What is the diagnosis for Hepatic (liver) Encephalopathy?

From the Guidelines

Diagnosing hepatic encephalopathy (HE) requires a systematic approach, starting with screening all patients with cirrhosis, regardless of their liver function status, as recommended by experts with strong agreement 1. To diagnose HE, it is essential to investigate signs strongly suggestive of the condition, such as asterixis, psychomotor slowing, sleep–wake inversion, temporospatial disorientation, and impaired consciousness 1. The West-Haven classification is the most frequently used clinical classification of HE, categorizing it into overt HE (grades 2–4) and covert HE (grades 0–1), with the latter including minimal HE and grade 1 HE 1.

Key Diagnostic Steps

• Screen all patients with cirrhosis for HE, as the prevalence of covert HE is high, affecting more than two-thirds of patients, and the onset of HE is a leading risk factor for poor outcomes 1.
• Investigate signs strongly suggestive of HE, such as asterixis and psychomotor slowing, in patients with suspected overt HE 1.
• Use the animal naming test among available assessments to investigate covert HE in all patients with cirrhosis, as recommended by experts with strong agreement 1.
• Consider neuropsychological testing, which is the reference examination for the diagnosis of covert HE, allowing for precise characterization of the neuropsychological pattern, although access to these tests may be challenging in routine clinical settings 1.

Additional Diagnostic Considerations

• Laboratory tests, including liver function tests, ammonia levels, complete blood count, electrolytes, renal function, and glucose, can support the diagnosis but are not diagnostic alone 1.
• Brain imaging (CT or MRI) and electroencephalography may be necessary to exclude other causes of altered mental status and to show characteristic triphasic waves in severe cases, respectively 1.
• Identifying and managing precipitating factors, such as gastrointestinal bleeding, infection, constipation, and medication non-compliance, is crucial in the diagnosis and treatment of HE 1.

The diagnosis of HE is primarily clinical, based on the presence of cognitive impairment in a patient with liver disease after ruling out other potential causes, and is often confirmed by clinical improvement after treatment with lactulose or rifaximin, which reduce ammonia production in the gut 1.

From the FDA Drug Label

The primary endpoint was the time to first breakthrough overt HE episode. A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 and asterixis grade of 1 Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period.

To diagnose hepatic encephalopathy (HE), a marked deterioration in neurological function and an increase of Conn score to Grade ≥2 is used. In patients with a baseline Conn score of 0, a breakthrough overt HE episode is defined as an increase in Conn score of 1 and asterixis grade of 1. Key factors to consider in the diagnosis include:

• Neurological function: a marked deterioration
• Conn score: an increase to Grade ≥2
• Asterixis grade: an increase to 1 in patients with a baseline Conn score of 0 2

From the Research

Diagnosis of Hepatic Encephalopathy

To diagnose hepatic encephalopathy (HE), the following steps can be taken:

• Initial evaluation of the patient presenting with overt HE should include a careful search for predisposing factors, including underlying infection, gastrointestinal (GI) bleeding, electrolyte disturbances, hepatocellular carcinoma, dehydration, hypotension, and excessive use of benzodiazepines, psychoactive drugs, or alcohol 3.
• The West Haven criteria can be used to assess the severity of neurological dysfunction in overt HE 4.
• Psychometric tests or electrophysiological evaluation can be used to diagnose minimal hepatic encephalopathy (MHE) or covert HE (CHE) 4, 5.
• A 'STROOP' smartphone app has been developed to allow clinicians to test for covert hepatic encephalopathy (CHE) 5.

Classification of Hepatic Encephalopathy

HE can be classified into different types, including:

• Minimal HE (MHE): characterized by subtle impairment in mental state, with no overt clinical symptoms 4, 6.
• Covert HE (CHE): characterized by behavioral abnormalities and impairment in activities of daily living with intact sensorium 7.
• Overt HE (OHE): characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor, and coma 4.
• Episodic HE: generally triggered by one or more precipitant factors 4.
• Recurrent HE: characterized by repeated episodes of HE 4.
• Persistent HE: characterized by persistent cognitive impairment and neurological dysfunction 4.

Pathophysiology of Hepatic Encephalopathy

The pathophysiology of HE is complex and multifactorial, involving:

• Disturbance of the urea cycle due to liver disease, leading to increased production of ammonia 7.
• Ammonia-induced astrocytic swelling and cerebral edema 7.
• Cerebral oxidative/nitrosative stress and the synergistic effects of increased cerebral ammonia and alteration in neurotransmitters, neurometabolites, and cortical excitability due to systemic inflammation 7.
• Neuroinflammatory processes, including the role of inflammatory cytokines like TNF-α, IL-6, IL-17 7.
• Disrupted enterohepatic circulation in end-stage liver disease, leading to elevation of bile acids and induction of neuroinflammation 7.
• Manganese and zinc deposition, causing multiple psychomotor symptoms observed in HE 7.
• Gut environment, with toxins such as ammonia and inflammatory cytokines produced by impaired intestinal flora accessing the circulation through porto-systemic anastomoses and exacerbating or precipitating HE 7.