Download ammonia levels in cld

AMMONIA LEVELS & HEPATIC
ENCEPHALOPATHY
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;114:188-93.
• 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.
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
How Does Ammonia Cause AMS?
How Does Ammonia Cause AMS?
• We still don’t know
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
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.
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
Ammonia Levels and Encephalopathy
• What does the literature say:
- Does an ammonia level help us diagnose
hepatic encephalopathy?
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
Wes Haven Score
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
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
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
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”
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
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
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
Nicalao et al 2003
• Grade 0: 75 +/- 52
• Grade 1 & 2: 174 +/- 67
• Grade 3 & 4: 234 +/- 94
• A = on presentation
• B= upon immediate resolution of symptoms
• C = 48 hours after recovery
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.”
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
Kundra et al 2005
• Correlation coefficient 0.3
- HE: mean venous ammonia 59 +/- 30
- No HE: mean venous ammonia 42 +/- 18
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.
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
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
Operator Variability
• Torniquet effect
- levels rise with increased torniquet time
• Need to collect on ice
• Result is time sensitive
Ammonia Levels and Encephalopathy
• What does the literature say:
- Does an ammonia level help us diagnose
hepatic encephalopathy?
Ammonia Levels and Encephalopathy
• What does the literature say:
- Does an ammonia level help us diagnose
hepatic encephalopathy?
NO
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
Take Home Message
• Serum ammonia levels are neither sensitive or
specific for hepatic encephalopthy in chronic
liver disease
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
• 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.
• 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.
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