Heavy chain disease

Q. Why do light chains appear in the urine in mu heavy chain disease but not in alpha or gamma heavy chain diseases?

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Coagulation tests in 400 words or less

Making a blood clot involves three steps:

  1. blood vessel constriction
  2. platelet plug formation, and
  3. fibrin formation (also called coagulation).

There are lab tests that evaluate steps 2 and 3 (nobody talks much about poor step 1). Let’s look at the main tests that are used to evaluate step 3.

If you think back to the basics of the coagulation cascade, you might recall that there are two arms – an extrinsic arm and an intrinsic arm – which come together in the final common pathway, which ends up turning fibrinogen into fibrin. When somebody is bleeding, and you think it’s due to a coagulation problem (as opposed to a platelet problem), it’s helpful to know what part of the cascade is screwed up. That helps you figure out what’s wrong with the patient (is it hemophilia? or liver disease? or coumadin overdose?).

There are two main tests for evaluating the cascade: one for the extrinsic arm (the INR) and one for the intrinsic arm (the PTT). There are other tests too – but those will have to be for another post.

1. The INR

In the olden days, this test was called the prothrombin time (or PT), and it was extremely variable from lab to lab. Now, the lab applies a mathematical correction to the PT to make the results more consistent. The new name for the nice standardized PT is the INR, or “international normalized ratio.”

Whatever. What you do in this test is add thromboplastin (which acts like tissue factor, the thing that kicks off the coagulation cascade in vivo) to patient plasma, and wait to see how long it takes for fibrin to form. This test (for reasons we’ll have to discuss in another post, since we’ve limited this one to 400 words) measures the extrinsic pathway, which is that arm of the coagulation cascade that involves tissue factor, factor VII, and the final common pathway (X, V, II, and fibrinogen).

2. The PTT

The PTT, or partial thromboplastin time, is performed by adding just some phospholipid to the patient’s plasma and waiting to see how long it takes to form fibrin. It’s called the “partial thromboplastin” time because initially, it was found that by adding a part of thromboplastin to a test tube, you could activate fibrin formation. It turns out that the part of thromboplastin people were adding was just phospholipid, and that thromboplastin consists of both phospholipid and tissue factor. This test measures the intrinsic pathway, which is that arm of the cascade involving factors XI, IX, VIII and the final common pathway.

Whew. Okay, that was 431 words. Close enough.

Thyroid lab tests explained in under 150 words

Q. I have been trying to figure out the two basic thyroid lab tests, TSH and T4. If you have a high TSH and a low T4 does that mean that the pituitary gland is going crazy to reach homeostasis but the thyroid is not responding? And inversely, if the T4 is high and the TSH is low does that mean for some reason the thyroid is working overtime due to a disease like Graves disease, and the pituitary is trying to compensate by not producing TSH?

A. Yes! That’s exactly right. When the two (TSH and T4) are opposite of each other – high T4/low TSH or low T4/high TSH – that means that the problem is intrinsic to the thyroid gland (Graves disease or Hashimoto thyroiditis, for example) and the pituitary is trying to control the thyroid by producing more or less TSH. Those are the most common types of thyroid disease – those that are intrinsic, or primary to the thyroid gland itself.

On the other hand, if both TSH and T4 are either low or high – high T4/high TSH or low T4/low TSH – that means that the process is being driven by TSH. Either there’s a pituitary adenoma making a ton of TSH, or the pituitary is not working well for whatever reason (it’s been radiated, or has undergone necrosis) and it’s not making enough TSH.

Image credit: akay (http://www.flickr.com/photos/akay/245002004/), under cc license.

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.

A quick summary of primary immunodeficiencies

Antibody

When people talk about immunodeficiency states, they’re usually talking about secondary immunodeficiencies, like AIDS.

The primary immune deficiencies really don’t get much press. Which is unfortunate, because although they are much less common than secondary immune deficiencies, they still occur, and it’s important to understand them for that reason alone. Plus, they are very testable – either on board exams, or on class exams.

Time is short, though, and you need to know the basic points for each one without having to wade through a lot of chapters in a textbook. So, without further ado, here is a short, bullet-pointed list of the main disorders, with particular emphasis on the part of the immune system that is affected, and the clinical manifestations of the disease.

X-linked agammaglobulinemia

  • Pre-B cells can’t differentiate into B cells
  • Patients have no immunoglobulin (Ig)
  • X-linked (so seen only in males)
  • Presents at 6 months of age (when maternal Ig runs out)
  • Patients get recurrent bacterial infections
  • Treatment: intravenous pooled human Ig

Common variable immunodeficiency

  • Group of disorders characterized by defective antibody production
  • Affects males and females equally
  • Presents in teens or twenties
  • Basis of Ig deficiency is variable (hence the name) and often unknown
  • Patients more susceptible to infections, but also to autoimmune disorders and lymphoma!

Isolated IgA deficiency

  • Most common of all primary immune deficiencies
  • Cause is unknown
  • Most patients asymptomatic
  • Some patients get recurrent sinus/lung infections or diarrhea (IgA is the major Ig in mucosal secretions)
  • Possible anaphylaxis following blood transfusion (patients have anti-IgA antibodies, and there is IgA in transfused blood!)
  • Increased incidence of autoimmune disease (who knows why)

Hyper-IgM syndrome

  • Patients make normal (or even increased) amounts of IgM
  • But can’t make IgG, IgA, or IgE!
  • X-linked in most cases
  • Patients also have a defect in cell-mediated immunity
  • Patients have recurrent bacterial infections and infections with intracellular pathogens (e.g., Pneumocystis jiroveci)

DiGeorge syndrome

  • Developmental malformation affecting 3rd and 4th pharyngeal pouches
  • Thymus doesn’t develop well
  • Patients don’t have enough T cells
  • Infections: viral, fungal, intracellular pathogens
  • Patients may also have parathyroid hypoplasia
  • Treatment: thymus transplant!

Severe combined immunodeficiency

  • Group of syndromes with both humoral and cell-mediated immune defects
  • Patients get all kinds of infections
  • Lots of very different genetic defects
  • Half of cases are X-linked
  • Treatment: bone marrow transplantation

The best way to remember these might be to make a little chart, with the diseases in one column, and subsequent columns for transmission (X-linked or not), immunologic defect (e.g., no immunoglobulin production), and clinical features (e.g., infant with recurrent bacterial infections).