Portal systemic encephalopathy

How can I be sure that the patient has portal systemic encephalopathy (hepatic encephalopathy)?

Portal systemic encephalopathy, or hepatic encephalopathy (HE), is a common problem observed in the setting of acute liver failure, surgical portosystemic shunts without chronic liver disease, or, most commonly, in the setting of chronic liver disease. Overt HE is distinguished from minimal hepatic encephalopathy (MHE) that is not diagnosed by clinical findings; rather, it is diagnosed only by specialized neuropsychometric and neurophysiologic testing. MHE is not discussed here.

Overt HE is characterized by a spectrum of clinical symptoms that are potentially reversible, including diminished mentation and neuromuscular abnormalities. Overt HE in the setting of portal hypertension and cirrhosis has no pathognomonic symptoms or signs: it may present with a wide spectrum of cognitive symptoms ranging from subtle alterations in attention span to disorientation to coma and death. The most common finding on physical examination in the noncomatose patient is asterixis, a flapping tremor.

The symptoms of HE may mimic other disease states, such as transient ischemic attacks (TIA)/cardiovascular accidents, intracranial hemorrhage (spontaneous or traumatic), brain tumors, post-ictal states, or other toxic metabolic encephalopathies, such as drug overdose and alcohol intoxication. Focal findings on neurological examination may be suggestive of an ischemic brain injury. A history of head trauma may be suggestive of intracranial hemorrhage. History of a seizure disorder or a recent witnessed seizure should raise the possibility of a post-ictal state. A possible suicide attempt should raise the question of medication-induced toxic encephalopathy. When there is reason for concern, testing should be performed on the patient with diminished mentation to exclude these entities.

The constellation of clinical features of overt HE is wide. Symptoms range from shortened attention span, impaired addition and subtraction, and sleep disturbance (Grade 1) to disorientation, inappropriate behavior, lethargy, slurred speech, and personality changes (Grade 2) to gross disorientation and somnolence (Grade 3) to coma with little, if any, response to noxious stimuli.

A tabular or chart listing of features and signs and symptoms

Clinical signs and symptoms of hepatic encephalopathy

West Haven criteria Precipitating factors for hepatic encephalopathy

Grade 1 Trivial lack of awareness, shortened attention span, sleep disturbance, altered

mood

– Asterixis may be present.

Grade 2 Lethargy, disorientation to time, amnesia of recent events, inappropriate behavior, slurred speech, apathy, personality change

– Asterixis is present.

Grade 3 Somnolence, confusion, gross disorientation, bizarre behavior

– Asterixis usually absent. May see clonus, nystagmus, and/or positive Babinski sign.

Grade 4 Coma and lack of response to noxious stimuli

Differential diagnoses of hepatic encephalopathy

Transient ischemic event/cardiovascular accident

Intracranial hemorrhage

Brain tumor

Brain abscess

Meningitis/encephalitis

Toxic-metabolic, including accidental or intentional drug overdose

Alcohol intoxication or withdrawal

Post-ictal state

Hypoxia

How can I confirm the diagnosis?

The diagnosis of HE is usually a clinical one. Knowledge of the presence of chronic liver disease is helpful. HE is thought to occur in the setting of advanced liver disease and portal hypertension because gut-derived toxins (including ammonia) either are not metabolized by the injured liver or bypass the liver completely because of collateral formation as a result of portal hypertension.

Despite the chronicity of the underlying disease state, patients with HE are not symptomatic all of the time. In fact, symptoms may rapidly develop and then rapidly resolve with medical therapy. This is because HE is frequently characterized by a precipitating factor. The presence of a precipitating factor must be sought and treated. The presence of a precipitating factor supports the diagnosis.

Although ammonia is thought to be central to the pathogenesis of HE, serum ammonia levels are generally unhelpful in the setting of suspected HE. Patients with full-fledged HE may have normal or only mildly elevated ammonia levels, and patients without HE may have elevated ammonia levels. It is not appropriate to treat asymptomatic patients with elevated ammonia levels and, therefore, routine measurements of serum ammonia are NOT recommended.

In milder cases of HE, the presence of asterixis is helpful for diagnosis.

If other diagnoses are of concern, head CT/MRI should be performed to rule out an ischemic event or intracranial hemorrhage. EEG can be obtained if seizure activity is suspected. Lumbar puncture may be obtained if meningitis is of concern. A toxic screen should also be obtained.

Diagnostic tests

Blood tests

• Serum electrolytes and creatinine

• Phosphate levels

• Serum glucose

• Serum hemoglobin

• Serum alcohol levels

• Toxic screen

• Blood cultures

Urine culture

Physical examination

• Observe for signs of trauma.

• Vital signs, including temperature

• Focal neurological findings on examination

• Assess for asterixis and reflexes.

Chest film, PA, and lateral

• Consider head CT/MRI.

• Consider EEG.

Neuropsychometric and neurophysiologic tests are almost always unnecessary for diagnosis of overt HE.

What other diseases, conditions, or complications should I look for in patients with hepatic encephalopathy?

Precipitating factors

Common precipitating factors include dehydration and/or electrolyte abnormalities, constipation, upper GI bleeding, infection of any kind, including spontaneous bacterial peritonitis (SBP), or ingestion of psychoactive medications, such as narcotics, anti-depressants, anxiolytics, anti-histamines, and/or sedatives/sleeping medications. HE is also frequently observed in the setting of a transvenous intrahepatic portosystemic shunt (TIPS). Portal vein thrombosis and hepatocellular carcinoma may also precipitate HE. Excessive dietary protein intake may also be associated with acute HE. Most incidents of HE are associated with a precipitating factor. Such factors must be identified and treated.

If patients present with HE and an underlying diagnosis of advanced liver disease is not yet established, abdominal imaging should be obtained to visualize the liver and rule out hepatocellular carcinoma. A complete work-up to rule out causes of advanced liver disease should be undertaken. Upper endoscopy should also be performed to rule out esophageal and gastric varices in the setting of advanced liver disease and portal hypertension (thrombocytopenia).

Patients with HE are at increased risk for falling and may have traumatic injuries, including bone fractures and head injuries. They also are at increased risk for aspiration pneumonia.

What is the right therapy for the patient with hepatic encephalopathy?

Therapy of overt HE has two important components: (1) treatment of the acute event and (2) prevention of recurrence.

Treatment of acute event (initial therapy)

Identification and treatment of precipitating factors

Once a diagnosis of overt HE is confirmed, precipitating factors must be identified and treated. Patients on diuretics with hypovolemia may require gentle intravenous hydration despite the presence of fluid overload (edema and ascites). Electrolyte abnormalities must be identified and corrected, particularly hyponatremia.

Infection must be ruled out. Patients with ascites must undergo diagnostic paracentesis to rule out SBP. The only symptom of SBP may be HE. Urinary tract infection (UTI), pneumonia, cellulitis, or any other systemic infection may provoke a bout of HE. Blood cultures and urine analysis/cultures should be performed on patients with overt HE.

Patients with UGI bleeding from any source (gastroesophageal varices, portal hypertensive gastropathy, peptic ulcer disease, Mallory-Weiss tear, etc.) may have HE as a result of increased generation of ammonia from blood digested in the small bowel. Endoscopy should be performed and therapeutic intervention implemented if there is any concern for UGI bleeding in the patient with HE. Incidentally, patients with a source of bleeding in the LGI tract do not have HE because the blood is not digested. All psychoactive medications, including narcotics, anxiolytics, anti-depressants, anti-histamines, and sedatives, should be evaluated very carefully and withheld if possible because they may be contributory.

Ammonia reduction strategies

Increased clearance and decreased production. First-line therapy for treatment of HE in the U.S. is lactulose, a nonabsorbable disaccharide. Humans lack the intestinal disaccharidase to digest lactulose, and it passes through the small bowel to the colon. Colonic bacteria retain the ability to digest the sugar. Lactulose is metabolized to short-chain fatty acids in the colon. The result is a slight acidification of the colon with entrapment of bacterial-derived ammonia in the colon as poorly absorbed ammonium and increased colonic transit thought to impair bacterial ammonia production. Both mechanisms are thought to contribute to efficacy. Patients may rapidly improve from a symptomatic standpoint after a single dose of lactulose and subsequent bowel movement.

Decreased production. Antibiotics are second-line therapy for treatment of overt HE, either used in conjunction with lactulose in patients with severe HE or instead of lactulose in patients who do not tolerate lactulose. Antibiotics are thought to exert a beneficial effect by decreasing ammonogenic colonic bacteria and thereby reducing ammonia production. Many antibiotics have been used. The best data are for neomycin and rifaximin. In small studies, both have shown promise in the treatment of acute HE. Other antibiotics, including metronidazole and oral vancomycin, have also been used, although the data supporting this indication is weak.

Excessive protein intake is associated with HE by increasing ammonia production. Nevertheless, strict dietary restriction is NOT recommended as it is thought to expedite muscle wasting.

Acarbose is an oral hypoglycemic agent that decreases enteric glucose absorption. The subsequent presence of glucose in the gut alters the bacterial milieu such that ammonogenic bacteria are reduced, thereby reducing ammonia production. However, hypoglycemia is a possible consequence. Additional studies are required prior to routine use of this agent for overt HE.

Increased clearance. Sodium benzoate increases systemic ammonia clearance by increasing urinary secretion of hippurate. Data is preliminary and routine usage is not recommended.

L-ornithine L-aspartate (LOLA) increases systemic ammonia clearance by providing the substrate to convert ammonia to urea and glutamine. Data is preliminary and routine usage is not recommended.

Zinc is a cofactor in the urea cycle (that metabolizes ammonia). Zinc deficiency is observed in patients with advanced cirrhosis. Zinc sulfate should be considered in patients with HE and zinc deficiency.

Alteration of neurotransmission

Dopaminergic agents such as bromocriptine and branched chain amino acids (thought to provide a more favorable amino acid milieu in the CNS) have been advocated for treatment of HE; however, there is little data supporting usage of these agents in HE.

The benzodiazepine antagonist flumazenil has also been used in patients with severe HE and there was a short-lived improvement in a small minority of patients. However, the medication is only available in IV form. Because the beneficial effects are rare and transient, routine usage of flumazenil is not recommended. If patients with severe HE are thought to have a contribution from benzodiazepines, a diagnostic test to assess reversibility with flumazenil could be considered.

Prevention of hepatic encephalopathy recurrence

Although many of the medications used to treat acute HE are maintained after the patient returns to baseline to theoretically reduce recurrence, there is poor data to support efficacy of many of the commonly used approaches.

Lactulose

Lactulose has been first line for prevention of HE recurrence despite a paucity of data to support its use for this indication. There has been a high failure rate of lactulose noted on an anecdotal basis to prevent recurrent HE. This includes patients compliant with the medication.

Antibiotics such as neomycin and metronidazole have also been used to help prevent recurrence of HE. However, the efficacy of these agents is questionable for this indication. Furthermore, nephrotoxicity and ototoxicity are of concern with long-term use of neomycin, and neurotoxicity is of concern with usage of metronidazole.

Rifaximin

A recent randomized, controlled, multicenter placebo-controlled trial seeking to prevent recurrence of HE in a group of high-risk patients was recently published. The study enrolled patients at least 18 years old with chronic liver disease and histories of at least two bouts of definitive HE within the prior 6 months but at baseline mental status upon enrollment.

Patients received rifaximin or placebo for 24 weeks. Lactulose could be administered at the discretion of the investigator. The primary endpoint was recurrence of HE and the key secondary endpoint was hospitalization for recurrent HE. Ninety-one percent of patients in both groups received lactulose, and the amount taken was similar in the two groups.

Rifaximin reduced the rate of recurrent HE in the high-risk group by 58% over 24 weeks and the rate of hospitalization related to recurrent HE by 50%. The results were highly statistically significant. Furthermore, rifaximin was tolerated well with a side-effect profile similar to placebo.

At present, all patients with histories of HE should be treated with rifaximin to reduce the risk of recurrence. Patients may or may not receive concomitant lactulose after they return to baseline from the acute event at the discretion of the treating physician.

Dietary protein restrictions

Strict dietary protein restriction is not recommended. However, excessive protein ingestion should be avoided.

Precipitating factors for hepatic encephalopathy

Dehydration/hypovolemia

Electrolyte abnormalities

– Hyponatremia most common but also must correct potassium, calcium, and phosphate

abnormalities

Constipation

Infection/sepsis

– Spontaneous bacterial peritonitis

– Pneumonia

– Urinary tract infection

– Cellulitis

– Bacterial cholangitis

Upper GI bleeding

Psychoactive medications

– Narcotics

– Anxiolytics/benzodiazepines

– Antidepressants

– Antihistamines

– Sedatives/sleeping medications

Excessive protein intake

Portal vein thrombosis

Hepatocellular carcinoma

Therapeutic alternatives for the treatment of acute hepatic encephalopathy

Recommended

– Nonabsorbable disaccharides: lactulose

– Antibiotics: rifaximin, neomycin, metronidazole, oral vancomycin

Not routinely recommended

– Zinc sulfate

– Sodium benzoate

– L-ornithine L-aspartate (LOLA)

– Acarbose

– Bromocriptiine

– Flumazenil

Avoid

– Strict dietary protein restriction

What is the most effective initial therapy?

1. Exclude other medical conditions that may mimic HE.

2. Identify and correct precipitating factors.

3. Aggressive medical therapy

– Lactulose 30 cc (2 tablespoons) every hour until there is a bowel movement and/or clinical improvement. Then begin 30 cc (2 tablespoons) twice daily, with dose adjustments to maintain 3 to 4 watery bowel movements daily. Enemas (300 cc lactulose in 700 cc tap water) may be administered if necessary.

– Rifaximin 550 mg p.o. twice daily.

– Alternatively to lactulose, some literature suggests aggressive therapy with 4 liters of polyethylene glycol may lead to more rapid resolution of acute HE.

4. Dietary recommendations: 1-1.5 g/kg body weight protein is recommended.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Lactose

Lactulose should be dosed to yield 3 to 4 loose watery bowel movements daily. The effective dose is variable for each patient. In the acute setting, patients should be administered lactulose at a dose of 30 cc/hr until there is a bowel movement and/or clinical improvement. Thereafter, lactulose should be dosed at 30 cc twice daily. The following should be noted:

1. Lactulose dosage should be adjusted so that the patient has 3 to 4 watery bowel movements daily. The dosage may need to be adjusted on a daily basis by the patient in this regard. If a patient already has 3 to 4 bowel movements daily, he or she will likely be unable to take lactulose after resolution of the acute event.

2. If patients are deeply encephalopathic (including coma), lactulose should be administered by nasogastric tube or by enema (300 cc lactulose in 700 cc of tap water). Enemas may be useful to decrease the risk of aspiration pneumonia in patients with severe HE.

3. Lactulose is poorly tolerated over the long term. It has an extremely sweet taste. Furthermore, side effects include nausea, increased flatus, and severe diarrhea. In fact, diarrhea may cause hypovolemia and provoke HE on occasion. Many patients refuse to take it or are noncompliant with a regular schedule.

4. Patients may or may not be maintained on lactulose once they have returned to baseline mentation. This should be determined on an individual basis at the discretion of the treating physician.

Rifaximin

Rifaximin at a dosage of 550 mg twice daily should be administered in all patients who have had a bout of overt HE to help prevent recurrence. Fortunately, the side-effect profile is comparable to placebo.

Neomycin can be considered as an alternative to rifaximin (1 gm twice daily) if the patient cannot obtain rifaximin. The efficacy is unclear for prevention of recurrence of HE and close follow up to assess for possible nephrotoxicity and ototoxicity is mandated.

Treatment failure can be defined as inability to resolve HE or by frequent recurrence.

Inability to resolve hepatic encephalopathy

The clinician must revisit the diagnosis of HE and attempt to rule out other causes of diminished mentation. In addition, the clinician must revisit and determine whether all provocative factors for HE have been identified and treated properly. There are no other recommended treatment options for patients with refractory HE.

Frequent recurrence

The clinician must determine whether all provocative factors for HE have been identified and treated properly. If patients are on diuretics, diuretic dosages may need to be decreased or discontinued despite fluid overload. Psychoactive medications may need to be discontinued.

Medication compliance must be assessed and encouraged.

If a TIPS is in place, the clinician must consider narrowing or occluding the TIPS – if recurrent HE is incapacitating.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Neomycin is considered second-line therapy instead of rifaximin if rifaximin cannot be obtained. It should not be used in combination with rifaximin. Side effects, including nephrotoxicity and ototoxicity, must be monitored.

Zinc sulfate can be considered as an adjunct to first-line therapy (dosage 220 mg twice daily). It is generally well tolerated, although it can decrease intestinal absorption of other divalent cations such as copper.

Other medications are available but use is not recommended.

Listing of these, including any guidelines for monitoring side effects.

Second-line therapies for hepatic encephalopathy

• Neomycin if rifaximin cannot be obtained.

• Zinc sulfate if HE continues to recur despite aggressive medical therapy.

How should I monitor the patient with hepatic encephalopathy?

Patients with acute HE must be monitored closely until symptoms have resolved. If patients are somnolent or comatose, they may require mechanical ventilation to protect the airway. Patients who are less compromised may be hospitalized in the general inpatient unit.

Once patients return to baseline mentation, they should be monitored with frequent outpatient assessments. Patients should be evaluated in the outpatient setting at least every 3 months if there is a recent history of HE. Medication compliance, particularly with lactulose, should be assessed at each visit. Medication toxicity (excessive diarrhea on lactulose, nephrotoxicity, or ototoxicity on neomycin should be assessed).

HE in the setting of advanced liver disease confers a poor prognosis (<50% 1-year survival and <25% 3-year survival). If patients are liver transplantation candidates, a bout of HE should be sufficient for referral to a tertiary care center for liver transplantation evaluation.

What's the evidence?

Ferenci, P, Lockwood, A, Mullen, K. “Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congress of Gastroenterology, Vienna, 1998”. Hepatology. vol. 35. 1998. pp. 716-21. (Excellent review of HE.)

Bass, NM, Mullen, KD, Sanyal, A. “Rifaximin treatment in hepatic encephalopathy”. N Engl J Med. vol. 362. 2010. pp. 1071-81. (Evidence to support usage of rifaximin to prevent recurrent HE in a high-risk population.)

Ahs-Nielsen, B, Gluud, C. “Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomized trials”. BMJ. vol. 328. 2004. pp. 1046(Excellent review of evidence regarding non-absorbable disaccharides, including lactulose.)

Williams, R, James, OF, Warnes, TW, Morgan, MY. “Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding mulit-centre study”. Eur J Gastroenterol Hepatol. vol. 12. 2000. pp. 203-8. (Treatment of acute HE with rifaximin.)

Strauss, E, Tramote, R, Silva, EP. “Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy”. Hepatogastroenterology. vol. 39. 1992. pp. 542-5. (Treatment of acute HE with neomycin.)

Blei, AT, Cordoba, J. “Hepatic encephalopathy”. Am J Gastroenteorol. vol. 96. 2001. pp. 1968-76. (ACG guidelines for management of HE.)

Rahimi, RS, Singal, AG, Cuthbert, JA, Rockey, DC. ” Lactulose vs polyethylene glycol 3350—electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial”. JAMA Intern Med. vol. 174. 2014 Nov. pp. 1727-33. (Trial of golytely vs lactulose.)

Vistrup, H, Amodio, P, Bajaj, J. ” Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver”. Hepatology. vol. 60. 2014. pp. 715-735. (AASLD-EASL guidelines for the management of HE.)

Barbaro, G, Di Lorenzo, G, Soldini, M. “Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter, double-blind, placebo-controlled, cross-over study”. Hepatology. vol. 28. 1998. pp. 374-8. (Study examines the use of flumazenil in severe HE.)

Bismuth, M, Funakoshi, N, Cadranel, JF, Blanc, P. “Hepatic encephalopathy: from pathophysiology to therapeutic management”. Eur J Gastroenterol Hepatol. vol. 23. 2011. pp. 8-22. (Excellent contemporary review of HE.)

**The original author for this chapter was Steven Flamm. The chapter was revised by Dr. Bruce R. Bacon.

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