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Tony Breu

28 Mar, 11 tweets, 5 min read

1/11
Why is alkaline phosphatase elevated in biliary obstruction?

This question was debated for decades. The current explanation is NOT what I had expected.

Will you be surprised too?

2/
Let's start with a question.

What explanation have you heard for the increased alkaline phosphatase (AP) in biliary obstruction?

3/
One potential explanation is that AP leaks into the blood when hepatocytes are injured.

The problem: AP isn't markedly elevated in conditions with marked acute liver injury. For example, AP is only mildly elevated in acute viral hepatitis.

bit.ly/39kxaom

4/
In one study of 386 patients with acute liver injury (mean ALT 2,784), the mean AP was in the normal range.

That AP isn't simply leaked into the blood fits with the observed delay in its elevation after acute biliary obstruction.

pubmed.ncbi.nlm.nih.gov/28440304/

5/
For decades, it was assumed that the liver cleared AP from blood and excreted it into bile, just as it did bilirubin.

Biliary obstruction would therefore lead to an elevated AP.

This “retention” theory was accepted as fact until the 1960s.

pubmed.ncbi.nlm.nih.gov/13830463/

6/
Beginning in the 1960s, evidence mounted against the "retention" theory.

In 1964, Clubb et al showed that clearance of AP is independent of the patency of the bile duct.

The problem isn't with an inability to excrete AP into bile. It isn't retained!

pubmed.ncbi.nlm.nih.gov/5835974/

7/
The next clue: AP synthesis INCREASES after bile duct obstruction!

This was shown in a 1970 study in which cycloheximide - a known inhibitor of protein synthesis - blunted the rise in AP seen in biliary obstruction.

ncbi.nlm.nih.gov/pubmed/5415676

8/
What prompts the rise in AP synthesis?

The leading hypothesis is that increased concentrations of BILE ACIDS induce the increase.

This was demonstrated in a study in which taurocholate (a bile acid) led to a dramatic rise in AP activity.

pubmed.ncbi.nlm.nih.gov/488632/

9/
Next, the increased protein synthesis was found to result from enhanced mRNA translation (as opposed to increased mRNA transcription).

pubmed.ncbi.nlm.nih.gov/3710426/

10/
The final step is the secretion of AP into blood. The exact mechanism is not clear.

I do wonder whether an increased rate of secretion is required.

Given the increased synthesis of liver AP in obstruction, a stable secretion rate would still lead to elevated blood levels.

11/11
💥SUMMARY💥

➣ Bile acids accumulate during biliary obstruction; this drives...
➣ Increased alkaline phosphatase (AP) synthesis; this occurs via...
➣ Increased mRNA translation

• • •

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More from @tony_breu

Tony Breu

@tony_breu

21 Mar

1/12
Why do we use ACE inhibitors in scleroderma renal crisis?

I learned this early in training but never understood why these drugs were so game-changing.

Let's have a look.

2/
To start, a few key features of scleroderma renal crisis (SRC). Most patients present with:

• Abrupt onset of hypertension
• Oliguric acute kidney injury
• Normal urinalysis

Up to 50% have signs of microangiopathic hemolytic anemia.

pubmed.ncbi.nlm.nih.gov/27641135/

3/
Decades ago, the mortality for scleroderma involving the kidney was high with SRC considered universally fatal.

Things began to change in the 1970s.

pubmed.ncbi.nlm.nih.gov/4587746/

Read 12 tweets

Tony Breu

@tony_breu

13 Mar

1/14
How does fever help us fight infections?

For millennia, fever has been recognized as a beneficial response to invading pathogens.

If this is so, why don't we have a resting temperature of 102°F (38.9°C)? Wouldn't that protect us even better?

Let's have a look.

2/
Fever emerged approximately 600 million years ago and is conserved in vertebrates. This suggests its benefit.

As you'll see in the next tweet, even ectothermic (cold-blooded) vertebrates demonstrate a "febrile" response.

pubmed.ncbi.nlm.nih.gov/24692136/

3/
In a 1975 study, ectothermic lizards were infected with A. hydrophila and placed in environments at varying temperatures.

😀75% survived at 42°C (107.6°F)
😕25% survived at 38°C (100.4°F)
🥴0% survived at 34°C (93.2°F)

🔑↑temperatures = ↑survival

pubmed.ncbi.nlm.nih.gov/1114347/

Read 18 tweets

Tony Breu

@tony_breu

27 Jan

1/14
Why is cerebrospinal fluid (CSF) glucose low in bacterial meningitis?

Before we review potential mechanisms, I'm interested in the explanation you've heard/used.

What do you think causes low CSF glucose (hypoglycorrhachia)?

2/
First, let's examine the most common causes of hypoglycorrhachia.

☞ While bacterial meningitis is the single most common cause, it accounts for fewer than a quarter of cases.

We'll come back to this.

pubmed.ncbi.nlm.nih.gov/24326618/
pubmed.ncbi.nlm.nih.gov/26299186/

3/
Now to the potential mechanisms. A number of hypotheses have been offered to explain hypoglycorrhachia.

🔹Bacterial consumption of glucose
🔹WBC consumption
🔹Brain consumption
🔹Decreased entry into CSF

...and others

Let's examine these.

Read 14 tweets

Tony Breu

@tony_breu

30 Dec 20

1/16
Why do B12 and folate deficiencies lead to HUGE red blood cells?

And, if the issue is DNA synthesis, why are red blood cells (which don't have DNA) the key cell line affected?

For answers, we'll have to go back a few billion years.

2/
RNA came first. Then, ~3-4 billion years ago, DNA emerged.

Among their differences:
🔹RNA contains uracil
🔹DNA contains thymine

But why does DNA contains thymine (T) instead of uracil (U)?

pubmed.ncbi.nlm.nih.gov/12110897/

3/
🔑Cytosine (C) can undergo spontaneous deamination to uracil (U).

In the RNA world, this meant that U could appear intensionally or unintentionally. This is clearly problematic. How can you repair RNA when you can't tell if something is an error?

pubmed.ncbi.nlm.nih.gov/18837522/

Read 16 tweets

Tony Breu

@tony_breu

28 Nov 20

1/17
How does calcium "stabilize the cardiac membrane" in hyperkalemia?

I learned early in my intern year to use calcium in the setting of severe hyperkalemia.

I never really learned how it works. The answer requires some history. And uncovers a forgotten alternative treatment.

2/
First, some history.

While Sidney Ringer was developing his eponymous fluid, he observed that increasing potassium content led to progressively weaker ventricular contractions.

He reported these findings in 1883.

pubmed.ncbi.nlm.nih.gov/16991336/

3/
How does hyperkalemia affect the heart? To understand the answer, recall that the generation of an action potential is dependent on the:

(1) resting membrane potential (−90mV for myocytes)
(2) threshold potential (-70mV)
(3) activation state of membrane sodium channels

Read 17 tweets

Tony Breu

@tony_breu

25 Oct 20

1/14
Why is secondary dengue infection more likely to cause hemorrhagic fever than primary infection?

Not all infections confer immunity, but why would prior exposure lead to WORSE outcomes?

To answer these questions, we'll need to discuss "Original Antigenic Sin".

Let's go!

2/
Dengue is caused by any of the four dengue virus serotypes (DENV 1-4).

Dengue hemorrhagic fever (DHF) is a severe form of dengue characterized by vascular leakage, hemorrhage, and thrombocytopenia.

This can lead to organ failure and death.

apps.who.int/iris/bitstream…

3/
The biggest risk factor for DHF is secondary infection (i.e. patients with DHF have been infected with dengue once before).

Multiple cohorts have shown that DHF is rare the first time someone is infected.

pubmed.ncbi.nlm.nih.gov/23471635/

Read 14 tweets

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