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USMLE® Step 1 style questions USMLE

4 questions

A 40-year-old man is being examined for exercise intolerance. The patient develops severe shortness of breath 5 minutes after exercising. The patient also complains of knee pain that worsens throughout the day and improves with rest. Family history is significant for an uncle with ulcerative colitis. Echocardiography reveals a thickening of the walls of both ventricles. ECG reveals low-voltage electrical activity. A biopsy of the heart is taken and reveals infiltration of the walls of the ventricles by inclusion that has apple green color under polarized light. Which of the following has most likely resulted in this patient’s cardiac abnormalities?  

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Sam Gillespie, BSc

In amyloidosis, “amyloid” refers to starch-like, and it goes back to an observation made by the German scientist Rudolf Virchow, who saw mysterious deposits in the tissue that stained blue with iodine, just like plant starch.

As it turns out, amyloids are actually just proteins that take on an abnormal shape, which makes them stick together and settle in tissues.

And amyloidosis is the name for the disease that develops as a result of the tissue damage from these protein deposits.

Normally, our cells produce thousands of proteins each and every moment, and these proteins need to fold into a particular shape in order to do their jobs properly.

If a protein folds incorrectly, it’s normally spotted right away and destroyed by proteases, which are enzymes that chop up larger proteins into tiny bits.

In amyloidosis, there are a few different ways that protein folding can go wrong.

One way is when normal proteins are produced in enormous amounts, and just a small fraction of them fold incorrectly.

A second option is that abnormal proteins with incorrect amino acid sequences are produced in normal amounts, and they fold incorrectly.

Either way, the misfolded proteins, called amyloids start to build up.

Sometimes there’s simply too many of them for the protease to handle, and other times, the way that they’re folded makes them tough to break down - a bit like a pistachio that doesn’t have an opening for your fingers to work with. Nightmare.

When the amyloid proteins get excreted out of the cell, they tend to clump together forming a rigid, insoluble structure called a β-sheet - like a folded sheet of paper.

These β- sheets then deposit in the extracellular space of tissues and cause damage.

So amyloidosis is a process where there are extra protein deposits, and there are many different proteins and diseases that follow that same underlying process.

In general, amyloidosis can be systemic, meaning that those protein deposits occur in multiple organ systems, or it can be localized, meaning that they occur in one organ.

Until recently, systemic amyloidosis was further broken down into primary amyloidosis, which is where amyloidosis was thought to be the main problem, and secondary amyloidosis, which is where there was another known disease process that resulted in the protein deposits.

However, this is not totally accurate, since an underlying disease process has been identified even in the primary form.

OK, so, AL amyloidosis, previously known as primary amyloidosis, is where “A” refers to amyloidosis and “L” refers to the immunoglobulin light chain as the protein that gets misfolded and deposited.

In plasma cell disorders, like multiple myeloma, plasma cells in the bone marrow produce more light chains than heavy chains, and those excess light chains leak out into the blood.

Since there are so many light chains, some misfold into AL proteins, and build up in various tissues.

In AA amyloidosis, previously known as secondary amyloidosis the misfolded protein comes from serum amyloid A.

Under normal conditions, serum amyloid A is a properly folded protein that’s an acute phase reactant meaning that it’s secreted into the bloodstream by the liver whenever there’s inflammation.

But when inflammation goes on for too long, like in rheumatoid arthritis, inflammatory bowel disease, various cancers, or hereditary immune disorders like Familial Mediterranean fever, there’s lots of serum amyloid A in the blood.

And a small proportion of the serum amyloid A spontaneously folds incorrectly into AA amyloids, which end up accumulating within tissues creating amyloidosis.

In systemic amyloidosis, amyloids deposit in various organs.

In the kidneys, amyloid deposits can damage the podocytes, which are the cells that line the glomerulus.

When the podocytes are damaged, proteins like albumin spill into the urine, which results in proteinuria - protein in the urine, typically greater than 3.5 grams per day and hypoalbuminemia - which is low albumin in the blood.

Over time, with less protein in the blood the oncotic pressure falls, and that drives water out of the blood vessels and into the tissues, called edema.

Albumin and other proteins that normally inhibit the synthesis of lipids, or fat, so losing them leads to hyperlipidemia - which is increased levels of lipid in the blood.

Those are the hallmarks of nephrotic syndromeproteinuria, hypoalbuminemia, edema, and hyperlipidemia.

Now, in the heart, amyloid deposits can make the heart walls stiff and non-compliant and that can lead to restrictive cardiomyopathy, which is when the ventricle is unable to stretch out and fill up with blood.

Over time that can lead to congestive heart failure.

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