A known complication of cirrhosis of the liver is newly altered level of awareness (LOA). Although several entities can cause altered LOA, hepatic encephalopathy (HE) must be near the top of your differential because it is associated with poor survival and a high risk of recurrence when left untreated.¹ 

Unfortunately, the definition of HE is rather nebulous: “a brain dysfunction caused by liver insufficiency and/or porto-systemic shunting; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma.” HE is graded in four stages accordingly. The characteristic asterixis may be absent in stage 1 and missed in stage 4. (While present in stage 4, it is often overlooked because patients are too obtunded to follow commands; however, asterixis can still be elicited by the clinician passively). As a result, HE can be difficult to diagnose in the emergency department.¹ 

Below, I outline a simple seven-step approach to diagnosis and treatment of HE. 

Step 1: Rule Out Other Causes 

Rule out alternative or concurrent causes of altered LOA, including sepsis, renal failure, alcohol withdrawal, intracranial hemorrhage, or trauma. 

Step 2: Assess/Address Precipitants 

Assess for and address common precipitants of HE, which include medications (ie, nonadherence or overdosed diuretics, or benzodiazepines), gastrointestinal bleeding, hypokalemia, alkalosis, volume depletion, and sepsis. Addressing and treating precipitating factors in HE management is important because almost 90 percent of patients with HE can be effectively treated by correcting the precipitating factor alone. If your HE treatment does not produce the expected effect, you must reconsider the diagnosis or search for unrecognized precipitating factors and correct them. 

Step 3: Make the Diagnosis

After excluding other altered LOA causes, consider HE. Look for the constellation of symptoms that includes personality changes as reported by the patient’s family (eg, apathy, irritability, or disinhibition), disturbances of the sleep-wake cycle (ie, excessive daytime sleepiness or complete reversal of the sleep-wake cycle), and extrapyramidal dysfunction (eg, muscular rigidity, bradykinesia, monotony, slowness of speech, parkinsonian-like tremor, dyskinesia).² The physical examination plays a major role. The onset of asterixis or disorientation heralds onset. Asterixis can be easily elicited by actions that require postural tone (eg, hyperextension of the wrists with separated fingers or rhythmic squeezing of the examiner’s fingers). If the patient cannot follow commands due to LOA, one trick to elicit asterixes is to place the patient’s forearm on the stretcher railing and forcibly extend the wrist. However, remember that asterixes are not specific for HE and are also seen in patients with renal insufficiency. A reversal of HE manifestations with treatment clinches the diagnosis. 

Step 4: Ammonia Levels

The number-one recommendation on the Choosing Wisely Canada website’s Hepatology page is, “Don’t order serum ammonia to diagnose or manage hepatic encephalopathy.” Elevated serum ammonia levels do not add diagnostic or prognostic value in liver patients suspected of HE because encephalopathy may precede the rise in ammonia levels.³ Ideally, we would like to know how much ammonia enters the brain, not how much is in the blood. A common pitfall is to incorrectly rule out HE via a normal ammonia level—ammonia levels can be normal or near normal in HE. Serial measurements of ammonia may help evaluate the efficacy of ammonia-lowering drugs. But have a low threshold to treat HE on speculation, as this condition is difficult to definitively diagnose in the emergency department. 

Lactulose has been found to significantly reduce mortality and serious complications of HE in a Cochrane review of 38 randomized controlled trials (RCTs). Dosing is 20 g (30 mL) orally and is titrated to three to four soft stools per day.⁴ A common myth is that increasing the dose of lactulose will be effective after standard doses have failed. But overdosing lactulose can lead to worsening volume depletion, aspiration, hypernatremia, and even precipitation of HE.¹ If the patient with HE is rendered NPO, polyethylene glycol (PEG) via nasogastric dosed at 4 L over four hours has been shown to resolve HE more rapidly than lactulose in one small RCT of hospitalized patients.^5,6 

It is important to understand that patients with HE have excess gamma aminobutyric acid (GABA) stimulation. This makes them sensitive to GABAergic medications such as benzodiazepines and propofol. Such medications should be dose-adjusted or avoided whenever possible. When endotracheal intubation is necessary, ketamine may be a better choice of induction agent than propofol for this reason. 

Step 5: Top Off Fluids, Glucose, Potassium 

One way to remember some of the important aspects of treating HE is that everything besides the liver enzymes and liver function tests tends to be low: circulatory volume, serum potassium, and glucose. For fluid replacement, consider albumin in addition to normal saline for patients with a low serum albumin, as there is some RCT evidence (although weak) that it may improve outcomes when added to lactulose in patients with HE.⁷ Intravenous albumin will likely be especially effective in patients with concurrent hepatorenal syndrome and/or acute liver failure. 

It is important to understand that patients with HE have depleted glycogen stores. That’s why a single bolus of D50W is unlikely to achieve normoglycemia for an extended period of time. An ongoing infusion of D10W or D25W is often required to prevent hypoglycemia and worsening LOA. 

Another pitfall is ignoring mild hypokalemia. Treat even the mildest hypokalemia because low potassium contributes to hyperammonemia by decreasing ammonia excretion. Correcting hypokalemia is thought to decrease ammonia levels in patients with HE.⁸ Magnesium also must be corrected if low because failure to address hypomagnesemia will make potassium replacement ineffective. 

Step 6: Assess/Treat Cerebral Edema 

Cerebral edema resulting from rapid accumulation of ammonia in the brain is the most common cause of death in patients with HE.⁹ While ammonia levels generally do not help diagnose or prognosticate hepatic encephalopathy (a fact many are surprised to learn), a Danish study suggests that arterial ammonia levels >150 µmol/L, measured within 24 hours of reaching grade III hepatic encephalopathy, were associated with a higher likelihood of developing cerebral edema.¹⁰ Cerebral edema in these patients may be clinically subtle, so maintain suspicion in comatose patients with HE. If signs of raised intracranial pressure are present, keep the head of the bed elevated at 45 degrees and consider hypertonic saline (20 mL of 30 percent sodium chloride targeting a serum sodium level of 145–150 mmol/L). Mannitol is not recommended for treating cerebral edema in this setting.¹¹ 

Step 7: Consider Rifaximin for Antimicrobial Coverage 

Rifaximin 400–550 mg orally is the antibiotic of choice for long-term maintenance in patients with recurrent HE because it is poorly absorbed in the gut and therefore both reaches and covers ammonia–producing E. coli. Initiating this drug in the emergency department is reasonable. Rifaximin in combination with lactulose is effective for the prevention of HE recurrence.¹² 

Summary 

Next time you are faced with an altered LOA patient who is flapping their wrists as soon as you extend them, remember that HE is a clinical diagnosis and that serum ammonia levels are unreliable. Assume high central nervous system ammonia levels and treat with lactulose and/or polyethylene glycol and rifaximin. Intravenous albumin must be considered in the patient with HE, especially if they are in acute liver failure and have a low threshold to treat for HE on speculation because it is a diagnosis of exclusion. 

A special thanks to Dr. Walter Himmel and Dr. Brian Steinhart, the guest experts on the EM Cases podcast that inspired this article.

References

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2. Montagnese S, De Pittà C, De Rui M, et al. Sleep-wake abnormalities in patients with cirrhosis. Hepatology. 2014;59(2):705-712. 
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