Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a common and debilitating complication of cirrhosis, and is characterized by cognitive impairment which occurs as the consequence of a complex series of alterations in brain functioning due to impaired liver function and portosystemic shunting. Although the pathophysiology of HE remains incompletely understood, there are several prevailing hypotheses to explain the biological origins for the distinct behavioral, cognitive, and motor changes seen in patients with chronic liver disease.

The most commonly recognized hypothesis stems from observing that increased concentrations of ammonia in the central nervous system (CNS) occur as a consequence of the failure of the cirrhotic liver to metabolize nitrogen-containing compounds, and thereby result in toxicity to neurons with associated cognitive deficits. Altered ammonia metabolism certainly plays an important role in HE, also known as portosystemic encephalopathy (PSE), as proven by the beneficial effects of serum ammonia reduction through pharmacotherapy on symptom improvement. However, elevated serum ammonia concentration is not necessary for PSE to occur, and there is no direct linear relationship between serum ammonia levels and symptom severity; in fact, patients with cirrhotic and noncirrhotic liver disease may have elevated serum ammonia levels in the absence of clinical PSE. Other hypotheses involve the role of other neurotransmitters such as γ-aminobutyric acid (GABA), glutamate, opiates, or GABA-induced benzodiazepine-like compounds.

A common pathway to HE is the development of early cerebral edema, astrocyte swelling, and oxidative stress in the brain which is associated with the production of reactive oxygen and nitrogen species. In addition, disruption of oscillatory networks in the brain has been demonstrated in PSE patients on magnetoencephalography and may underlie their cognitive and motor abnormalities.

There are multiple well-established risk factors which may precipitate HE, including volume depletion/dehydration, infection, gastrointestinal (GI) bleeding, constipation, electrolyte imbalance, or use of CNS depressants, particularly narcotics and benzodiazepines. GI bleeding is a particularly common cause of PSE due to the combination of nitrogen-rich blood to the gut and volume depletion.

Clinical Picture

The clinical presentation of HE can be quite variable and includes a spectrum of mental states, ranging from mild alterations (e.g., sleep/wake reversal, change in mood, and forgetfulness) to progressive degrees of lethargy, obtundation, and coma, as classified in the West Haven criteria. In the most serious stage of PSE, patients may develop a deep coma stemming from progressive cerebral edema, and eventually brainstem herniation ( Fig. 151.1 ), which is characteristically observed in patients with acute or fulminant liver failure, although this may be seen in patients with acute on chronic liver failure.

The four grades within the West Haven criteria are summarized in Table 151.1 . Grade 4 encephalopathy is associated with an increased risk for severe cerebral edema, and therefore requires close clinical monitoring in an intensive care unit.

TABLE 151.1

Grading/Staging System for Hepatic Encephalopathy

Grade	Characteristics
1	Altered sleep patterns, altered mood, irritability, inability to maintain attention
2	Lethargy, altered speech, increased memory loss, dysarthria
3	Progressive stupor, decreased level of consciousness, but responsive to stimuli
4	Coma, unresponsive to painful stimuli

Physical examination findings of PSE may be subtle. The most common clinical sign associated with PSE is asterixis, which reflects an irregular myoclonic lapse of posture with loss of muscle tone. A characteristic “flap” (see Fig. 151.1 ) or “liver flap” may be seen when patients are asked to extend their arms, dorsiflex the wrists, and spread their fingers. In patients who are unable to participate in this exam maneuver, the presence of diffuse clonus may also signal the presence of PSE. Although not universally present, the presence of a musty, fruity odor on a patient's breath, called fetor hepaticus, may also signal PSE.

Although the focus of the diagnosis and management of HE is on clinically overt disease, there has been increasing recognition of a subclinical form called minimal hepatic encephalopathy, previously described as “subclinical hepatic encephalopathy.” Obvious clinical symptoms or exam findings may be lacking, although increasing data support an association between minimal HE and clinical outcomes including decreased attention span, decreased driving skill, and reduced quality of life. Lactulose therapy has been shown to improve clinical symptoms and quality of life in some patients with HE.