Ammonia Levels and Hepatic Encephalopathy in Patients with Known Chronic Liver Disease
Ammonia Levels and Diagnosis of HE
Even with proper collection and processing, ammonia levels in patients with CLD do not reliably diagnose HE. Gundling et al.19 determined the sensitivity and specificity of venous ammonia levels ≥ 55 µmol/L to diagnose HE to be 47.2% and 78.3%, respectively, by using a gold standard of the WHC and the critical flicker frequency test (a psychophysiologic test). The positive predictive and negative predictive values of ammonia were 77.3% and 48.6%, with an overall diagnostic accuracy of 59.3%. Approximately 60% of the patients with Grade 3 WHC HE had a normal ammonia level in this study. Ong et al16 found that only 31% of patients with CLD and no evidence of HE had a normal ammonia level.In other words, CLD patients with normal ammonia levels can have HE, and patients with elevated ammonia levels may have normal cognitive functioning.
Furthermore, ammonia levels are not a valid tool to diagnose HE even with an oral glutamine challenge.20 Most importantly, HE is a clinical diagnosis reached following the exclusion of other likely causes of cerebral dysfunction, independent of the ammonia level.
Ammonia Levels and Staging HE
The grading of HE was introduced to assess the response to an intervention in patients with HE enrolled in clinical trials.21 Tools like the WHC (Table) categorize the severity of HE. Nicolao et al.15 noted significant overlap in the levels of ammonia between patients with HE Grades 1 and 2 when compared with patients with Grades 3 and 4. This considerable overlap in levels of ammonia was more evident among patients with Grades 0 to 2 per Ong’s study.16 Most importantly, hospitalists do not need ammonia levels to determine that a patient has HE Grade 3 or HE Grade 4 symptoms, as the stage is graded on clinical grounds only. Once other causes for cerebral dysfunction have been ruled out, the ammonia level does not add to the clinical picture.
Serial Ammonia Levels and Resolution of HE
If the ammonia hypothesis is the sole explanation for the pathogenesis of HE, then the resolution of HE symptoms should be associated with normalization of ammonia levels. Physicians have commonly followed ammonia levels serially throughout a hospital stay. Nicolao et al.15 evaluated the association of ammonia with HE. They noted that some of the CLD patients had unchanged or increasing levels of ammonia despite overt neurological improvement from their HE.15 Some have argued that the normalization of ammonia levels lag behind the clinical improvement by 48 hours after resolution of symptoms. In the Nicolao et al.15 study, ammonia levels for almost all of the patients did not normalize 48 hours after resolution of neurologic symptoms. Moreover, 29% of the patients were noted to have higher venous ammonia levels 48 hours after the resolution of neurologic symptoms.15 These data underscore why serial measurements of ammonia in patients with CLD are not useful. For patients with overt symptoms, clinicians can determine improvement based on serial exams.
RECOMMENDATIONS
- HE is a diagnosis of exclusion and is made on clinical grounds.
- Do not check serum ammonia levels in patients with CLD to diagnose HE, to assess the severity of HE, or to determine whether HE is resolving.
- Use your clinical evaluation to determine the severity and course of HE.
- Treatment should be tailored according to clinical findings, not ammonia levels.
CONCLUSION
The attraction of the ammonia theory to explain HE continues to lead physicians to check and follow blood ammonia levels in patients with CLD and suspected HE. However, ammonia measurement, as in the clinical vignette, should be replaced by a thorough clinical evaluation to rule out other causes for altered mental status. Serial exams of the patient should guide management, not ammonia levels.
Disclosure
The authors report no conflicts of interest.
Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Let us know what you do in your practice and propose ideas for other “Things We Do for No Reason” topics. Please join in the conversation online at Twitter (#TWDFNR)/Facebook, and don’t forget to “Like It” on Facebook or retweet it on Twitter.
