EASL Clinical Practice Guidelines

Definition of the disease/condition

Overview

Advanced liver disease and portosystemic shunting (PSS), far from being an isolated disorder of the liver, have well-known consequences on the body and, notably, on brain functioning. The alterations of brain functioning, which can produce behavioral, cognitive, and motor effects, were termed portosystemic encephalopathy (PSE) [3] and later included in the term HE [4].

Unless the underlying liver disease is successfully treated, HE is associated with poor survival and a high risk of recurrence [[5], [6]]. Even in its mildest form, HE reduces health-related quality of life and is a risk factor for bouts of severe HE [[7], [8],[9]].

Definition of HE

This definition, in line with previous versions [[10], [11]], is based on the concept that encephalopathies are “diffuse disturbances of brain function" [5] and that the adjective “hepatic" implies a causal connection to liver insufficiency and/or perihepatic vascular shunting [6].

Epidemiology

The incidence and prevalence of HE are related to the severity of the underlying liver insufficiency and PSS [[12], [13], [14],[15]]. In patients with cirrhosis, fully symptomatic overt HE (OHE) is an event that defines the decompensated phase of the disease, such as VB or ascites [7]. Overt hepatic encephalopathy is also reported in subjects without cirrhosis with extensive PSS [[8], [9]].

The manifestation of HE may not be an obvious clinical finding and there are multiple tools used for its detection, which influences the variation in the reported incidence and prevalence rates.

The prevalence of OHE at the time of diagnosis of cirrhosis is 10%–14% in general [[16], [17], [18]], 16%–21% in those with decompensated cirrhosis [[7], [19]], and 10%–50% in patients with transjugular intrahepatic portosystemic shunt (TIPS) [[20], [21]]. The cumulated numbers indicate that OHE will occur in 30%–40% of those with cirrhosis at some time during their clinical course and in the survivors in most cases repeatedly [22]. Minimal HE (MHE) or covert HE (CHE) occurs in 20%–80% of patients with cirrhosis [[23], [24], [25], [26], [27], [81]]. The prevalence of HE in prehepatic noncirrhotic portal hypertension (PH) is not well defined.

The risk for the first bout of OHE is 5%–25% within 5 years after cirrhosis diagnosis, depending on the presence of risk factors, such as other complications to cirrhosis (MHE or CHE, infections, VB, or ascites) and probably diabetes and hepatitis C [[28], [29], [30], [31], [32]]. Subjects with a previous bout of OHE were found to have a 40% cumulative risk of recurring OHE at 1 year [33], and subjects with recurrent OHE have a 40% cumulative risk of another recurrence within 6 months, despite lactulose treatment. Even individuals with cirrhosis and only mild cognitive dysfunction or mild electroencephalography (EEG) slowing develop approximately one bout of OHE per 3 years of survival [[34], [35]].

After TIPS, the median cumulative 1-year incidence of OHE is 10%–50% [[36], [37]] and is greatly influenced by the patient selection criteria adopted [38]. Comparable data were obtained by PSS surgery [39].

It gives an idea of the frequent confrontation of the health care system by patients with HE that they accounted for approximately 110,000 hospitalizations yearly (2005–2009) [40] in the United States. Though numbers in the European Union (EU) are not readily available, these predictions are expected to be similar. Furthermore, the burden of CLD and cirrhosis is rapidly increasing [[41], [42]], and more cases will likely be encountered to further define the epidemiology of HE.

Clinical presentation

Hepatic encephalopathy produces a wide spectrum of nonspecific neurological and psychiatric manifestations [10]. In its lowest expression [[43], [44]], HE alters only psychometric tests oriented toward attention, working memory (WM), psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures [[45], [46]].

As HE progresses, personality changes, such as apathy, irritability, and disinhibition, may be reported by the patient's relatives [47], and obvious alterations in consciousness and motor function occur. Disturbances of the sleep-wake cycle with excessive daytime sleepiness are frequent [48], whereas complete reversal of the sleep-wake cycle is less consistently observed [[49], [50]]. Patients may develop progressive disorientation to time and space, inappropriate behavior, and acute confusional state with agitation or somnolence, stupor, and, finally, coma [51]. The recent ISHEN (International Society for Hepatic Encephalopathy and Nitrogen Metabolism) consensus uses the onset of disorientation or asterixis as the onset of OHE [65].

In noncomatose patients with HE, motor system abnormalities, such as hypertonia, hyper-reflexia, and a positive Babinski sign, can be observed. In contrast, deep tendon reflexes may diminish and even disappear in coma [52], although pyramidal signs can still be observed. Rarely, transient focal neurological deficits can occur [53]. Seizures are very rarely reported in HE [[54], [55], [56]].

Extrapyramidal dysfunction, such as hypoimia, muscular rigidity, bradykinesia, hypokinesia, monotony and slowness of speech, parkinsonian-like tremor, and dyskinesia with diminished voluntary movements, are common findings; in contrast, the presence of involuntary movements similar to tics or chorea occur rarely [[52], [57]].

Asterixis or “flapping tremor” is often present in the early to middle stages of HE that precede stupor or coma and is, in actuality, not a tremor, but a negative myoclonus consisting of loss of postural tone. It is easily elicited by actions that require postural tone, such as hyperextension of the wrists with separated fingers or the rhythmic squeezing of the examiner's fingers. However, asterixis can be observed in other areas, such as the feet, legs, arms, tongue, and eyelids. Asterixis is not pathognomonic of HE because it can be observed in other diseases [57] (e.g., uremia).

Notably, the mental (either cognitive or behavioral) and motor signs of HE may not be expressed, or do not progress in parallel, in each individual, therefore producing difficulties in staging the severity of HE.

Hepatic myelopathy (HM) [58] is a particular pattern of HE possibly related to marked, long-standing portocaval shunting, characterized by severe motor abnormalities exceeding the mental dysfunction. Cases of paraplegia with progressive spasticity and weakness of lower limbs with hyper-reflexia and relatively mild persistent or recurrent mental alterations have been reported and do not respond to standard therapy, including ammonia lowering, but may reverse with liver transplantation (LT) [59].

Persistent HE may present with prominent extrapyramidal and/or pyramidal signs, partially overlapping with HM, in which postmortem brain examination reveals brain atrophy [60]. This condition was previously called acquired hepatolenticular degeneration, a term currently considered obsolete. However, this cirrhosis-associated parkinsonism is unresponsive to ammonia-lowering therapy and may be more common than originally thought in patients with advanced liver disease, presenting in approximately 4% of cases [61].

Apart from these less-usual manifestations of HE, it is widely accepted in clinical practice that all forms of HE and their manifestations are completely reversible, and this assumption still is a well-founded operational basis for treatment strategies. However, research on liver-transplanted HE patients and on patients after resolution of repeated bouts of OHE casts doubt on the full reversibility. Some mental deficits, apart from those ascribable to other transplantation-related causes, may persist and are mentioned later under transplantation [135]. Likewise, episodes of OHE may be associated with persistent cumulative deficits in WM and learning [14].

Classification

Hepatic encephalopathy should be classified according to all of the following four factors [10].

  1. According to the underlying disease, HE is subdivided into
    • Type A resulting from ALF
    • Type B resulting predominantly from portosystemic bypass or shunting
    • Type C resulting from cirrhosis
    The clinical manifestations of types B and C are similar, whereas type A has distinct features and, notably, may be associated with increased intracranial pressure and a risk of cerebral herniation. The management of HE type A is described in recent guidelines on ALF [[62], [63]] and is not included in this document.
  2. According to the severity of manifestations. The continuum that is HE has been arbitrarily subdivided. For clinical and research purposes, a scheme of such grading is provided (Table 2). Operative classifications that refer to defined functional impairments aim at increasing intra- and inter-rater reliability and should be used whenever possible.
    Table 2
    WHC and clinical description.

    All conditions are required to be related to liver insufficiency and/or PSS.
  3. According to its time course, HE is subdivided into
    • Episodic HE
    • Recurrent HE denotes bouts of HE that occur with a time interval of 6 months or less.
    • Persistent HE denotes a pattern of behavioral alterations that are always present and interspersed with relapses of overt HE.
  4. According to the existence of precipitating factors, HE is subdivided into
    • Nonprecipitated or
    • Precipitated, and the precipitating factors should be specified. Precipitating factors can be identified in nearly all bouts of episodic HE type C and should be actively sought and treated when found (Table 3).
      Table 3
      Precipitating factors for OHE by decreasing frequency.

      Modified from Strauss E, da Costa MF The importance of bacterial infections as precipitating factors of chronic hepatic encephalopathy in cirrhosis. Hepato-gastroenterology 1998;45:900–904.∗More recent unpublished case series confirm the dominant role of infections.

A fifth classification, according to whether or not the patient has acute-on-chronic liver failure (ACLF), has recently been suggested [64]. Although the management, mechanism, and prognostic impact differ, this classification is still a research area.

Differential diagnoses

The diagnosis requires the detection of signs suggestive of HE in a patient with severe liver insufficiency and/or PSS who does not have obvious alternative causes of brain dysfunction. The recognition of precipitating factors for HE (e.g., infection, bleeding, and constipation) supports the diagnosis of HE. The differential diagnosis should consider common disorders altering the level of consciousness (Table 4).

Table 4
Differential diagnosis of HE.



Hyponatremia and sepsis can both produce encephalopathy per se and precipitate HE by interactions with the pathophysiological mechanisms. In end-stage liver disease, uremic encephalopathy and HE may overlap.

Recommendations

Every case and bout of HE should be described and classified according to all four factors, and this should be repeated at relevant intervals according to the clinical situation. The recommendations are summarized in Table 5.

Table 5
HE description and clinical example.



The HE patient should be characterized by one component from each of the four columns. Example of a recommended description of a patient with HE: “The patient has HE, Type C, Grade 3, Recurrent, Precipitated (by urinary tract infection)." The description may be supplemented with operative classifications (e.g., the Glasgow Coma Score or psychometric performance).