Primary biliary cirrhosis

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Primary biliary cirrhosis

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High Yield Notes
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Primary biliary cirrhosis

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In primary biliary cholangitis, jaundice occurs when most of the have been destroyed.

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USMLE® Step 1 style questions USMLE

3 questions
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A 66-year-old woman comes to the clinic because of hypopigmentation of her hands and skin for several years as well as fatigue and steatorrhea. Examination shows xanthoma and hepatosplenomegaly in addition to peripheral hypopigmentation. Liver function tests show increased GGT and ALP concentrations. Anti-mitochondrial antibodies are present. A recent bone densitometry shows a T-score consistent with osteoporosis. Which of the following is the most likely diagnosis?

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Content Reviewers:

Rishi Desai, MD, MPH

Contributors:

Tanner Marshall, MS

Primary biliary cholangitis and cirrhosis, or PBC, is an autoimmune disease where the T cells attack the cells that line the smaller-sized bile ducts in the liver.

As the cells are damaged or destroyed by immune attack, they start letting bile leak through their tight junctions and into the interstitial space, where it can get into the blood and the other liver cells.

This can cause inflammation and symptoms that are similar to cholestasis and obstructive jaundice, both of which there’s some disturbance in bile flow.

At first it presents as chronic inflammation, which is where it gets the name cholang-itis, for inflammation of the bile ducts, but advanced stages of the disease leads to cirrhosis as more cells are destroyed both from the autoimmune attack and infiltration of bile.

As with a lot of autoimmune diseases, the exact reason why T-cells start attacking these bile duct cells is unknown, and it’s likely related to genetic predisposition in combination with environmental triggers, and is associated with other autoimmune diseases like autoimmune hepatitis and Sjogren’s syndrome.

PBC tends to affect women at a much higher rate than men, about a 9:1 female to male ratio.

For some reason that has yet to be completely figured out, in almost all cases of PBC, your body creates antibodies to mitochondria, specifically a mitochondrial protein called PDC-E2; for that reason, one of the most notable markers in PBC are these antibodies to mitochondrial proteins (or AMAs) in the patient’s blood, as many as 95% of patients with PBC have AMAs in their blood.

Why though, are the bile duct cells specifically targeted? Don’t all cells have mitochondria? Shouldn’t these AMA’s be targeting all cells then?

One theory is based on a concept called molecular mimicry, where the antigens that bring about this autoimmune response are really similar to another protein, but different enough so that the immune system gets confused and thinks it’s a foreign version of that particular protein.

Here’s an example of two people’s cells, they both have this triangle protein, but they have different colored triangles, each person’s immune knows that these are their own proteins, their own self-proteins and that they shouldn’t attack, but they have antibodies for proteins that are very similar, but definitely different from self, so say they have antibodies for triangles, just different colored triangles, so like person A has red, yellow, and blue, just not green, and person B has green, yellow, and blue, and not red. So both these people’s immune systems are like yep, these are all self so we’re good.

But now say person B’s red triangle turns into a green triangle instead, the immune system’s like...huh, weird, that’s not red, that must not be ours, and so the green triangle antibody binds it and the immune system kicks in, destroys the cell, and starts making a ton of these matched antibodies.

So similarly with PBC, you’ve got these AMAs for foreign versions of the PDC-E2 protein in your mitochondria, so like maybe yours is a red triangle, so you don’t have antibodies to red triangle PDC-E2 because your immune system knows that red equals self.

So the theory is, and mind you this is most definitely a theory, on why patients with PBC have a ton of these AMAs in their blood for PDC-E2 is that some infection or maybe a chemical in the bile ducts, an environmental trigger of some kind, damages a bile duct cell in such a way that now it shows a protein that happens to be really similar to PDC-E2 in structure, so it’s a triangle, but it’s different enough to be non-self, so maybe it’s green in color instead of red; and this triggers an immune response to this particular green-triangle protein, which is similar but not the same as the red-triangle protein in the mitochondria, and so the immune system starts pumping out these green-triangle anti- mitochondrial antibodies or AMAs, even though the target antigen isn’t even necessarily from the mitochondria, it’s just sort of mimicking the structure of the mitochondrial protein! Wild eh? That’s the theory, anyway, and sort of helps explain why just the bile duct cells are being attacked, and not all cells.