Do you have to check an ammonia level if you’re concerned about encephalopathy?

Sometimes, you might be told to order a serum ammonia level on a patient who is encephalopathic, whether they have a history of liver disease or not. Why? Does the ammonia level actually matter?

I would argue for most cases, no. There are specific situations in which serum ammonia is a good prognostic or diagnostic test:

  • Acute liver failure (or acute fatty liver of pregnancy)–associated with risk of cerebral herniation and poorer outcomes
  • Patients who have inborn errors of metabolism–can suggest a diagnosis of urea cycle disorders
  • Reyes syndrome–can be suggestive of this diagnosis
  • Monitoring of ammonia-lowering therapy–in the research phase as far as I know

If you have a patient with cirrhosis or chronic liver disease who comes in with hepatic encephalopathy, though, the serum ammonia level is almost certainly not going to change your management. Ask yourself: If the ammonia level is 20 in a patient with major hand flapping, will you stop their lactulose? If it’s 140 in an alert cirrhotic will you get a head CT to look for cerebral herniation? Probably no, and no. It’s generally agreed that a serum ammonia level >100 is probably bad. And then there’s the question of arterial, venous, or partial pressure–better to just not get it in the first place. It also costs anywhere from $30-50.

Study results vary on whether the serum ammonia level is correlated with encephalopathy. For example, this study of about 120 patients suggests that it is, whereas this study of about 20 patients suggests not,  and this study says yes for ALF but not for patients with chronic liver disease. Even if the majority of evidence tips (pun not intended) towards ammonia levels and encephalopathy being correlated, no one has been able to define specific numerical cut-offs for what levels correlate with mild, moderate, or severe hepatic encephalopathy. So ammonia levels remain clinically not useful for managing most cases of hepatic encephalopathy. I rest my case with this clinical vignette and discussion by Phillip Ge and Bruce Runyon.

NB: I recommend this comprehensive review of the physiology of ammonia: it covers where and how ammonia is made, and how ammonia acts as a neurotoxin in the body. I can honestly say it was the first time I enjoyed reading about glutaminases.

If my patient is on antibiotics and has a history of C. difficile, should I put them on prophylactic oral vancomycin?

Example: you have a lovely 68-year old male with a history of two episodes of C. difficile infections after getting antibiotics in the setting of a hip surgery three months ago. He is admitted to your service with pneumonia and you decide he should get a 5-day course of levofloxacin. He has no abdominal pain or diarrhea (yet). Would PO vancomycin would help prevent recurrence of C. diff? 

In this case, the answer is a weak “yes.” There is no randomized controlled trial data showing that PO vanc prevents recurrence. However, there is a retrospective study of 172 patients in Quebec with a diagnosis of C. diff who were exposed to antibiotics for whatever reason within 90 days of their diagnosis. Those patients who had at least one recurrence of C. diff who got PO vanc had half the risk of getting C. diff again. Because the study looked at patients within 90 days of diagnosis, it’s unclear whether patients who had C. diff from a longer time ago would get the same benefits. A second study from 2016 of over 200 patients showed that patients who got PO vanc had a 4% risk of recurrence, whereas patients who didn’t had a 27% risk. Notably, this study only surveilled patients for 4 weeks after their antibiotic course, and the patients weren’t randomized–I got the sense that the patients who were offered PO vanc were “sicker.”

The regimen that I have seen most often is 125 mg PO vancomycin QID, but the second study, for example, reported 125 mg PO vancomycin BID or daily, so regimens are all over the place.

How long should patients continue PO vanc prophylaxis for? Again, no strong right answer. I have seen patients told to take PO vanc for only as long as they are on other antibiotics, for a week after finishing, or to do a slow taper/pulse down. However, there is a clinical trial  that has set the time course of PO vanc as 5 days after stopping other antibiotics, which sounds pretty good. What if it’s longer than a week, or a month? I did have a patient who required lifelong oral suppressive antibiotics…and we made the decision to keep her on PO vanc lifelong as well.

Do probiotics prevent recurrence of C. diff? The 2018 IDSA guidelines cite unclear evidence on whether probiotics prevent recurrence. While probiotics are fine for the general population (might as well try it if it won’t hurt), there are rare cases of fungemia/invasive infection that have been reported, in patients who are immunocompromised, have PICC lines, or are otherwise severely ill.

How is fecal microbiota transplant (FMT) performed?

Fecal microbiota transplant (FMT) is an effective and durable method of treating recurrent or refractory C. difficile infections. There are several routes of administration:

  • Nasogastric tube: patient takes PPI beforehand, NG tube is inserted, 50-60 cc of fecal slurry is pushed into the tube
  • Endoscopy: 200-250 cc of fecal slurry is delivered by flex sigmoidoscopy or colonsocopy (to the cecum)
  • Capsules: frozen capsules of slurry taken over several weeks (experimental)

Is there any difference between these different routes of delivery? Capsules were first devised at Massachusetts General Hospital; clinical trials are ongoing and they are not widely available. NG tube vs. endoscopy have been compared, and although some have not found a difference, some conclude that endoscopy is superior. For example, this study of 50 patients from the University of Alabama at Birmingham showed that patients who had endoscopy delivery of FMT had a greater rate of “cure” (improvement of symptoms in 2 weeks) and fewer repeat FMT treatments. However, you do have to evaluate each patient individually: some patients may find the idea of an NG tube too repulsive, some may be too sick to undergo endoscopy, etc. Importantly, FMT is felt to be safe for immunocompromised patients, too.

Tangent: according to the 2018 IDSA guidelines for treatment of C. diff, PO vancomycin or fidaxomicin are now considered agents of choice for a first episode of C. diff, no matter the severity. Keep your metronidazole on the shelves! It’s no longer recommended. 

Is it safe to give Tylenol to this patient with liver injury or elevated LFTs?

It is a widely held belief that Tylenol (acetaminophen, or paracetamol, depending on where you are) should not be used in patients with chronic liver disease or transaminitis because the drug will worsen liver injury or cause acetaminophen toxicity, the most common kind of drug-induced liver injury. However, underuse of Tylenol may lead to overuse of other pain medications, like NSAIDs or opiates, which come with their own problems. 

This review in the British Journal of Clinical Pharmacology goes through studies of healthy adults and adults with liver disease, including cirrhosis to look at the evidence for our fear of Tylenol. Essentially, the studies on Tylenol are small, and ALT naturally fluctuates (thus some of the previous methodology linking rise in ALT and Tylenol may have been questionable). The authors conclude that heavy alcohol use, malnutrition/fasting, underweight status, and sepsis may put patients at risk for acetaminophen toxicity, but Tylenol is still not 100% contraindicated for these groups. They state:

We have not found any case reports of hepatotoxicity secondary to therapeutic doses of paracetamol in adults with pre‐existing CLD who did not have at least one of these risk factors.

Therapeutic dose of acetaminophen is 4 g/24 hours. Therefore, it’s recommended that if you have patients with the above risk factors, aim to give them 2-3 g/24 hours. If they are developing rapidly deteriorating liver function (acute liver injury or failure), then it might be time to stop.
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Does my patient have hepatorenal syndrome?

This is intended to provide a quick list for diagnosis of HRS, since HRS is a diagnosis of exclusion and should only be made once other conditions are “ruled out.” HRS is a clinical diagnosis, and there is no one perfectly sensitive or specific test. But if your patient meets these criteria, you should be worried.

  1. Ascites is present
  2. There is an AKI (creatinine >1.5)
  3. Rule out infection: there is no UTI or pyelonephritis
  4. Rule out prerenal injury: there is no improvement in serum Cr after resuscitation with 2 days of 1 mg/kg albumin, 100 g max
  5. Rule out intrinsic disease: there is no hematuria (>50 RBCs) or proteinuria (>0.5 g) to suggest renal disease
  6. Rule out meds: no nephrotoxic meds recently given
  7. Rule out hypotension/ATN: no signs of ATN in the urine, no shock or profound hypotension

In the past, there were minor criteria including oliguria (<0.5 L urine output/day), low urine sodium (<20), and low serum sodium. These were found to have poor specificity and were dropped in 2007.

There are two types of HRS: Type 1 is rapid (develops in <2 weeks) and severe, with a 10% survival rate over 3 months. Type 2 is more gradual and on a spectrum with diuretic-resistant ascites.

You should also ask yourself: what triggered this episode of HRS? Common precipitants include infection (check a chest x-ray for pneumonia, urine studies for UTI, blood cultures, and rule out SBP), prerenal causes (not giving enough albumin after large-volume paracentesis, diuretics), post-TIPS, and nephrotoxic drugs.

Help with transplant immunosuppressant maintenance regimens

Immunosuppressants aim to prevent this from happening:

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Organ rejection.

But too much immunosuppression can cause this:

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Drug toxicity and dead fish.

That’s why people can’t just be on ONE immunosuppressant after transplant: the doses required would be too toxic, so the effect is spread out over 2-3 medications.

Considering that the historical option was total body irradiation, we’ve come a long way. Azathioprine was the first chemical immunosuppressant, but cyclosporine, which came onto the scene in the 1970s, revolutionized kidney transplant survival rates.

***One of my chiefs last year made an amazing figure on maintenance transplant immunosuppression. It is worth this whole post and I highly encourage you to take a look!***

For us peons, what are the commonly used immunosuppressants? 

Mechanism of Action Starting doses Monitoring required Side effects
Tacrolimus (Prograf) Calcineurin inhibitor (CNI) 0.075-0.2 mg/kg/day Cr, drug trough Neurotoxicity, nephrotoxicity, diabetes, alopecia *many drug interactions
Cyclosporine (Neoral) Calcineurin inhibitor (CNI) 2-6 mg/kg/day Cr, drug level Neurotoxicity, nephrotoxicity, diabetes, hypertrichosis, gingival hypertrophy
Mycophenolate mofetil ## (CellCept, MMF) Purine analogue, prevents T cell proliferation 500-1000 mg daily CBC, drug trough GI/diarrhea, myelosuppression, lymphoid neoplasm *many drug interactions, needs dose adjusted for renal failure
Azathioprine (Imuran) Purine analogue, prevents T cell proliferation 1-3 mg/kg/day (maintenance) CBC, LFTs, Cr, check TPMT Nausea/vomiting, myalgias, leukopenia, transaminitis
Sirolimus (Rapamycin) mTOR inhibitor Weight based; 1-5 mg/day (maintenance) Drug level Pneumonitis, arthralgias, edema, hypertension, bone marrow suppression, hyperlipidemia
Everolimus (Afinitor) mTOR inhibitor 0.75-1 mg twice daily Drug level arthralgias, edema, hypertension, bone marrow suppression, hyperlipidemia
Prednisone The dozens of things steroids do Varies widely, minimum 7.5 mg every other day or 5 mg daily n/a Osteopenia, diabetes, headache, Cushing’s, weight, cataracts, psychosis (and many others)

## Mycophenolate can be either mycophenolate mofetil vs. sodium. The difference is that the sodium formulation (Myfortic) is an enteric capsule that may prevent some GI effects like diarrhea(?) but the jury is still out.

What are the major side effects of immunosuppression?

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From the National Kidney Foundation

What is the underlying biology? ***This is a gross oversimplification.

Normally, T cells go scouting and if they encounter an antigen-presenting cell with foreign material on it, a chain reaction of events is started: calcineurin is activated, leading to a surge of IL-2 and its receptor, IL-2R, which upregulates the mTOR pathway, which leads to DNA nucleotide synthesis so that the T cell can multiply and generate an immune response.

Notice that the bolded words are the targets of the 6 immunosuppresants in the chart above.

Transplant pharmacology is REALLY COMPLICATED and you can do an entire fellowship training program for this. This is an excellent, but 100-page document from a Canadian transplant website. Here are two organ-specific guides/reviews regarding immunosuppression:

When should a PPI be stopped?

There are a few reasons why patients are started on PPIs in the inpatient setting: in the setting of an acute upper GI bleed; long periods of no oral intake; high doses of steroids that require PPI prophylaxis. The problem is that when these patients are discharged, the PPI is often carried forward as a “new medication” that is then carried forward by outpatient providers, even if the indication for which they were started on PPIs has resolved.

PPIs should be continued in patients with Barrett’s esophagus, hypersecretory states (Zollinger Ellison), symptomatic GERD, and patients at high risk for bleeding (on NSAIDs, cirrhotics). But just because someone has had bleeding or a peptic ulcer doesn’t mean they have to be on a PPI for life! For low-risk patients with a first-time ulcer, you should reassess whether they need to continue a PPI 2 months afterwards. The PPI should be stopped when the acute indication has passed or, in the case of GERD, the patient has been asymptomatic for about 3 months. The lengths of time depends: Up To Date says, “As a general rule, active duodenal ulcers should be treated for four weeks and gastric ulcers for eight weeks.”

It is important to periodically assess whether a patient is a candidate for tapering and discontinuing their PPI because there are a number of downsides to PPIs:

  • increased susceptibility to gastroenteritis and C. diff infections
  • decreased absorption of vitamin B, iron, and calcium
  • decreased calcium absorption then has implications for osteoporosis
  • ?increased risk of aspiration pneumonia

Esophageal pH testing can be used to prove that someone does not have GERD, but it can be a bit cumbersome to arrange. The most important factors to consider are someone’s symptom profile and their risk for becoming symptomatic or bleeding in the future.

See this ACP Internist article about strategies for stopping PPIs. If a patient complains of “acid rebound” following taper of PPI, then they likely have symptomatic GERD and should actually continue their PPI.