Introduction

Alterations in mental status, ranging from subtle neurocognitive deficits (minimal hepatic encephalopathy) to hepatic coma, commonly complicate end-stage liver disease. The pathogenesis is thought to be linked to elevated serum ammonia levels, attributable to the shunting of blood directly from the portal circulation into the venous system without exposure to hepatocytes that line the sinusoids. Thus the term portosystemic encephalopathy (PSE) is often used to reinforce the notion that shunting plays a key role. Low-grade cerebral edema is likely the underlying brain injury; however, unlike the hepatic encephalopathy of fulminant hepatic failure, PSE is not associated with significant elevations in intracranial pressure and is therefore not directly associated with mortality.

This section outlines a practical approach to PSE, both acute in onset and in patients who are chronically affected by this challenging problem.

Clinical Presentations of Portosystemic Encephalopathy

Following a 1998 consensus conference, hepatic encephalopathy has been classified into three types: acute, recurrent, or persistent. This classification is based on the underlying etiology. As most episodes of encephalopathy occur in patients with known cirrhosis, the focus will be on the recognition of this particular subtype.

Precipitating Factors and Their Management

Clinicians are commonly presented with the situation where a stable cirrhotic patient, often well-compensated, presents with the relatively rapid onset of neurological disturbance (as described above), which come under the umbrella of “hepatic encephalopathy”. In the majority of these instances a specific precipitant can be identified and treated; in only rare situations is PSE attributable to sudden worsening of the underlying chronic liver disease. As ammonia remains the leading candidate for a role in PSE, it is useful to start with conditions that may affect its serum levels.

Increased Ammonia Load

Ammonia remains the leading candidate as the agent implicated in hepatic encephalopathy, and serum levels are often measured as a result. While the information gained may be of some use in patients not already known to have liver disease, knowledge of the exact ammonia level rarely alters clinical decision making. Further, venous ammonia levels are of little use due to degradation of red blood cells; an arterial sample shipped on ice to the lab for prompt measurement should be obtained if the information is to be useful.

A sudden increase in arterial ammonia levels can be caused by gastrointestinal bleeding, dehydration, renal insufficiency, or, in relatively rare cases, dietary indiscretions (high protein intake). These conditions frequently coexist, and can be determined by history, physical examination, and blood tests, and appropriate treatments instituted (which are beyond the scope of this chapter).

Constipation

Constipation alone can precipitate PSE, and in patients with a history of well-controlled encephalopathy this may be due to non-compliance with lactulose therapy. In addition, medications that cause constipation (narcotics, for example) can aggravate PSE in addition to worsening it through direct central nervous system effects (see below).

Infections

Bacterial infections are the most common cause of death in patients with cirrhosis and they are implicated in PSE. In sepsis, hemodynamic disturbances with associated renal dysfunction may further worsen PSE. In patients presenting with the abrupt onset of encephalopathy, even if a fever is absent, investigations should include an ascitic tap with fluid analysis for cell count and cultures, as well as urine and blood cultures, sputum cultures if appropriate, and chest X-ray. A low threshold for the introduction of broad-spectrum antibiotics should be observed until a specific etiology has been determined.

Electrolyte Disturbances

Cirrhotic patients commonly receive diuretics, which can precipitate hyponatremia, hyperkalemia, and acid–base disturbances. The former is particularly associated with new onset or worsening of already present PSE, thus regular monitoring of renal function and electrolyte levels in patients receiving diuretics is very important.

Medications

Any medication that can cause sedation is more likely to do so in patients with cirrhosis. These include benzodiazepines, opioids, antihistamines, some antinauseants, cough suppressants (which contain codeine), and drugs such as chlordiazepoxide. Patients with cirrhosis and their care-givers should be cautioned to avoid or minimize the use of such medications.

Acute Brain Injury

Although focal neurological symptoms or signs are certainly seen in patients with PSE, such as a transverse myelitis or a parkinsonian-like illness, they are relatively uncommon. CT of the brain should be performed if focal deficits are present. Intracranial bleeding may occur spontaneously or in response to minor trauma in coagulopathic cirrhotic patients. Many patients with alcoholic cirrhosis have a history of falls, and a chronic subdural hematoma may present with symptoms difficult to distinguish from PSE. In such patients, brain computed tomography should be performed if a clear precipitant of PSE has not been readily identified.

Worsening Liver Disease

Although an uncommon cause of PSE, patients with established cirrhosis may have sudden deterioration in liver function. This can be due to a toxic injury (alcohol, drugs), to portal vein (or, less commonly, hepatic vein) thrombosis (and one must think of a complicating hepatocellular carcinoma in this scenario), or following a general anesthetic for what would ordinarily be considered “minor” surgery (a hernia repair is a common example). A thorough history and the appropriate imaging should help to exclude these possibilities.

Specific Measures to Treat Portosystemic Encephalopathy

Diet

Dietary protein restriction was at one time commonly instituted in patients with PSE. It is now clear that it can worsen nutritional status in cirrhotic patients, and is no longer recommended. Protein intake of 0.8 to 1.0 g/kg/day is generally sufficient to maintain normal nitrogen balance. It may be appropriate to recommend reduction in protein from more dense sources (red meats, for example) and their substitution with vegetable proteins, that is protein “modification” rather than restriction.

Drug Treatment

Lactulose has been the mainstay of PSE treatment for many years (Box 8.1). It works to reduce ammonia both via a direct osmotic laxative effect and via the lowering of stool pH. It is typically given at a dose of 20 g once or twice daily and titrated to achieve two to three loose bowel motions per day. In patients whose level of consciousness or state of agitation does not permit oral dosing, lactulose can be given in enema form, typically as a 30% solution (300 mL of lactulose brought up to a liter with tap water). Lactulose should not be given by a nasogastric tube in comatose patients as lactulose can cause severe lung damage if it is aspirated.