by: Nicolas Ah Mew, MD

Many families and doctors who care for individuals with organic acidemias are very familiar with the fact that blood ammonia levels can be elevated during illness and also in health. Nevertheless, there are still many gaps in our knowledge, and the effect of high ammonia levels in these disorders is still not well understood. Here are some answers to common questions regarding elevated ammonia levels in organic acidemias:

Although we don’t know for certain, one of the leading theories, backed by experiments performed in cells and in rats, is that propionic or methylmalonic acid blocks an enzyme in another pathway – the urea cycle – whose purpose is to convert ammonia into urea. During illness, in particular during the newborn period, ammonia can rise to over 20 times the upper limit of normal or higher, and may cause or contribute to lethargy or coma.

 

The only agreement among metabolic specialists is that sick patients should receive lots of calories, either through the gut or through an intravenous line, in order to help promote anabolism. Also, patients who are in a coma may need to receive hemodialysis, which can remove ammonia and organic acids very rapidly from the body.

There are several medications which have been shown via clinical trials to decrease high ammonia levels, but only in patients with urea cycle disorders. These include sodium benzoate, Ammonul, Buphenyl , Ravicti and N-carbamylglutamate (Carbaglu). None of the published clinical trials to-date have looked at whether these medications are effective in the organic acidemias. Although many doctors still choose to prescribe these drugs off-label to PA or MMA patients, this is not without risk.

The question of whether these drugs are safe and effective in the organic acidemias is an important one. As a result, we are currently conducting a randomized controlled trial of N-carbamylglutamate (NCG) in patients with PA or MMA during hospitalizations with high ammonia levels.  This study is being conducted at 9 sites (Boston, Cleveland, Colorado, Los Angeles, New York, Pittsburgh, Philadelphia, Stanford, and Washington DC). The aim of the study is to determine if giving NCG during hospitalizations with hyperammonemia will result in a more rapid normalization of ammonia levels, and whether this results in a faster clinical recovery and shorter length of hospitalization.

Ammonia scavengers, such as Ammonul or Buphenyl, are often prescribed to organic acidemia patients hospitalized with high ammonia levels, but there is no published clinical trial evidence for this, and there is even perhaps a theoretical harm of worsening the acidemia.

Should chronically elevated levels of ammonia in PA or MMA be treated with medications?
Chronically elevated levels of ammonia indicate a metabolic disturbance and warrant further investigation. While all of the above medications have occasionally been prescribed long-term, there is actually no scientific evidence for the effectiveness of any of these medications in PA/MMA. 

Ultimately, there is much we still do not know about the effect of high ammonia levels in the organic acidemias, which is why clinical trials to study these questions are so important. Although this question and answer piece only covers some of the basics, a more in-depth expert review of the management of PA and MMA was recently published: http://www.ojrd.com/content/pdf/s13023-014-0130-8.pdf