General Measures In the patient seeking medical attention with new onset HE, or an increase in a chronic condition, several questions must be promptly addressed, including:
Does the patient’s mental decline reflect HE or another condition? As mentioned previously, HE is in essence a diagnosis of exclusion so, particularly in patients with hepatic coma, other conditions that affect normal brain function should be excluded. An elevated blood ammonia level may be helpful in confirming the diagnosis of HE.
What if any factors contributed to development of HE in the patient? Non-compliance with therapy (especially lactulose), use of prescription sedatives and narcotics, gastrointestinal bleeding, infection, and constipation are potential causes of HE that should be identified and treated quickly.
Should the patient be monitored in an ICU setting, and possibly have an endotracheal tube placed to protect the airway and prevent aspiration, due to severe HE? Severe encephalopathy may culminate in full blown coma, at which point the patient may be at risk for aspiration.
Once the patient recovers, should driving and other high-risk activities be restricted? Several studies now clearly demonstrate that patients with liver disease and HE, even if “minimal”, have impaired driving fitness when 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. 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, HE is a sign of advanced and decompensated liver disease, Although medical therapy usually improves symptoms of chronic HE, the overall prognosis remains poor and appropriate patients without medical or other factors to the contrary to being eligible for a transplant should be promptly referred to a liver transplant program for evaluation.
The focus of the discussion here is on the treatment of HE in the setting of chronic liver disease (cirrhosis). HE is required for the diagnosis of acute liver failure, and although many of the features may be similar, including a critical role of toxins, the natural history and treatment of the disorder is distinct.
Diet In the past, great emphasis has been placed on the role of restricting dietary protein in patients with HE. 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. Diets that severely restrict protein should be avoided, except perhaps during an acute flair up of HE 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. Vegetable protein generally has a lower content of certain types of amino acids that may be metabolized by bacteria in the colon into compounds that contribute to HE. 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. Patients with established malnutrition may benefit from more intensive nutritional support.
Lactulose Lactulose has been a mainstay of therapy for HE for several decades. Intestinal bacteria degrade synthetic sugars 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 toxin production and improve symptoms of HE by several mechanisms, including:
Lactulose acts as a laxative by creating an 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 appears to promote movement of toxins from the blood stream into the colon.
Lactic acid may also inhibit colonic bacteria that produce toxins.
Lactulose is typically prescribed differently from one patient to the next in the amount of lactulose required to improve symptoms of HE. 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. Your doctor should spend adequate time with patients and their families outlining the pathogenesis of HE. The rationale for and appropriate dosing of lactulose helps improve compliance with and effectiveness of lactulose therapy. Since compliance with therapy is important for a beneficial effect, this discussion will 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 HE. This is particularly true if the patient continues to work and does not have ready access to the bathroom.
Rifaximin Rifaximin (Xifaxan) is a non-absorbable antibiotic was approved by the FDA for treatment of traveler's diarrhea and HE. It does not cause the troublesome diarrhea and bloating that is often associated with lactulose. Rifaximin is often prescribed for use WITH lactulose for patients that have extreme HE. Unfortunately, it is also quite expensive, it can be difficult to obtain for insurance reasons. Of course, if the drug prevents hospitalization for HE, it will likely prove to be cost effective in patients with encephalopathy. The most appropriate dosing of rifaximin 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). Several antibiotics have been used in addition to rifaximin, including metronidazole, oral vancomycin, paromomycin, and oral quinolones.
Zinc Deficiency of zinc is common in patients with cirrhosis. Zinc sulfate and zinc acetate have been used several clinical trials with mixed results. HE improved in 2 studies, while there was no improvement in mental function in 2 other studies. The main side effect of short-term therapy with zinc is gastrointestinal upset.