What ammonia levels correlate with the degree of hepatic encephalopathy?

From the Guidelines

Ammonia levels do not reliably correlate with the severity of hepatic encephalopathy (HE), despite elevated ammonia being a key factor in its pathophysiology. While patients with HE typically have elevated serum ammonia levels above the normal range of 35-50 μg/dL, the absolute ammonia concentration does not consistently predict the clinical grade of encephalopathy 1. Some patients with severe HE may have only modestly elevated ammonia levels, while others with minimal symptoms can have significantly high levels. This inconsistent correlation occurs because multiple factors beyond ammonia contribute to HE development, including inflammatory mediators, altered blood-brain barrier permeability, and cerebral edema.

Key Points to Consider

• The diagnosis of HE is through exclusion of other causes of brain dysfunction 1
• Hepatic encephalopathy should be divided into various stages of severity, reflecting the degree of self-sufficiency and the need for care 1
• Increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with CLD 1
• A normal ammonia value calls for diagnostic reevaluation 1
• Ammonia levels greater than 200 umol/L are associated with an increased risk of intracranial hypertension and hepatic encephalopathy in ALF patients 1
• Arterial ammonia levels should be monitored in patients with hyper-acute ALF and elevated and sustained arterial ammonia levels (>150 mMol/l) 1

Clinical Implications

• Clinicians should not rely solely on ammonia levels to determine the presence or severity of hepatic encephalopathy
• Clinical assessment using grading systems like the West Haven criteria remains the cornerstone for determining HE severity and guiding treatment decisions
• Ammonia testing can support the diagnosis of HE, but it should be used in conjunction with clinical assessment and other diagnostic tools.

From the Research

Ammonia Levels and Hepatic Encephalopathy

• The correlation between ammonia levels and the severity of hepatic encephalopathy is a topic of ongoing research, with some studies suggesting a positive correlation 2, 3, 4.
• A study published in 2000 found that arterial partial pressure of gaseous ammonia (pNH3) correlated more closely with the degree of clinical and electrophysiological abnormalities in hepatic encephalopathy than total ammonia levels 2.
• Another study published in 2003 found that ammonia levels, including arterial and venous total ammonia and partial pressure of ammonia, increased with the severity of hepatic encephalopathy, but found no additional advantage of measuring partial pressure of ammonia compared to total ammonia levels 3.
• However, more recent studies have suggested that ammonia levels may not be a reliable guide for clinical management of patients with hepatic encephalopathy, with one study finding no correlation between ammonia levels and the severity of overt hepatic encephalopathy 5, and another finding that ammonia levels did not influence lactulose therapy in patients with hepatic encephalopathy 6.

Specific Ammonia Levels

• A study published in 2005 found that plasma ammonia levels (PAL) were significantly higher in patients with acute liver failure (ALF) than in those with chronic liver disease (CLD), and that PAL correlated with the severity of hepatic encephalopathy in ALF patients 4.
• The same study found that the mean PAL in ALF patients was 172.1 micromol/L, compared to 58.75 micromol/L in CLD patients with hepatic encephalopathy and 42.17 micromol/L in CLD patients without hepatic encephalopathy 4.
• Another study published in 2020 found that an ammonia level of >72 μmol/L was considered abnormal, but that this did not guide therapy in clinical practice 6.

Limitations and Controversies

• The use of ammonia levels in clinical practice is problematic due to interlaboratory variability in sample handling and processing, which can affect ammonia measurements 5, 6.
• The correlation between ammonia levels and the severity of hepatic encephalopathy remains controversial, with some studies finding a positive correlation and others finding no correlation 2, 3, 5, 6, 4.