EASL Clinical Practice Guidelines

Alternative causes of altered mental status

Disorders to be considered

The neurological manifestations of HE are nonspecific. Therefore, concomitant disorders have to be considered as an additional source of central nervous system dysfunction in any patient with CLD. Most important are renal dysfunction, hyponatremia, diabetes mellitus (DM), sepsis, and thiamine deficiency (Wernicke's encephalopathy); noteworthy also is intracranial bleeding (chronic subdural hematoma and parenchymal bleeding).

Interaction between concomitant disorders and liver disease with regard to brain function

Hyponatremia is an independent risk factor for development of HE in patients with cirrhosis [[140], [141]]. The incidence of HE increases [142] and the response rate to lactulose therapy decreases [143] with decreasing serum sodium concentrations.

Diabetes mellitus has been suggested as a risk factor for development of HE, especially in patients with hepatitis C virus (HCV) cirrhosis [144], but the relationship may also be observed in other cirrhosis etiologies [145].

An increased risk to develop HE has also been shown in patients with cirrhosis with renal dysfunction [146], independent of the severity of cirrhosis.

Neurological symptoms are observed in 21%–33% of patients with cirrhosis with sepsis and in 60%–68% of those with septic shock [147]. Patients with cirrhosis do not differ from patients without cirrhosis regarding their risk to develop brain dysfunction with sepsis [148], although it is assumed that systemic inflammation and hyperammonemia act synergistically with regard to the development of HE.

Thiamine deficiency predominantly occurs in patients with ALD, but may also occur as a consequence of malnutrition in end-stage cirrhosis of any cause. The cerebral symptoms disorientation, alteration of consciousness, ataxia, and dysarthria cannot be differentiated as being the result of thiamine deficiency or hyperammonemia by clinical examination [149]. In any case of doubt, thiamine should be given IV before glucose-containing solutions.

Effect of the etiology of the liver disease upon brain function

Data upon the effect of the underlying liver disease on brain function are sparse, except for alcoholism and hepatitis C. Rare, but difficult, cases may be the result of Wilson's disease.

Even patients with alcohol disorder and no clinical disease have been shown to exhibit deficits in episodic memory [150], working memory and executive functions [151], visuoconstruction abilities [152], and upper- and lower-limb motor skills [153]. The cognitive dysfunction is more pronounced in those patients with alcohol disorder who are at risk of Wernicke's encephalopathy as a result of malnutrition or already show signs of the problem [154]. Thus, it remains unclear whether the disturbance of brain function in patients with ALD is the result of HE, alcohol toxicity, or thiamine deficiency.

There is mounting evidence that HCV is present and replicates within the brain [[155], [156], [157], [158]]. Approximately half of HCV patients suffer chronic fatigue irrespective of the grade of their liver disease [[159], [160]], and even patients with only mild liver disease display cognitive dysfunction [[161], [162]], involving verbal learning, attention, executive function, and memory. Likewise, patients with primary biliary cirrhosis and primary sclerosing cholangitis may have severe fatigue and impairment of attention, concentration, and psychomotor function irrespective of the grade of liver disease [[163], [164], [165], [166], [167], [168]].

Diagnostic measures to differentiate between HE and cerebral dysfunction resulting from other causes

Because HE shares symptoms with all concomitant disorders and underlying diseases, it is difficult in the individual case to differentiate between the effects of HE and those resulting from other causes. In some cases, the time course and response to therapy may be the best support of HE. As mentioned, a normal blood ammonia level in a patient suspected of HE calls for consideration. None of the diagnostic measures used at present has been evaluated for their ability to differentiate between HE and other causes of brain dysfunction. The EEG would not be altered by DM or alcohol disorders, but may show changes similar to those with HE in cases of renal dysfunction, hyponatremia, or septic encephalopathy. Psychometric tests are able to detect functional deficits, but are unable to differentiate between different causes for these deficits. Brain imaging methods have been evaluated for their use in diagnosing HE, but the results are disappointing. Nevertheless, brain imaging should be done in every patient with CLD and unexplained alteration of brain function to exclude structural lesions. In rare cases, reversibility by flumazenil may be useful.