The pathogenesis of HE has been studied for more than five decades and has yet to be fully elucidated. CHE and OHE share a common pathogenesis with multifactorial etiologies [9]. These include ammonia , cerebral edema, and inflammatory mediators.

Increased peripheral ammonia crosses the blood–brain barrier (BBB) and represents a key neurotoxin in the pathogenesis of HE. A major source of ammonia is the intestinal flora and urease-producing bacteria that convert glutamine into glutamate and ammonia. Via the splanchnic circulation, ammonia is metabolized by the liver and renally excreted. In a cirrhotic liver, hyperammonemia results from decreased functioning of hepatocytes and shunting of the blood into the systemic circulation [10]. During times of muscle wasting, release of glutamine from muscle cells into circulation leads to excessive ammonia production, worsening HE [11]. In the setting of systemic alkalosis, the kidneys increase ammonia reabsorption to serve as a buffer and this in turn leads to hyperammonemia.

Ammonia toxicity is thought to affect the brain via astrocytes, which are the unique neural cells that metabolize ammonia via glutamine synthetase and help regulate the BBB [12]. In astrocytes, overwhelming levels of ammonia lead to increased production of glutamine which changes the osmotic gradient and causes intracellular swelling and generalized cerebral edema. As astrocytes become impaired, so does the regulation of the BBB, allowing ammonia to accumulate within the brain, worsening cerebral edema [13, 14].

Proinflammatory cytokines work in conjunction with ammonia to worsen cerebral edema in HE. Inflammation may be secondary to infection, hemorrhage , or intestinal bacterial overgrowth, all common in cirrhotics [15]. High circulating levels of inflammatory markers, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), are thought to play a role as well [16]. TNF has been shown to affect astrocyte function with increased BBB permeability [17]. Other factors implicated in the pathogenesis of HE include increased inhibitory gamma-aminobutyric acid (GABA) receptors, alterations of excitatory glutamate and catecholamine receptors [18–20].

The development of HE in cirrhotics portends a poor prognosis. Those with more advanced liver disease are at greater risk of developing HE [21]. Not only do CHE and OHE affect survival but they also impact a patient’s health-related quality of life (HRQOL) and daily functioning as members of society [6, 7].

CHE increases the risk of progression to OHE and has significant impact on daily activities (Table 16.2) [22, 23]. Through self-assessed questionnaires such as the Sickness Impact Profile (SIP) and Short Form Healthy Survey (SF-36), studies have shown that CHE has a negative impact on emotional behaviors, social interactions, level of alertness, and recreational activities; the more severe the liver disease, the worse the HRQOL [23, 24]. CHE has a strong association with driving impairment and traffic violations [25–27]. Future studies should be directed at methods to evaluate driving function and identify those at higher risk of driving impairment. Previous studies by Bajaj et al. have shown that not only does HE place a burden on the patient but there are socioeconomic, financial, and personal burdens on caretakers. Specifically, deleterious effects on personal health and sense of entrapment were observed [28]. CHE also negatively impacts work performance, notably those involved in complex, occupational tasks [29]. OHE is associated with increased hospitalization, infection, and mortality rates compared to cirrhotics without OHE [6, 21].

CHE continues to remain a difficult diagnosis to make as it is not clinically evident. Establishing the diagnosis is focused on assessing deficits in attention and processing speed [30]. Testing strategies are divided into three areas: paper and pencil psychometric tests, computerized psychometric tests, and neurophysiological evaluation. In 1998, the hepatic encephalopathy group at the World Congress of Gastroenterology supported a paper–pencil test called the psychometric hepatic encephalopathy score (PHES) as the gold standard for diagnosing CHE. The PHES was specifically designed to detect impairments in attention, processing speed, response inhibition, and visuospatial awareness. The initial seven tests were revised to five tests with better sensitivity. The revised PHES consists of number connection test A (NCT-A) and B (NCT-B), line-tracing test, digit symbol test, and serial dotting test. Each of these five tests is scored from 1 to 3 and a total cutoff score of 4 or lower showed sensitivity and specificity of 96 and 100 %, respectively, for the diagnosis of CHE. The PHES is predominantly used outside of the USA, having been validated in Italy, Germany, and Spain [31, 32]. In the USA, there is no validated test due to copyright issues, and concerns over the cost and resources involved in such tests. Alternatively, the Working Group of Hepatic Encephalopathy has recommended the following four tests: NCT-A, NCT-B, the digits symbol test, or the block design test. Impairment in at least two of these tests, two or more standard deviations beyond matched controls, is indicative of HE [1].

The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) has recommended the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as a tool to diagnose CHE [33]. The RBANS is an approximately 25-min paper–pencil test, which is less time consuming than PHES. It has been used to diagnose other cognitive disorders such as traumatic brain injury, multiple sclerosis, and dementia. The test assesses cortical and subcortical domains. The modified RBANS focuses specifically on cognitive deficits associated with OHE and CHE. The modified RBANS is available for use in the USA, but like the PHES, it is not routinely performed because of copyright concerns and its cost, as a psychologist must interpret the results.

Paper–pencil testing requires adept motor function and multiple cognitive abilities to complete the test successfully. Computerized testing relies on reaction time as one only has to push buttons. The inhibitory control test (ICT) evaluates response inhibition and attention span [34]. The test takes place on a computer screen, and target letters, such as X and Y, are presented on the screen every 500 ms. The “lures” are the non-X and Y targets interspersed throughout target letters. For example, a screen will read one letter at a time and a patient should press the button only when the X and Y’s are displayed. The percentage of times a patient responds to the targets and lures are recorded. Studies have shown good sensitivities for this test, comparable to the PHES [35]. The ICT test is easily administered, inexpensive, and reproducible, making it an attractive diagnostic tool for CHE . Another such test is the Cognitive Drug Research (CDR) battery that uses five psychometric tests to assess cognition and is presented as a set of yes/no responses [36]. The CDR shows comparable results to the PHES and is validated in populations such as dementia [37]. Although not validated in the USA, the CDR test has reproducible results, is easy to use, and only takes 30 min to complete, also making it a good diagnostic tool for CHE .

The third category for diagnosing CHE is neurophysiological evaluation. The critical flicker frequency (CFF) measures cortical function and correlates with psychometric abnormalities [38]. Patients are shown initial light pulses that gradually reduce in frequency, making it easier to detect when the light appears to flicker. A frequency of 39 Hz and below diagnoses CHE with sensitivity of 80 % and specificity of 65 %, results that correlate with paper and pencil testing [39]. CFF is convenient, has minimal costs, and does not require a psychologist to interpret, making it a potential future screening option.

The Stroop app test is a short, valid, and reliable tool used to screen for CHE. Originally studied by Bajaj et al. in 2013, the Stroop application is available on smartphones and iTunes and tests psychomotor speed and cognitive alertness, with focus on the attention system [40]. Though it needs to be further validated in multiple populations, the Stroop test is easy to use, inexpensive, and accessible which would make it a reasonable screening tool for CHE [41]. Other testing strategies include spectral electroencephalography (EEG), used to predict prognosis and mortality in cirrhotics with HE and evoked potentials, where visual, sensory, and auditory stimuli are applied to the brain and response times are evaluated [42, 43]. EEG’s are limited by the large equipment needed, the amount of time it takes, cost, and the requirement of an expert neurologist to interpret the EEG [44].

The 2014 AASLD/EASL guidelines have streamlined the strategies used to diagnose CHE for single-center and multicenter studies. Investigators at single-center sites can employ one modality with which they are familiar that has established norms. Multicenter studies, however, would require at least two types of modalities (paper–pencil (PHES or equivalent), computerized (Scan, Stroop, ICT, CDR, etc.) or neurophysiological tests (CFF, EEG, etc.)) to be impaired in order to increase uniformity of diagnosis between different centers [2].

OHE is diagnosed clinically and there are several systems that have been used to risk-stratify severity of disease. The West Haven criteria (WHC) are one of the most widely used stratification systems that assist with the management of CHE and OHE (Table 16.3) [45]. Though subjective and not clinically obvious, CHE , consisting of stages 0 and 1, is diagnosed with a set of neuropsychological evaluations described above. OHE, consisting of stages 2 through 4, is diagnosed clinically. Other methods used to assess mental status include the Glasgow Coma Scale for those with moderate to severe HE and the HE scoring algorithm (HESA) which uses psychometric and clinical evaluations [46, 47]. In 2012, Salam et al. proposed a simple eight question modified-orientation log (MO-log) for inpatient cirrhotics that rapidly evaluates the depth of disorientation in a more standardized manner and is able to predict inhospital mortality. Further studies are needed to validate the MO-log in larger populations [48].

OHE is a diagnosis of exclusion, meaning that other causes of altered mentation and motor dysfunction should first be ruled out, including cerebrovascular attacks (CVA), cerebral hematomas, infection, and other metabolic disorders. The diagnosis of OHE should focus on the neurological examination. Signs that favor HE tends to be more global than focal, such as those in CVA. In WHC stages 2 and 3, patients with OHE exhibit signs of hyperreflexia and asterixis. Asterixis is not pathognomonic for HE, as it is also seen in uremia and other disease processes. Other motor exam findings include bradykinesia, rigidity, and tremors. Slurred speech, fetor hepaticus, and ataxia may also be found.

Laboratory studies are generally not needed but may aid in ruling out other causes of encephalopathy including renal failure, sepsis, and electrolyte derangements. Ammonia levels are not needed to diagnose OHE and may not predict or correlate with actual outcomes [49]. The accuracy of ammonia levels are influenced by multiple factors, including the use of a tourniquet, fist clenching, and immediate placement of the sample on ice. Though not a validated diagnostic tool, brain imaging may help exclude other causes of altered mental status. Computed tomography (CT) and magnetic resonance imaging (MRI) may show cerebral edema in those with HE.

Treatment strategies for HE should be based on the severity and acuity of disease. While most patients with only CHE are managed and treated as outpatients, OHE is treated in both in-hospital and outpatient settings. Therapeutic goals vary based on CHE , acute OHE, or chronic OHE (Table 16.4).

Treatment of CHE improves quality of life and psychometric testing. The administration of lactulose and rifaximin has been shown to improve outcomes but there is no standard of care at this time [2]. A recent open-label study using probiotics demonstrated a reduction in OHE episodes but this approach needs to be validated using a placebo-controlled trial [50]. Bajaj et al. conducted a randomized control trial using yogurt with probiotic compared to no treatment; none of the subjects in the yogurt group developed OHE [51]. Larger multicentered trials that target clinically relevant outcomes are needed to assess patient comfort and valid therapeutic outcomes in treating CHE.