Portal Systemic Encephalopathy & Hepatic Encephalopathy

ESSENTIALS OF DIAGNOSIS

Diagnosis can often be made during physical examination by checking for fetor hepaticus and asterixis, and evaluating mental status using serial 7’s and the “A” deletion test.
Precipitating factors include gastrointestinal bleeding, sepsis, azotemia, sedative or analgesic use, and noncompliance with medications.
Consider other causes (eg, infections, intracranial bleeding, metabolic abnormalities), in patients with known cirrhosis and prior evidence of portal system encephalopathy who present with altered mental status.
Mental changes in patients with subclinical or minimal hepatic encephalopathy can impair automobile handling skills; patients and their families should be advised of this risk.

GENERAL CONSIDERATIONS

Hepatic encephalopathy, also referred to as portal systemic encephalopathy (PSE), is a complex neuropsychiatric disorder resulting from chronic parenchymal liver disease with liver cell failure, often in conjunction with portal systemic shunts, either naturally occurring or surgically created. However, PSE can occur in individual with normal liver tests or with large spontaneous or surgically created shunts. PSE is characterized by changes in personality, level of consciousness, motor function, and cognition. Changes in cognition may be quite subtle, as pointed out in the following discussion.

Hepatic encephalopathy can be characterized as being episodic or chronic resistant. The episodic form may be spontaneous, precipitated, or recurrent; in the chronic resistant form, patients have persistent mild stage 1–2 or severe stage 2–4 disease. Patients can have minimal or subclinical encephalopathy with no obvious abnormalities in cognition, personality, or behavior but with abnormal psychometric tests. Patients with advanced chronic liver disease and long-standing portal systemic shunting may also develop evidence of non-Wilsonian hepatolenticular degeneration.

PATHOGENESIS

Table 45–1 summarizes putative toxins that have been implicated in the pathogenesis of hepatic encephalopathy. Although the precise pathogenesis of hepatic encephalopathy is unknown, accumulation of nitrogenous products derived from the gut can have adverse effects on brain function and is believed to play a major role.

Table 45–1. Putative toxins causing hepatic encephalopathy.

Toxin	Effects and Treatment Considerations
Ammonia (NH₃)	Produced by intestine; of bacterial origin Blocks chloride channels Modulates GABA receptor Upregulates peripheral benzodiazepine receptors Increases brain glutamine Elevated in portal blood Elevated in peripheral blood and CSF Precipitating factors often increase NH₃/N₂ load Treatment strategies aim to decrease blood NH₃ levels
Naturally occurring benzodiazepines (BZDs)	Bind to benzodiazepine site of GABA receptor Elevated levels in blood and CSF BZD antagonists induce amelioration, albeit transient Unresolved issues—source and identity of actual BZDs; mechanism of increase in PSE is uncertain
Short-chain fatty acids	Synergistic effects with NH₃ causing obtundation Lactulose decreases levels Lack of correlation between plasma levels and grade of hepatic encephalopathy
Mercaptans	Synergistic effects with NH₃ Lack of correlation between plasma levels and grade of hepatic encephalopathy
Aromatic amino acids	Patients with liver failure have increased aromatic amino acids and decreased branched-chain amino acids False neurotransmitters are not found in human brain
Manganese	Probably involved in development of extrapyramidal signs Results from portal systemic shunting and reduction in biliary secretion

Ammonia produced by the intestine may enter the systemic circulation as a result of decreased hepatic function or portal systemic shunts. Once in brain tissue, it can block chloride channels, modulate the γ-aminobutyric acid (GABA) receptor, upregulate peripheral benzodiazepine receptors, and increase brain glutamine. Several lines of evidence support the concept that ammonia plays a key role in the pathogenesis of hepatic encephalopathy. Ammonia levels are elevated in portal blood, peripheral blood, and cerebrospinal fluid (CSF). Factors precipitating PSE are often those that result in an increased nitrogen load and elevated blood ammonia levels. Treatment strategies are aimed at decreasing gut production of ammonia as well as decreasing blood ammonia levels. It should be pointed out, however, that there is often not a direct correlation between peripheral blood and ammonia levels and stages of hepatic encephalopathy.

Another putative gut-derived naturally occurring mediator is a benzodiazepine-like compound. Elevated benzodiazepine levels have been found in blood and CSF. Benzodiazepine antagonists can ameliorate encephalopathy, although this effect is often transient.

Other putative mediators include short-chain fatty acids, mercaptans, aromatic amino acids, and manganese. Manganese may deposit in basal ganglia and induce extrapyramidal symptoms.

CLINICAL FINDINGS

A. Symptoms and Signs

1. Physical findings

The diagnosis of PSE often can be made on the basis of physical examination alone. Patients may have a fetor hepaticus; this is a pungent breath odor caused by the breakdown products of sulfur-containing amino acids such as cysteine and methionine and consisting of dimethyl sulfides methanethiol and ethanethiol. Asterixis or a metabolic flapping tremor is characteristic but not pathognomonic of PSE. It can also occur in patients with chronic renal failure, pulmonary failure, and congestive heart failure.

Patients with PSE can have focal neurologic abnormalities such as increased deep tendon reflexes, unilateral or bilateral Babinski sign, and other findings such as ataxia, dysarthria, tremor, or myopathy, usually with long-standing chronic systemic shunting. These are infrequently encountered clinically.