Hepatic Encephalopathy

Author: Dr Tim Davern California Pacific Medical Center 2008-08-12

What is hepatic encephalopathy?

Hepatic encephalopathy is a potentially reversible disturbance of brain function due to liver (hepatic) failure. The syndrome is characterized by a broad spectrum of neuropsychiatric derangements including personality changes, intellectual impairment, and a depressed level of consciousness, and appears to be the result of neurotoxins that accumulate with liver failure.  Ammonia, which is usually metabolized by the liver, is a critical neurotoxin in the development of hepatic encephalopathy, but other toxins are also involved. The neuropsychiatric manifestations of hepatic encephalopathy are reversible with appropriate medical therapy, but the syndrome is a hallmark of advanced, decompensated liver disease and has an overall poor prognosis. Thus, certain patients with hepatic encephalopathy should be referred for liver transplantation.

Hepatic encephalopathy has a variety of symptoms, from very subtle cognitive impairment to full-blown coma. At the mild end of the spectrum, the term minimal encephalopathy refers to patients with cirrhosis who do not display clinically evident cognitive abnormalities, but who demonstrate cognitive impairments with formal neuropsychological testing. Despite its subtlety, minimal hepatic encephalopathy is an important diagnosis, as it has been associated with a reduced quality of life as well as impaired driving skill.

By definition, hepatic encephalopathy is an essential feature of acute liver failure (see knol on "Acute Liver Failure"). Although some of the clinical features of hepatic encephalopathy in acute and chronic liver failure are similar, advanced encephalopathy in acute liver failure is a harbinger for the development of brain swelling (cerebral edema), which is very rare in chronic liver disease. The focus of this knol is hepatic encephalopathy complicating chronic liver disease (cirrhosis).

What causes hepatic encephalopathy?

The pathogenesis (cause) of hepatic encephalopathy is complex and not completely defined, but it is clear that nitrogenous wastes, particularly ammonia, derived from the gut play a major role in the observed disruptions of brain function. Bacteria residing in the large bowel (colon) produce ammonia that is absorbed into the bloodstream leading to the liver. Under normal circumstances, ammonia is efficiently detoxified in the liver so that relatively little escapes into the general circulation bathing the brain. However, with advanced liver disease, whether acute or chronic, the detoxification of ammonia and other toxins by the liver fails, and they accumulate in the blood and disturb brain function. This failure results in part from an inadequate mass of normally functioning liver cells (hepatocytes), and also from a propensity of blood to shunt (short circuit) around the liver with advanced liver disease, particularly cirrhosis. For example, hepatic encephalopathy is one of the most frequent complications of a transjugular intrahepatic portosystemic shunt (TIPS), a device that can be placed in patients with cirrhosis to control severe gastrointestinal bleeding or fluid retention. With TIPS placement, blood from the portal vein containing relatively high levels of ammonia and other toxins passes through the shunt placed within the liver rather than percolating through the liver itself, as it normally does. Importantly, although ammonia plays a central role in the pathogenesis of hepatic encephalopathy, several other putative toxins have also been implicated, including chemicals called mercaptans as well as others.

Although the underlying pathogenesis of hepatic encephalopathy remains unclear, a number of precipitants (or triggers) that exacerbate underlying encephalopathy have been clearly defined. Such precipitants are important to rapidly identify and treat because without specific and effective intervention, the patient’s encephalopathy may not improve. Common precipitants that may trigger an episode of severe hepatic encephalopathy in patients with otherwise stable liver disease include:

• Infection: Although infection involving almost any site, including the urinary tract and lungs, many trigger hepatic encephalopathy in patients with advanced cirrhosis, infection of ascites (abdominal fluid) - called spontaneous bacterial peritonitis (SBP) - is one of the most frequent triggers of encephalopathy. Sampling ascites fluid using a needle, a procedure called paracentesis, is required to determine if SBP is present.
• Gastrointestinal bleeding: Patients with cirrhosis frequently suffer from bleeding in the digestive tract, usually from dilated veins in the esophagus (esophageal varices).  Digested blood represents a large protein load in the gut which can lead to higher levels of ammonia and other toxins  and, not surprisingly, hepatic encephalopathy is frequent in this setting.
• Medications: Drugs that suppress the central nervous system, particularly opiate pain medications (e.g., codeine) and benzodiazepines (e.g. diazepam, lorazepam), may trigger hepatic encephalopathy.
• Electrolyte problems: Low serum sodium (hyponatremia) and potassium (hypokalemia) are common in cirrhotic patients treated with diuretics and both can worsen hepatic encephalopathy. Hypokalemia appears to exacerbate encephalopathy in part by stimulating ammonia production from the kidneys.
• Dietary indiscretion: Excessive consumption of protein, particularly from large red meat meals, seems to exacerbate hepatic encephalopathy in occasional patients, but this appears to represent a relatively rare trigger of severe encephalopathy.
• Constipation: Slow transit of stool through the gut appears to increase the time for bacteria digest foodstuffs and make ammonia and other toxins, potentially triggering hepatic encephalopathy.
• Kidney failure: Dehydration from diuretic therapy and diarrhea, infection, some medications, and progression of liver disease can all lead to kidney failure, which in turn leads to decreased clearance of urea, ammonia, and other toxins that can contribute to encephalopathy.
• Other factors: A rise of blood pH (alkalosis), which often results from diuretics and resulting dehydration, may facilitate entry of ammonia into the brain and exacerbate encephalopathy.

What are the symptoms of HE?

Patients suffering hepatic encephalopathy may come to the doctor with a spectrum of symptoms. In mild cases, called minimal hepatic encephalopathy, the patient may have no symptoms but have cognitive deficits revealed by formal neuropsychiatric testing (e.g., number connection tests, etc.). With more advanced hepatic encephalopathy, fatigue, and at least mild deficits of memory, concentration, and coordination may become apparent. At this stage, common complaints by the patient include:
- “I feel like my head is in the clouds.”
- “I’ll walk into a room and forget why I am there.”
- “I am always tired…but I can’t sleep.”
- “I often forget what to say in mid-sentence.”
- “My boss is telling me that my work is slipping.”
- “My handwriting has changed to scribble,”
- “My hands shake so much, I can’t hold my coffee cup without spilling it.”

Nighttime insomnia is a very common and troublesome symptom associated with hepatic encephalopathy. In fact, patients with encephalopathy may ultimately sleep more during the day, with fitful naps, than at night, and this “day-night reversal” is a hallmark of more advanced hepatic encephalopathy. Family and friends frequently notice a deterioration of the patient’s cognitive function as well as a change in the patient’s personality—with frequent irritability, bouts of anger, and loss of social graces. They may also witness firsthand deterioration of the patient’s driving skills (“He would have run off the road if I hadn’t grabbed the wheel!”).

Two of the most common physical (as opposed to subjective) manifestations of hepatic encephalopathy are asterixis and fetor hepaticus. Asterixis is a non-synchronous and coarse tremor– known colloquially as a “liver flap” – that is best elicited by asking the patient to outstretch the hands with straight elbows, wrists cocked at 90 degrees, and fingers spread apart, instructions easily communicated with the command, “Stop traffic!” Although such a tremor is not specific for hepatic encephalopathy (it can also be seen with renal failure and other conditions), it certainly suggests the diagnosis in patients with liver disease. Fetor hepaticus is a musty sweet odor that is usually evident by casually sniffing the patient’s breath.

When symptoms of hepatic encephalopathy progress, the patient may slip into a stupor or even comatose state and be virtually unarousable. Such situations are medical emergencies, and the patient should be brought to medical attention immediately.

How is hepatic encephalopathy diagnosed?

Although it has some fairly distinct signs and symptoms (see above), hepatic encephalopathy is a diagnosis of exclusion because numerous other conditions can cause similar neuropsychiatric symptoms, including metabolic problems (e.g., hypoglycemia, renal failure), cerebral vascular accidents (stroke), drug toxicity (alcohol, narcotic, or benzodiazepine overdose), and infection (encephalitis, meningitis). Thus, patients with signs and symptoms of significant hepatic encephalopathy, particularly when acute in onset, will typically undergo blood testing (complete blood count, blood glucose, electrolytes, toxicology screen, liver and kidney function tests) and often a head CT (to exclude bleeding or other structural problems). However, treatment, most often with lactulose (see below), will usually also be started while awaiting results of these studies when the diagnosis of hepatic encephalopathy is suspected.

If present, an elevated blood ammonia level is helpful to confirm a diagnosis of hepatic encephalopathy, but a normal level does not completely rule out the diagnosis. Arterial blood samples for ammonia are probably more reliable than venous samples, and the blood should be processed without excessive delay in order to obtain accurate results. Following serial ammonia levels on patients with known hepatic encephalopathy, particularly in the outpatient setting, is of limited value.

Patients with minimal hepatic encephalopathy have few if any clinically overt signs and symptoms of the disorder. The diagnosis currently rests on formal neuropsychiatric testing, although ongoing research is focused on developing clinical tools to simplify and streamline the diagnosis.

What is the prognosis of hepatic encephalopathy?

Hepatic encephalopathy is a manifestation of advanced liver disease and as such is associated with a poor prognosis. Patients who have hepatic coma have a significant in-hospital mortality, often from aspiration (drawing stomach content into the lungs), infection, respiratory and multi-organ failure, while those with lesser degrees of hepatic encephalopathy still have a greater than 50% chance of dying within a year. Because of this, patients with hepatic encephalopathy should be referred for liver transplant if they are otherwise acceptable candidates (see Liver Transplant knol). 

Patients with minimal hepatic encephalopathy are at significant risk for developing more severe, clinically obvious encephalopathy within a year or two of diagnosis. Even before this progression, they may experience a decreased quality of life, suffer impaired driving skills, and be at risk for driving accidents. Whether early treatment of patients with minimal hepatic encephalopathy may forestall progression to clinically overt hepatic encephalopathy is currently being studied.

How is hepatic encephalopathy treated?

General Measures:

In the patient seeking medical attention with new onset hepatic encephalopathy, or an exacerbation of a chronic condition, several questions must be promptly addressed, including:

• Does the patient’s mental decline reflect hepatic encephalopathy or another condition? As mentioned above, hepatic encephalopathy is in essence a diagnosis of exclusion so, particularly in patients with hepatic coma, other conditions that affect normal brain function should be excluded. These are outlined above. An elevated blood ammonia level may be helpful in confirming the diagnosis of hepatic encephalopathy.
• What if any factors (precipitants) contributed to development of hepatic encephalopathy in the patient? Non-compliance with therapy (especially lactulose – see below), use of prescription sedatives and narcotics, gastrointestinal bleeding, infection, and constipation are potential precipitants that should be identified and treated quickly.
• Should the patient be monitored in an ICU setting, and possibly have an endotracheal tube prophylactically placed to protect the airway and prevent aspiration, due to severe hepatic encephalopathy? Severe encephalopathy may culminate in full blown coma, at which point the patient may be at risk for aspiration of gastric contents.
• Once the patient recovers, should driving and other high-risk activities be restricted? Several studies now clearly demonstrate that patients with liver disease and hepatic encephalopathy, even if “minimal”, have impaired driving fitness when rigorously tested by a qualified driving instructor. Such patients may represent a clear and present danger to themselves as well as others if they continue to drive despite recommendations to refrain from driving. Whether such patients should be reported to the DMV should be considered on a case-by-case basis. Ethical dilemmas also arise when the encephalopathic patient insists on continuing to work despite having an occupation that potentially puts others at risk (e.g., surgeon, police officer, airline mechanic, school bus driver, etc.).
• Should the patient be referred for liver transplantation? As mentioned above, hepatic encephalopathy is a sign of advanced and decompensated liver disease, Although medical therapy (described below) usually improves symptoms of chronic hepatic encephalopathy, the overall prognosis remains poor and appropriate patients without medical or psycho-social contraindications to transplant should be promptly referred to a liver transplant program for evaluation (see Liver Transplant knol).

The focus of the discussion here is on the treatment of hepatic encephalopathy in the setting of chronic liver disease (cirrhosis). Hepatic encephalopathy is required for the diagnosis of acute liver failure, and although many of the features may be similar, including a critical role of ammonia, the natural history and treatment of the disorder is distinct (see ALF knol).

Diet

In the past, great emphasis has been placed on the role of restricting dietary protein in patients with hepatic encephalopathy. The appeal of this idea is clear: reducing the amount of dietary protein will reduce the amount that reaches the colon and is thereby available for metabolism to ammonia by bacteria residing there. Animal experiments in the late 19th century also seemed to support this idea. When dogs with surgically created portosystemic shunts (impairing the ability of the liver to handle ammonia) were fed high protein diets, they developed abnormal behavior, impaired motor coordination, and ultimately stupor, similar to progressive hepatic encephalopathy in humans. Anecdotally, large protein meals (e.g., steak feasts) can also be associated with a reproducible decline in mental function in some patients with cirrhosis and chronic hepatic encephalopathy. However, severe protein restriction in such patients predictably results in progressive muscle wasting and malnutrition, which in turn have a poor outcome. Importantly, profound malnutrition is considered a contraindication to liver transplantation. Thus, diets that severely restrict protein should be avoided, except perhaps during an acute exacerbation of hepatic encephalopathy in a hospitalized patient in whom a brief period of protein deprivation may be appropriate.

As a rule, patients with cirrhosis and encephalopathy should receive adequate protein to prevent muscle loss, typically between 60-80 grams of protein per day. Consuming diets that are rich in vegetable proteins appears to be better tolerated in many patients than diets with abundant animal protein, especially from red meats. This probably reflects that such high fiber diets act as natural cathartics and thus decrease the exposure time of bacteria in the colon to dietary protein. Furthermore, vegetable protein generally has a lower content of certain types of amino acids (aromatic amino acids) that may be metabolized by colonic bacteria into compounds that contribute to hepatic encephalopathy. Supplementing a primarily vegetable diet with moderate amounts of well-cooked poultry and fish is acceptable; however, raw or undercooked shellfish (e.g., oysters) should be avoided to prevent infection with a number of pathogens, including Vibrio vulnificus, a rare but potentially serious infection in the setting of advanced cirrhosis. Patients with established malnutrition may benefit from more intensive nutritional support. Such patients may benefit from specialized treatment with oral or enteral supplements rich in branched-chain amino acids.

Lactulose

Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol), which is not available in the US, are non-absorbable disaccharides that have been a mainstay of therapy for hepatic encephalopathy for several decades. Both synthetic sugars are degraded by intestinal bacteria to lactic acid and other organic acids. Because humans lack the enzymes to split lactulose into its component sugars, it is not absorbed into the body, remains in the intestine, and ultimately arrives in the colon (large bowel) where bacteria normally living there can digest it. Lactulose appears to inhibit intestinal ammonia production and improve symptoms of hepatic encephalopathy by several mechanisms, including:

• Lactulose acts as a cathartic (causing emptying of the bowels) by creating an osmotic diarrhea, thereby decreasing both the bacterial load in the colon and the time that colonic bacteria have to metabolize protein into ammonia and other toxins.
• The conversion of lactulose to lactic acid by fermentation by colonic bacteria results in acidification of the gut lumen, which in turn appears to promote movement of ammonia from the blood stream into the colon.
• Gut acidification may also inhibit colonic bacteria that produce ammonia and lead to an increase in lactobacilli, which produce less ammonia.

Lactulose is typically prescribed as 2 tablespoons by mouth once or twice a day, although there is a large variation from one patient to the next in the amount of lactulose required to improve symptoms of hepatic encephalopathy. Likewise, some patients may not tolerate this standard dose due to diarrhea and bloating. Because of this, and the fact that lactulose is not absorbed from the gut and is generally quite safe, patients should be instructed to titrate (i.e., go up or down) on the dose so that they have 2 to 4 loose bowel movements a day. Indeed, the author believes that devoting adequate time with patients and their families outlining the pathogenesis of hepatic encephalopathy and the rationale for and appropriate dosing of lactulose helps improve compliance with and efficacy of lactulose therapy. Since compliance with therapy is important for a beneficial effect, this discussion should be reiterated at follow-up appointments.

Unfortunately, lactulose has a number of potentially troubling gastrointestinal side effects including diarrhea (which may be explosive and even lead to incontinence), flatulence, and abdominal cramping. These undesirable symptoms can contribute to noncompliance and exacerbations of hepatic encephalopathy. This is particularly true if the patient continues to work and does not have ready access to the bathroom. In such cases, alternative treatments (e.g., rifaximin) should be used if possible.

Rifaximin

Rifaximin (Xifaxan, Salix Pharmaceuticals, Inc, Morrisville, NC) is a nonabsorbable antibiotic, which is a derivative of the anti-tuberculous drug, rifampin, was approved approximately 4 years ago by the FDA for treatment of traveler's diarrhea. However, it had been used for over a decade quite successfully in Europe for treatment of chronic hepatic encephalopathy, as well as other conditions. Several clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day is as effective as lactulose (or lactilol) at improving symptoms of hepatic encephalopathy, and is quite safe and well tolerated by patients. In particular, it does not cause the troublesome diarrhea and bloating that is often associated with lactulose. Unfortunately, because it is not currently FDA-approved for hepatic encephalopathy and is also quite expensive (i.e., as much as $800 per month of therapy), it can be difficult to obtain for insurance reasons. Of course, if the drug prevents hospitalization for hepatic encephalopathy, it will likely prove to be cost effective in patients brittle encephalopathy. The most appropriate dosing of rifaximin (i.e., 400 mg two or three times a day; continuously or with 1 week “holidays” each month) is not clear. It addition, it is not clear whether treatment with the drug may foster antibiotic-resistant bacteria.

The rationale for treatment with antibiotics such as rifaximin is that they kill bacteria present in the bowel and thereby reduce bacterial conversion of protein to ammonia (and other toxic substances) there. Several antibiotics have been used in addition to rifaximin, including neomycin, metronidazole, oral vancomycin, paromomycin, and oral quinolones. Although used frequently in the past, neomycin, a non-absorbable aminoglycoside antibiotic, is less frequently prescribed now due to the risk of hearing loss and kidney failure that can occur with prolonged use of the drug due to low level absorption from the gut. In my opinion, having cared for patients with sustained hearing loss and kidney failure attributed to prior neomycin therapy, the drug should not be used given the availability of safe and effective alternatives, including rifaximin.

Zinc

Zinc is an essential cofactor for the optimal activity of several enzymes involved in ammonia disposal. Deficiency of zinc is common in patients with cirrhosis. Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in several clinical trials with mixed results. Hepatic encephalopathy improved in 2 studies, while there was no improvement in mental function in 2 other studies. The main side effects of short-term therapy with zinc are gastrointestinal upset.

Acarbose

A recent small study from Italy examined the efficacy of the diabetic drug acarbose (Precose®) for treatment of mild hepatic encephalopathy in cirrhotic patients with type 2 diabetes. Acarbose treatment was associated with significant improvement in performance on neuropsychological tests and blood tests of ammonia level. The acarbose was generally well tolerated and not associated with serious side effects. Acarbose was thought to exert a beneficial effect on hepatic encephalopathy by promoting the proliferation of intestinal saccharolytic (sugar metabolizing) bacterial flora at the expense of proteolytic (protein digesting) bacterial flora.  Thus, acarbose may be a reasonable treatment choice for cirrhotic patients with type 2 diabetes and mild hepatic encephalopathy.

Other agents

A number of other agents have been studied for treatment of hepatic encephalopathy including benzodiazepine receptor antagonists (e.g., flumazenil), L-ornithine-L-aspartate (LOLA), L-carnitine, and sodium salts of benzoate, phenylbutyrate, and phenylacetate. In addition, some studies suggest that antibiotic eradication of the gastric bacterium, Helicobacteria pylori, which produces a small but potentially significant amount of ammonia as part of its life cycle, may also improve symptoms of refractory hepatic encephalopathy. However, none of these interventions for hepatic encephalopathy has become standard treatment in the US at the current time.

References

Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A (2002). "Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998". Hepatology 35 (3): 716-21.