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Jul 16, 2018 26 tweets 12 min read Twitter logo Read on Twitter
What's the deal with Ammonia in hepatic encephalopathy?
A #cirrhosis QI #tweetorial

Try to answer this question while also showing
1) Ammonia levels dont matter
2) U should not restrict protein in patients with HE

Keywords: "ammonia hypothesis", sarcopenia
First, a poll:
Does Ammonia cause hepatic encephalopathy?
How did NH3 get involved with #HE in the first place?

Step 1: In 1877 Eck develops the first successful vascular anastamosis, a portocaval shunt. ncbi.nlm.nih.gov/pubmed/9186464
Step2: Pavlov improves it
Step3: Dogs get goofy after eating meat:"Meat stupor"
Step4: What's up with meat!?
Enter McDermott and this 100% bananas paper from 1954:
McDermott was awesome:
War hero, fixed Muhammad Ali's hernia, revolutionized liver surgery

Here is his obit: nytimes.com/2001/07/25/us/…
So, McDermott cared for a man with painless jaundice.

In the OR:
A 5cm pancreatic cancer with superior mesenteric vein involvement.

To resect in 1 stage, he smacked the portal vein onto the inferior vena cava- Eck fistula!

He pub'd this story in 1952:
Then the patient keeps getting readmitted for bizarre "irrational" behaviour which occasionally progresses to coma

Everyone was stumped

So they studied him to figure it out.

It took 6 months

They noticed he would get confused after eating meat

Could this be "meat stupor"?
What's in meat?
Amino acids and NH3 containing stuff!

To summarize, the highlights:

First they fed him urea -->HE
(Urea --> Ammonia)
So they fed him ammonia -->HE
Thus Ammonia -->HE.
Are you interested in what (specifically) ammonia does in the brain?

Lots of bad things
Let me send you to a few references:
ncbi.nlm.nih.gov/pubmed/10728803 @JHepatology
ncbi.nlm.nih.gov/pubmed/12668989 @HEP_Journal
So ammonia causes HE.

There, I said it

But is it the whole story?
Time for Jules Stahl and this 25 page single-author paper in @AnnalsofIM 1963

Turns out, Ammonia levels have nothing to do with grade of HE

We knew this in 1963!
Still true in 2003!
Low levels usually good but even 1 in 13 people with Grade 4 HE (coma) have stone-cold normal NH3.
And an ammonia level of 150 could mean anything from no HE to coma.
Somewhere, someone is doing sudoku with an ammonia of 210 just to prove a point
HE is a clinical diagnosis.
NH3 levels just cannot diagnose or grade HE.

But why?
Pts w/cirrhosis & portal htn circulate bacteria from the gut.

This causes inflammation

Inflammation enhances diffusion of NH3 into the brain
(review: aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.10…)

Don't forget: lots of HE is PRECIPITATED by what, u guessed it, infections (inflammation!)
Cool study: Shawcross induced hi-NH3 - a la McDermott, by infusing ammonia salts
This led to 🔽 cog function
Now, Abx 🔽 inflammation
Sp they gave Abx which 🔽 inflammation
Then they🔼 NH3 ...but there was no cognitive dysfunction!
One major reason the levels are useless:

We have no way of accounting for the impact (and amount) of inflammation.
Act 2:
Ammonia is bad and I certainly dont want to cause meat stupor!

Should I ask my patient with cirrhosis to eat a low protein diet?
Although NH3 levels are far from perfect, we definitely want to protect our brains from high NH3

If your liver is not working
and the portal HTN is shunting blood
We need a second line of defense

We have one:
It's the muscle!
Skeletal muscle accounts for >50% of NH3 metabolism in healthy people,
even more in patients with cirrhosis.

Lockwood followed radiolabelled NH3 to the muscle (JCI 1979;63);
Olde-Damink confirmed the role of muscle in many cool studies (e.g. Hepatology. 2002;36:1163)
What happens when NH3 gets to the muscle?

NH3 gets converted to glutamine at the price of a branch-chain amino acid (produced from muscle breakdown)

NH3 detox by the muscle is a catabolic process!
Restricting dietary protein is a great way to exacerbate catabolism and #sarcopenia in patients with cirrhosis
That's why patients with HE should have >1 g protein / kilogram body weight.

NH3 may rise after a protein-rich meal ... but it is safe

RCT: ncbi.nlm.nih.gov/pubmed/15246205
RCT: ncbi.nlm.nih.gov/pubmed/18627001
Guideline: ncbi.nlm.nih.gov/pubmed/16707194
So the next time you see a patient with cirrhosis are you going to check ammonia level?
And when you see them, are you going to recommend a low protein diet?
I hope you enjoyed this. Wanted to thank @tony_breu for his inspiration.

If you are interested in more stuff about ammonia, here's a plug for our paper "Refining the Ammonia Hypothesis" in @MayoProceedings sciencedirect.com/science/articl… with @Vilas_Pat and @ZGordonJiang

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More from @ebtapper

Oct 7, 2018
What is hepatorenal syndrome?
A #Livertwitter #tweetorial

Hepatology is awesome, exciting, but also humbling.
Nowhere is that clearer than HRS, a true unmet need for patients with ascites

1. What
2. Why
3. How to prevent/treat
4. ❤️ #cirrhosis physiology
1. Ascites trashes QOL & is deadly enough to merit mention in the bible(Fig1)
2. Ascites physiology damages other organs; Austin Flint said it 1st (Fig2)
3. HRS is the knockout punch of portal hypertension. What begins as elevated portal mmHg and ascites ends as HRS(Fig3)
1. HRS is not rare in pts w/ascites (Fig1)
2. HRS is deadly (Fig2)
3. For a definition of terms, check out the Ascites Club (that's a thing!)
ref: gut.bmj.com/content/gutjnl…
or see my review: amjmed.com/article/S0002-… (Fig3)
Read 13 tweets
Sep 27, 2018
Hepatic encephalopathy in the hospital (An ode to #lactulose):
A brief #livertwitter #tweetorial
1. Share the greatest t-shirt ever made
2. Rule out infection!
3. Laxation now! But how?

keywords: #cirrhosis, paracentesis, stool pH
1. This shirt, made by a patient, reminds us:
▶️HE is horrible, unpredictable
▶️Preventing HE is hard
▶️Dont be quick 2 label pts as 'noncompliant' - there's more to the story
▶️Our patients are awesome. Hepatology is the best

2. Think of hepatic encephalopathy as a biomarker.

For what? The answers form a mandatory checklist of sorts

1. Para to r/o SBP. Delay @ your patient's peril. (Fig1)
2. GI Bleeding?
3. UA/Blood Cultures/CXR
3. What's the Cr? Na? K?
review: nature.com/articles/s4139…
Read 14 tweets
Aug 20, 2018
Why is your pt's ALT (or AST) >1000?
A #livertwitter #tweetorial

1. Top 3 causes of acute liver injury
2. I always say it's ischemic hepatitis; 50% of the time, I'm right every time

Brought to u by:
@tonybreu et al. What causes severe ALI?
The liver is awesome.

Yet its vocabulary is ... limited.

We can all tell when it is upset - high ALT, AST.

But that could mean anything!

So what's your specific patient's specific reason for high ALT?
First - a poll:
What's the most common cause of severe acute liver injury
(ALT or AST > 10xULN)?
Read 11 tweets
Jul 25, 2018
Introducing the “The Hepatologist’s CBC”

A #cirrhosis #tweetorial all about the platelet

- Identify cirrhosis based on blood tests-
- Understand why platelets are low in #cirrhosis
- Describe the plt’s role in the #cirrhotic #coagulopathy

The hepatologist's dream:
identify patients with cirrhosis before complications like HCC and variceal bleeding.

Enter the platelet count
Shout out to JAMA's Rational Clin Exam Series & Udell et al's big beautiful systematic review ncbi.nlm.nih.gov/pubmed/22357834
Platelets are low in #cirrhosis.
We can use this to our advantage - even sparing biopsies.

Easy to do. E.g. Google: FIB-4
(ref aasldpubs.onlinelibrary.wiley.com/doi/abs/10.100…)

There are many platelet-based scores to help ID cirrhosis.
(review: ncbi.nlm.nih.gov/pubmed/2883446
Read 14 tweets
Jul 10, 2018
A celebration of paracentesis: a QI #Tweetorial

For all my twitter friends who care for inpatients with #cirrhosis

Take home messages: paras for all, FFP for none
Keywords: #SBP and the #cirrhotic #coagulopathy
First - which hospitalized patient needs a diagnostic para?

Patients with ascites and:
Spontaneous bacterial peritonitis (SBP) is a deadly condition. Appropriate tx can prevent hepatorenal syndrome and death.

How many patients are asymptomatic?


In this study from Pinzello et al, 1 in 3 patients with SBP were "silent"
Read 19 tweets

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