Megaloblastic anemia and macrocytosis

Megaloblastic anemia with hypersegmented neutrophil

Q. I’m confused how in megablastic anemia, cells become macrocytic due to immature nuclei when RBCs don’t have nuclei! Is it referring to the erythroblast precursors before the nuclei are lost?

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What’s the deal with ADAMTS 13?

Adam

Q. We learnt about a pretty rare disorder called thrombotic thrombocytopenic purpura (TTP) in which super-huge von Willebrand Factor (vWF) multimers are made which lead to occlusion of microcirculation. (more…)

Student questions about congenital heart defects

why

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.

Conjugated vs. unconjugated bilirubinemia

Liver

Here’s a little question to see if you remember the different causes of conjugated and unconjugated bilirubinemia

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 vs. unconjugated. 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’e 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 (like a congenital disorder where you’re missing an enzyme necessary for conjugation – for example, Gilbert syndrome).

If you’ve got 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 (like hepatitis, or biliary obstruction), 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. It could be a cause of unconjugated bilirubinemia, if the hemolysis is massive enough. If it’s just a low level of hemolysis, the liver could probably keep up, and you’d get a conjugated hyperbilirubinemia.

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.

Congenital heart defects

blended heart

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 the 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.

Risk factors for atherosclerosis

smoker

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.

How to live forever

fountain of youth 1

One of the reasons our cells die is because they are inherently programmed to have only 60 to 70 doublings. That’s it. After that, they die.

Why is that? (more…)