence of hemolytic disease occurs only in 1 of 10 such infants, and the hemolytic disease is severe enough to require treatment in only 1 in 200 cases.

There are a number of reasons why ABO incompatibility is rarely serious:

1. Most anti-A and anti-B antibodies are IgM (hence they don’t cross the placenta).
2. Neonatal RBCs express A and B poorly (the expression of A and B antigens increases as the baby grows).
3. Many cells other than red cells express A and B antigens and thus sop up some of the transferred antibody.

ABO hemolytic disease occurs almost exclusively in infants of A or B type born of group O mothers. Normal anti-A and anti-B antibodies are IgM and therefore don’t cross the placenta. For reasons not understood, however, some group O women have IgG anti-A and anti-B even without prior sensitization! In this situation, a firstborn child may be affected. Fortunately, even with transplacentally acquired antibodies, lysis of infant red cells is minimal.

ABO incompatibility is diagnosed with same tests as Rh incompatibility (DAT, IAT, Kleihauer-Betke test). There’s no effective protection against ABO incompatibility reactions! Good thing they’re not very common.

Treatment of HDN

It’s obviously way better to prevent HDN than to try treat it once it’s developed. That’s why the mother’s blood type is determined very early in pregnancy, and Rhogam is administered if mom is D negative.

If HDN does develop, there are several options for treatment. Minimally affected newborns can be treated with phototherapy (as in the photo above). Light oxidizes unconjugated bilirubin (toxic) to water-soluble, readily-excreted dipyrroles (harmless). Severely affected fetuses can be treated by total exchange transfusion of the infant (through umbilical vein). The mother can be treated with plasmapheresis (which removes antibody). High-dose intravenous immunoglobulin can be used too – but the best dosage and timing are not well-defined.

Photo credit:  treehouse1977 (http://www.flickr.com/photos/treehouse1977/3310309612/in/photostream/), under cc license.

Question: I’m a bit confused on the terminology of hypertension. Is secondary hypertension the same as malignant hypertension? Is systemic hypertension also the same as malignant hypertension?

Answer: “Systemic hypertension” is just general, all-over-the-body hypertension. It’s what people usually mean when they say “hypertension”.  There is also something different called “pulmonary hypertension” which we’ll talk about some other time when we’re discussing lung pathology.

There are two big divisions in systemic hypertension: benign hypertension and malignant hypertension. Benign hypertension accounts for almost all cases of systemic hypertension. It has a long clinical course. It can either be primary (almost all cases), in which the cause is unknown, or secondary (rare cases), in which you can figure out the cause (usually it’s renal disease).

Malignant hypertension accounts for only a small percentage of cases of systemic hypertension. It has a rapid and dangerous course. It usually arises in a patient with preexisting benign hypertension, but it can also arise in a person with normal blood pressure.

Q. I have been studying for boards and have run into an issue. I am wondering what markers are used to test if a patient has had an MI. Robbins says that troponin is the best overall but creatine kinase MB is also good. The Dental Decks say that myoglobin is the first to show. Another boards book says that troponin is the first to show up in the blood. I am wondering what you know from a clinical standpoint and if you know the truth behind this issue.

A. There are several laboratory tests (or “markers”) that can be used to detect myocardial infarction. They vary in sensitivity and specificity (especially in the first few hours after an infarct), and you have to correlate them with the patient’s symptoms and other co-existing medical conditions (as well as EKG and angiogram findings).

Here is a list of the tests with some pertinent facts about each:

1. Creatine kinase (total)

Creatine kinase (CK) is an enzyme present in cardiac and skeletal muscle that is released into the blood when cells are injured. An elevation in total CK means you either have skeletal muscle or cardiac muscle injury (in other words, it’s not specific for MI). This is a easy, cheap, widely-available test.

2. Creatine kinase (MB fraction)

CK has three isoenzymes: MM, MB, and BB. CK-MM and CK-MB are both found in cardiac and skeletal muscle, but CK-MB is much more specific for cardiac muscle. CK-BB is found in brain, bowel, and bladder.

CK-MB is a very good test for acute myocardial injury. It’s very specific (you don’t see elevations in CK-MB in other conditions very often), and it goes up very quickly and dramatically after MI (within 2-8 hours). It returns to normal within 1-3 days, which makes it a good test to use in diagnosing re-infarction.

Sometimes the CK total and CK-MB are reported in the form of a “cardiac index”, which is the ratio of total CK to CK-MB. This is a sensitive indicator of early MI.

Just to make things more complicated, it turns out there are two isoforms of CK-MB, conveniently called 1 and 2. CK-MB isoform 2 goes up even before the regular old CK-MB does. The results are usually reported as a ratio of isoform 2 to isoform 1; a ratio of 1.5 or more is a great indicator for early MI. However, to detect these isoforms, you have to do electrophoresis (which is a time-intensive test that has to be performed by skilled people), so the results take a while to get back.

3. Troponin I and T

Troponins are components of cardiac muscle that are released into the blood when myocardial cells are injured. They are very, very specific for myocardial muscle – even more specific than CK-MB. Troponins go up within 3-12 hours after the onset of MI (though the rise is more gradual than the steep bump you see with CK-MB). They remain elevated for a long time (5-9 days for troponin I and up to a couple weeks for troponin T), which means they’re great for diagnosing MI in the recent past (even up to a couple weeks previous to the test) but not so great for diagnosing re-infarction (unless the first infarction was over a few weeks ago). Troponin I is more specific than troponin T (which can be elevated rarely in skeletal muscle injury or renal failure).

4. Myoglobin

Myoglobin is a protein present in both skeletal and cardiac muscle that is released when cells are damaged. It’s a very sensitive indicator of muscle injury, and it’s also the first marker to go up in a myocardial infarction (even before CK-MB). It’s not specific for cardiac muscle, so you wouldn’t want to do this test as your only marker for ruling in an MI (because if the myoglobin is elevated, you wouldn’t know if it was due to an MI or a skeletal muscle injury). It is a good marker, though, for ruling out an MI (if the myoglobin is not elevated, you can be quite sure your patient hasn’t had an MI).

5. Lactate dehydrogenase

Lactate dehydrogenase (LDH) is an enzyme present in many different cells. There are 5 isoenzymes (1-5), each with different specificities for different types of tissue. In the case of cardiac injury, LDH isoenzyme 1 will go up, and usually you’ll see that isoenzyme 1 is higher than isoenzyme 2 (this is called a “flipped” pattern, because under normal circumstances, isoenzyme 2 is present in greater amounts than isoenzyme 1). The LDH starts going up in 12-24 hours following an MI, and it dissipates within a week or two. This test has been supplanted by the other markers discussed above – but you might still see older texts (or board questions, heaven forbid) that discuss this test as a marker for cardiac injury.

So, back to your question. Robbins and the Dental Decks are both correct, in a sense. Robbins is correct in saying that troponins are the best overall markers; they have the best combination of sensitivity, specificity, and ease of test performance of all the markers. CK-MB is second best, and might be the test to do if your lab doesn’t yet do troponins (although most labs do perform troponin assays now). The Dental Decks are also correct in saying that the first marker to go up is myoglobin (although they don’t mention the lack of specificity of this marker, which means that it’s not a good test to use for ruling in MI). The other boards book that says troponin is the first marker to go up is wrong; myoglobin is the first, followed by CK-MB (within 2-8 hours) and the troponins (within 3-12 hours). When in doubt, trust Robbins!

Photo credit: CarbonNYC (http://www.flickr.com/photos/carbonnyc/132922595/)