1. AMMONIA LEVELS & HEPATIC ENCEPHALOPATHY

2. References
Stahl J. Sutdies of blood ammonia in liver disease. Ann Intern Med 1963;58:1-24.
Ong JP, Aggarwal A, Krieger D, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003;114:
Nicolao F, Efrati C, Masini A, et al. Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy. J Hepatol 2003;38:441-6.
Kundra A, Jain A, Banga A, et al. Evaluation of plasma ammonia levels in patients with acute liver failure and chronic liver disease and its correlation with the severity of hepatic encephalopathy and clinical features of raised intracranial tension. Clin Biochem 2005;38:696-9.

3. Hepatic Encepalopathy (HE)
Thought to be due to failure of the liver to clear “toxic” products from the gut
- then act centrally to cause encephalopathy
Ammonia is one of these substances
Others are unknown

4. How Does Ammonia Cause AMS?

5. How Does Ammonia Cause AMS?
We still don’t know

6. How Does Ammonia Cause AMS?
Possibilities proposed
- secondary increase in other agents
- hyperactive GABA receptors
- alters BBB transport mechanisms
- impairs ATP synthesis via Krebs cycles
- astrocyte swelling
- consumption of branch chain amino acids used
in neurotransmitter synthesis

7. Common Precipitants of HE
Renal failure: decreased clearance of ammonia
Gastrointestinal bleeding: results in increased ammonia and nitrogen absorption from the gut
Infection: may result in increased tissue catabolism & thus increased blood ammonia levels.
Constipation: Constipation increases intestinal production and absorption of ammonia.
Medications: Drugs that act upon the CNS such as opiates, benzodiazepines, antidepressants and antipsychotics
Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion of NH4 + to NH3.

8. Ammonia Levels and HE
It is a common belief that a single elevated ammonia level in a patient with CLD can be used to rule in or out a diagnosis of HE
Seems to stem from a study in 1963 by Stahl that showed that elevated ammonia (loosely) correlated with hepatic coma

9. Ammonia Levels and Encephalopathy
What does the literature say:
- Does an ammonia level help us diagnose
hepatic encephalopathy?
It is reasonable to ask

10. Encephalopathy: Clinical Assessment
Hepatic encephalopathy is often graded using the Wes Haven Scoring System
There are several recent studies that have looked at Wes Haven Score and ammonia levels

11. Wes Haven Score

12. Wes Haven Criteria Score
Grade 0 - Minimal hepatic encephalopathy (previously known as subclinical hepatic encephalopathy). Lack of detectable changes in personality or behavior. Minimal changes in memory, concentration, intellectual function, and coordination. Asterixis is absent.
Grade 1 - Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria, depression, or irritability. Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected.
Grade 2 - Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time.
Grade 3 - Somnolent but can be aroused, unable to perform mental tasks, disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech
Grade 4 - Coma with or without response to painful stimuli

13. Ong et al 2003 Prospective study of 121 consecutive patients with CLD
Used West Haven Criteria to grade AMS
Measured total ammonia in arterial blood
Correlation coefficient was 0.61
Correlation of 0.5 to 0.75 is considered good

15. Ong et al 2003
Despite the trend for increased ammonia with increased AMS, there was so much overlap between the groups that it is hard to know how to use this data
- 70% without HE had a raised ammonia
level
- many with HE still had normal ammonia
levels

16. Conclusion
“because of the substantial overlap in ammonia levels between cirrhotic patients with and without hepatic encephalopathy, a single level has little clinical utility in the diagnosis of hepatic encephalopathy”

17. Nicolao et al 2003 Prospective study - 27 patients with CLD and HE
- 9 controls with no liver disease
Measure serial ammonia levels
Used
- arterial total ammonia
- venous total ammonia
- arterial partial pressure of ammonia
- venous partial pressure of ammonia
J Hepatology 2003

18. Partial Pressure of Ammonia
Partial pressure is a calculated value that allows for pH
It is thought to better reflect the amount of ammonia that enters the brain

19. Nicalao et al They found a correlation of 0.76
To get this they combined Grades 1 & 2 and Grades 3 & 4
Again there was enormous overlap which appears to limit the clinical usefulness of this test
In addition, resolution of HE was not associated with a change in ammonia level

20. Nicalao et al 2003 Grade 0: 75 +/- 52 Grade 1 & 2: 174 +/- 67

22. A = on presentation
B= upon immediate resolution of symptoms
C = 48 hours after recovery

23. Nicolao et al 2003: Conclusions
“Despite the significant correlation between pNH3 and hepatic encephalopathy, our study suggests that neither pNH3 nor arterial ammonia are, from a clinical point of view, more useful than venous ammonia: all three
determinations being limited both for the diagnosis of hepatic encephalopathy and for the clinical management of the patients.”

24. Kundra et al 2005
Prospective study of encephalopathy in acute and chronic liver disease
- 20 ALD
- 8 CLD and HE
- 12 CLD and no HE
Clinical Biochem 238?

25. Kundra et al 2005 Correlation coefficient 0.3
- HE: mean venous ammonia 59 +/- 30
- No HE: mean venous ammonia 42 +/- 18

27. Kundra: Conclusion
Raised PAL appears to be an important laboratory abnormality seen in patients with ALF and there seems to be a significant correlation between the severity of encephalopathy and PAL in these patients. However, among patients with CLD, the proportion of patients with PAL more than the upper limit of normal range is not significantly different between those with or without HE.

28. What Makes a Blood Test A Good Decision Making Tool?
Normal Level = absence of disease
Elevated Level = presence of disease
There is no overlap
Total level correlates with disease severity
No operator dependent variables

29. Ammonia Level Normal level does not exclude disease
Elevated levels do not equal disease
- 70 to 100% of patients with normal mental
state have raised ammonia levels
The level does not correlate with increasing confusion
Big operator variability

30. Operator Variability Torniquet effect
- levels rise with increased torniquet time
Need to collect on ice
Result is time sensitive

31. Ammonia Levels and Encephalopathy
What does the literature say:
- Does an ammonia level help us diagnose
hepatic encephalopathy?
It is reasonable to ask

32. Ammonia Levels and Encephalopathy
What does the literature say:
- Does an ammonia level help us diagnose
hepatic encephalopathy? NO
It is reasonable to ask

33. Conclusion
Serum ammonia levels do not correlate with hepatic encephalopathy in chronic liver disease
- may be normal in the presence of encephalopathy
- may be elevated in the absence of encephalopathy
Don’t base management on ammonia levels
Keep looking for another cause
Diagnose hepatic encephalopathy after you have ruled out all other causes

34. Take Home Message
Serum ammonia levels are neither sensitive or specific for hepatic encephalopthy in chronic liver disease

36. DD’s of HE
Intracranial lesions, such as subdural hematoma, intracranial bleeding, stroke, tumor, and abscess
Infections, such as meningitis, encephalitis, and intracranial abscess
Metabolic encephalopathy, such as hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, and uremia
Hyperammonemia from other causes, such as secondary to ureterosigmoidostomy and inherited urea cycle disorders
Toxic encephalopathy from alcohol intake, such as acute intoxication, alcohol withdrawal, and Wernicke encephalopathy
Toxic encephalopathy from drugs, such as sedative hypnotics, antidepressants, antipsychotic agents, and salicylates
Organic brain syndrome
Postseizure encephalopathy

37. High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed. The author has had excellent success using PEG-containing colonic lavage solutions, such as Go-LYTELY administered via nasogastric tube, in the acute management of hospitalized patients with severe hepatic encephalopathy.

38. Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.25,26,27 Similarly, rifaximin was as effective as neomycin and paromomycin. Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics.

39. West Haven Criteria 0 = no signs / symptoms
1 = trivial lack of awareness; anxiety; short
attention span; altered mood; no asterixis
2 = lethargy; minimal disorientation
3 = somnolent; grossly disorientated
4 = coma