Hepatic Encephalopathy

Introduction

Hepatic encephalopathy (HE) is defined as “a condition which reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease.”1 In clinical practice, the prevalence of this disorder ranges from 30% to 50% in patients when diagnosed clinically.2 Several other clinical conditions, such as alcoholic brain damage, extra-pyramidal consequences of liver disease, depression, and fatigue, are often diagnosed as HE given the nonspecificity of this clinical diagnostic pathway.3 This is a formidable challenge in research and in clinical assessment of patients because there is immense subjectivity in the diagnostic strategies for hepatic encephalopathy clinically.4

Description

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome characterized by the global depression of central nervous system (CNS) activity, with a gradual deterioration of higher mental and motor functions (Table 1). The syndrome is associated either with acute liver failure, commonly precipitated by drug overdose or viral hepatitis, or with chronic liver failure, frequently caused by alcoholic cirrhosis. Liver disease is the fourth largest cause of death in Americans between 45 and 54 years of age, and HE (including minimal HE) is associated with 50–70% of all patients with cirrhosis. Moreover, HE is more prevalent in nations with higher rates of liver disease than occur in the United States.

Table 1. Clinical stages of HE

Stage	Mental state	Neuromuscular state
I	Mild confusion, euphoria, depression, decreased attention, slowed analytical ability, irritability, sleep inversion	Mild incoordination, impaired handwriting
II	Drowsiness, lethargy, gross deficits in analytical ability, obvious personality changes, inappropriate behavior, intermittent disorientation; electroencephalogram abnormalities (high-amplitude, low-frequency waves with nonfocal changes)	Asterixis, ataxia, dysarthria, paratonia, apraxia
III	Somnolent but rousable, unable to perform analytical tasks, disorientation with respect to time and/or place, amnesia, rage, slurred speech	Hyperreflexia, muscle spasticity, Babinski’s sign present, seizures (rare)
IVA	Coma	Thalamic–subcortical spasticity of entire body; no response to painful stimuli
IVB	Deep coma	Death imminent

Although HE has been recognized since the beginning of recorded medical history, the precise pathogenic mechanisms responsible for the syndrome remain complex and poorly defined. Thus, the modalities for treating HE are still evolving. A profusion of metabolic abnormalities and gut-derived toxins result from hepatic failure, resulting in significant alterations in neurotransmission and CNS energy metabolism, superimposed upon a characteristic astrocyte pathology (Alzheimer type II degeneration). Thus, it is difficult to ascribe the neurological and psychiatric manifestations of HE to the presence of a single agent or to changes in a particular metabolic pathway. However, since HE is a metabolic encephalopathy, with few neuroanatomical abnormalities observed in patients who die of either acute or chronic liver failure, it has the potential to be completely reversible.

The neurological manifestations of HE (Table 1) are determined by two principal components of the underlying liver disease: hepatocellular failure and systemic shunting of portal venous contents (Figure 1). Normally, potentially neurotoxic substances are absorbed from the gut and detoxified by the liver. However, in hepatocellular failure these agents may avoid catabolism by passing through the diseased liver unmetabolized and into the systemic circulation (portal–systemic shunting). Alternatively, these toxins may bypass the liver altogether and enter the systemic circulation through portal-venous shunts that are either surgically constructed, or formed spontaneously as a result of portal hypertension associated with cirrhosis. Once these gut-derived substances reach the brain, they modify CNS function either by altering metabolic processes such as oxidative metabolism or neurotransmitter synthesis, or by interacting directly with neurotransmitter receptors.

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Figure 1. The concept of portal–systemic shunting as it contributes to the development of HE. Nitrogenous substances arising from the gastrointestinal (GI) system normally are absorbed into the portal venous system and delivered to the liver, where they are extracted and metabolized. However, in liver disease these substances may pass directly into the systemic circulation or bypass the liver completely via portal–venous shunts. Once these compounds enter the systemic circulation, they may gain entry to the central nervous system (CNS) by a variety of mechanisms, including high-capacity active transport or facilitated diffusion, resulting in abnormal brain function. Reprinted from Basile AS, Jones EA, Skolnick P, et al. (1991) The pathogenesis and treatment of hepatic encephalopathy: Evidence for the involvement of benzodiazepine receptor ligands. Pharmacological Reviews 43: 27–71, with permission of the American Society for Pharmacology and Experimental Therapeutics.

Classification

The nomenclature of hepatic encephalopathy (HE) has been a source of confusion, with some terms implying different meanings to different investigators. A new classification of HE takes into account both the type of hepatic abnormality and the duration/characteristics of HE symptoms, categorizing HE in groups and subgroups:

• a.

• Encephalopathy associated with acute liver failure (type A, for acute).

• b.

• Encephalopathy associated with portal–systemic bypass and no intrinsic hepatocellular disease (type B, for Br-pass).

• c.

• Encephalopathy associated with cirrhosis and portal hypertension and/or portal–systemic shunts (type C, for cirrhosis).

We can divide type C further into:

• c.1.

• Episodic HE. Subdivided into precipitated and spontaneous, depending on the presence of precipitating factors. “Recurrent encephalopathy” refers to the occurrence of at least two episodes of episodic HE within 1 year.

• c.2.

• Persistent HE. Includes cognitive deficits that impact negatively on social and occupational functioning, and is subdivided into mild and severe. Treatment-dependent persistent HE is a subgroup in which overt symptoms develop promptly after discontinuing medication.

• c.3.

• Minimal HE. Refers to abnormalities of cognition, affection/emotion, behavior, or bioregulation that are not usually detected by regular clinical examination; diagnosis requires specific neuropsychological and neurophysiological tests.