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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

2014; Lippincott Williams & Wilkins; Volume: 60; Issue: 2 Linguagem: Inglês

10.1002/hep.27210

1527-3350

Hendrik Vilstrup, Piero Amodio, Jasmohan S. Bajaj, Juan Córdoba, Péter Ferenci, Kevin D. Mullen, Karin Weißenborn, Philip Wong,

Drug-Induced Hepatotoxicity and Protection

The AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This guideline has been approved by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver and represents the position of both associations. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD/EASL Practice Guidelines Subcommittee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup, with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong (1) or weak (2). The literature databases and search strategies are outlined below. The resulting literature database was available to all members of the writing group (i.e., the authors). They selected references within their field of expertise and experience and graded the references according to the GRADE system.1 The selection of references for the guideline was based on a validation of the appropriateness of the study design for the stated purpose, a relevant number of patients under study, and confidence in the participating centers and authors. References on original data were preferred and those that were found unsatisfactory in any of these respects were excluded from further evaluation. There may be limitations in this approach when recommendations are needed on rare problems or problems on which scant original data are available. In such cases, it may be necessary to rely on less-qualified references with a low grading. As a result of the important changes in the treatment of complications of cirrhosis (renal failure, infections, and variceal bleeding [VB]), studies performed more than 30 years ago have generally not been considered for these guidelines. Hepatic encephalopathy (HE) is a frequent complication and one of the most debilitating manifestations of liver disease, severely affecting the lives of patients and their caregivers. Furthermore, cognitive impairment associated with cirrhosis results in utilization of more health care resources in adults than other manifestations of liver disease.2 Progress in the area has been hindered by the complex pathogenesis that is not yet fully elucidated. Apart from such biological factors, there remains the larger obstacle that there are no universally accepted standards for the definition, diagnosis, classification, or treatment of HE, mostly as a result of insufficient clinical studies and standardized definitions. Clinical management tends to be dependent on local standards and personal views. This is an unfavorable situation for patients and contrasts with the severity of the condition and the high level of standardization in other complications of cirrhosis. The lack of consistency in the nomenclature and general standards renders comparisons among studies and patient populations difficult, introduces bias, and hinders progress in clinical research for HE. The latest attempts to standardize the nomenclature were published in 2002 and suggestions for the design of HE trials in 2011. Because there is an unmet need for recommendations on the clinical management of HE, the EASL and the AASLD jointly agreed to create these practice guidelines. It is beyond the scope of these guidelines to elaborate on the theories of pathogenesis of HE, as well as the management of encephalopathy resulting from acute liver failure (ALF), which has been published as guidelines recently. Rather, its aim is to present standardized terminology and recommendations to all health care workers who have patients with HE, regardless of their medical discipline, and focus on adult patients with chronic liver disease (CLD), which is, by far, the most frequent scenario. As these guidelines on HE were created, the authors found a limited amount of high-quality evidence to extract from the existing literature. There are many reasons for this; the elusive character of HE is among them, as well as the lack of generally accepted and utilized terms for description and categorization of HE. This makes a practice guideline all the more necessary for future improvement of clinical studies and, subsequently, the quality of management of patients with HE. With the existing body of evidence, these guidelines encompass the authors' best, carefully considered opinions. Although not all readers may necessarily agree with all aspects of the guidelines, their creation and adherence to them is the best way forward, with future adjustments when there is emergence of new evidence. 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.7-9 Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or PSS; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. 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 The incidence and prevalence of HE are related to the severity of the underlying liver insufficiency and PSS.12-15 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,16-18 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.23-27, 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.28-32 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. 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.54-56 Extrapyramidal dysfunction, such as hypomimia, 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 diseases57 (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 Hepatic encephalopathy should be classified according to all of the following four factors.10 According to the underlying disease, HE is subdivided into 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. According to its time course, HE is subdivided into According to the existence of precipitating factors, HE is subdivided into No universal criteria for diagnosis Local standards and expertise required • Trivial lack of awareness • Euphoria or anxiety • Shortened attention span • Impairment of addition or subtraction • Altered sleep rhythm • Lethargy or apathy • Disorientation for time • Obvious personality change • Inappropriate behavior • Dyspraxia • Asterixis • Somnolence to semistupor • Responsive to stimuli • Confused • Gross disorientation • Bizarre behavior 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. 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). 1. Hepatic encephalopathy should be classified according to the type of underlying disease, severity of manifestations, time course, and precipitating factors (GRADE III, A, 1). 2. A diagnostic workup is required, considering other disorders that can alter brain function and mimic HE (GRADE II-2, A, 1). 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. Judging and measuring the severity of HE is approached as a continuum.65 The testing strategies in place range from simple clinical scales to sophisticated psychometric and neurophysiological tools; however, none of the current tests are valid for the entire spectrum.11, 66 The appropriate testing and diagnostic options differ according to the acuity of the presentation and the degree of impairment.67 The diagnosis of OHE is based on a clinical examination and a clinical decision. Clinical scales are used to analyze its severity. Specific quantitative tests are only needed in study settings. The gold standard is the West Haven criteria (WHC; Table 2, including clinical description). However, they are subjective tools with limited interobserver reliability, especially for grade I HE, because slight hypokinesia, psychomotor slowing, and a lack of attention can easily be overlooked in clinical examination. In contrast, the detection of disorientation and asterixis has good inter-rater reliability and thus are chosen as marker symptoms of OHE.67 Orientation or mixed scales have been used to distinguish the severity of HE.68, 69 In patients with significantly altered consciousness, the Glasgow Coma Scale (GCS; Table 6) is widely employed and supplies an operative, robust description. Diagnosing cognitive dysfunction is not difficult. It can be established from clinical observation as well as neuropsychological or neurophysiological tests. The difficulty is to assign them to HE. For this reason, OHE still remains a diagnosis of exclusion in this patient population that is often susceptible to mental status abnormalities resulting from medications, alcohol abuse, drug use, effects of hyponatremia, and psychiatric disease (Table 4). Therefore, as clinically indicated, exclusion of other etiologies by laboratory and radiological assessment for a patient with altered mental status in HE is warranted. Minimal hepatic encephalopathy and CHE is defined as the presence of test-dependent or clinical signs of brain dysfunction in patients with CLD who are not disoriented or display asterixis. The term "minimal" conveys that there is no clinical sign, cognitive or other, of HE. The term "covert" includes minimal and grade 1 HE. Testing strategies can be divided into two major types: psychometric and neurophysiological.70, 71 Because the condition affects several components of cognitive functioning, which may not be impaired to the same degree, the ISHEN suggests the use of at least two tests, depending on the local population norms and availability, and preferably with one of the tests being more widely accepted so as to serve as a comparator. Testing for MHE and CHE is important because it can prognosticate OHE development, indicate poor quality of life and reduced socioeconomic potential, and help counsel patients and caregivers about the disease. The occurrence of MHE and CHE in patients with CLD seems to be as high as 50%,72 so, ideally, every patient at risk should be tested. However, this strategy may be costly,73 and the consequences of the screening procedure are not always clear and treatment is not always recommended. An operational approach may be to test patients who have problems with their quality of life or in whom there are complaints from the patients and their relatives.74 Tests positive for MHE or CHE before stopping HE drug therapy will identify patients at risk for recurrent HE.33, 75 Furthermore, none of the available tests are specific for the condition,76 and it is important to test only patients who do not have confounding factors, such as neuropsychiatric disorders, psychoactive medication, or current alcohol use. Testing should be done by a trained examiner adhering to scripts that accompany the testing tools. If the test result is normal (i.e., negative for MHE or CHE), repeat testing in 6 months has been recommended.77 A diagnosis of MHE or CHE does not automatically mean that the affected subject is a dangerous driver.78 Medical providers are not trained to formally evaluate fitness to drive and are also not legal representatives. Therefore, providers should act in the best interests of both the patient and society while following the applicable local laws.78 However, doctors cannot evade the responsibility of counseling patients with diagnosed HE on the possible dangerous consequences of their driving, and, often, the safest advice is to stop driving until the responsible driving authorities have formally cleared the patient for safe driving. In difficult cases, the doctor should consult with the authorities that have the expertise to test driving ability and the authority to revoke the license. Although the above-described tests have been used to test for MHE and CHE, there is, most often, a poor correlation between them because HE is a multidimensional dysfunction.86 Learning effect is often observed with psychometric tests and it is unclear whether current HE therapy plays a role in the test performance. Therefore, interpretation of these tests and consideration of the results for further management need an understanding of the patient's history, current therapy, and effect on the patient's daily activities, if signs of HE are found. For multicenter studies, the diagnosis of MHE or CHE by consensus should utilize at least two of the current validated testing strategies: paper-pencil (PHES) and one of the following: computerized (CRT, ICT, SCAN, or Stroop) or neurophysiological (CFF or EEG).66 In the clinical routine or single-center studies, investigators may use tests for assessing the severity of HE with which they are familiar, provided that normative reference data are available and the tests have been validated for use in this patient population.66 High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients with CLD.87 However, in case an ammonia level is checked in a patient with OHE and it is normal, the diagnosis of HE is in question. For ammonia-lowering drugs, repeated measurements of ammonia may be helpful to test the efficacy. There may be logistic challenges to accurately measure blood ammonia, which should be taken into consideration. Ammonia is reported either in venous, arterial blood, or plasma ammonia, so the relevant normal should be used. Multiple methods are available, but measurements should only be employed when laboratory standards allow for reliable analyses. Computed tomography (CT) or magnetic resonance (MR) or other image modality scans do not contribute diagnostic or grading information. However, the risk of intracerebral hemorrhage is at least 5-fold increased in this patient group,88 and the symptoms may be indistinguishable, so a brain scan is usually part of the diagnostic workup of first-time HE and on clinical suspicion of other pathology. 3. Hepatic encephalopathy should be treated as a continuum ranging from unimpaired cognitive function with intact consciousness through coma (GRADE III, A, 1). 4. The diagnosis of HE is through exclusion of other causes of brain dysfunction (GRADE II-2, A, 1). 5. Hepatic encephalopathy should be divided into various stages of severity, reflecting the degree of self-sufficiency and the need for care (GRADE III, B, 1). 6. Overt hepatic encephalopathy is diagnosed by clinical criteria and can be graded according the WHC and the GCS (GRADE II-2, B, 1). 7. The diagnosis and grading of MHE and CHE can be made using several neurophysiological and psychometric tests that should be performed by experienced examiners (GRADE II-2, B, 1). 8. Testing for MHE and CHE could be used in patients who would most benefit from testing, such as those with impaired quality of life or implication on employment or public safety (GRADE III, B, 2). 9. Increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with CLD. A normal value calls for diagnostic reevaluation (GRADE II-3, A, 1). At this time, only OHE is routinely treated.10 Minimal hepatic encephalopathy and CHE, as its title implies, is not obvious on routine clinical examination and is predominantly diagnosed by techniques outlined in the previous section. Despite its subtle nature, MHE and CHE can have a significant effect on a patient's daily living. Special circumstances can prevail where there may be an indication to treat such a patient (e.g., impairment in driving skills, work performance, quality of life, or cognitive complaints). Liver transplantation is mentioned under the treatment recommendations. General recommendations for treatment of episodic OHE type C include the following: 10. An episode of OHE (whether spontaneous or precipitated) should be actively treated (GRADE II-2, A, 1). 11. Secondary prophylaxis after an episode for overt HE is recommended (GRADE I, A, 1). 12. Primary prophylaxis for prevention of episodes of OHE is not required, except in patients with cirrhosis with a known high risk to develop HE (GRADE II-3, C, 2). 13. Recurrent intractable OHE, together with liver failure, is an indication for LT (GRADE I). A four-pronged approach to management of HE is recommended (GRADE II-2, A, 1): 14. Initiation of care for patients with altered consciousness 15. Alternative causes of altered mental status should be sought and treated. 16. Identification of precipitating factors and their correction 17. Commencement of empirical HE treatment Patients with higher grades of HE who are at risk or unable to protect their airway need more intensive monitoring and are ideally managed in an intensive care setting. Alternative causes of encephalopathy are not infrequent in patients with advanced cirrhosis. Technically, if other causes of encephalopathy are present, then the episode of encephalopathy may not be termed HE. In the clinical setting, what transpires is treatment of both HE and non-HE. Controlling precipitating factors in the management of OHE is of paramount importance, because nearly 90% of patients can be treated with just correction of the precipitating factor.89 Careful attention to this issue is still the cornerstone of HE management. In addition to the other elements of the four-pronged approach to treatment of HE, specific drug treatment is part of the management. Most drugs have not been tested by rigorous randomized, controlled studies and are utilized based on circumstantial observations. These agents include nonabsorbable disaccharides, such as lactulose, and antibiotics, such as rifaximin. Other therapies, such as oral branched-chain amino acids (BCAAs), intravenous (IV) L-ornithine L-aspartate (LOLA), probiotics, and other antibiotics, have also been used. In the hospital, a nasogastric tube can be used to administer oral therapies in patients who are unable to swallow or have an aspiration risk. Lactulose is generally used as initial treatment for OHE. A large meta-analysis of trial data did not completely support lactulose as a therapeutic agent for treatment of OHE, but for technical reasons, it did not include the largest trials, and these agents continue to be used widely.90 Lack of effect of lactulose should prompt a clinical search for unrecognized precipitating factors and competing causes for the brain impairment. Though it is assumed that the prebiotic effects (the drug being a nondigestible substance that promotes the growth of beneficial microorganisms in the intestines) and acidifying nature of lactulose have an additional benefit beyond the laxative effect, culture-independent studies have not borne those out.75, 91 In addition, most recent trials on lactulose have been open label in nature. Cost considerations alone add to the argument in support of lactulose.92 In some centers, lactitol is preferred to lactulose, based on small meta-analyses of even smaller trials.93, 94 In populations with a high prevalence of lactose intolerance, the use of lactose has been suggested.95 However, the only trial to show that stool-acidifying enemas (lactose and lactulose) were superior to tap-water enemas was underpowered.96 The use of polyethylene glycol preparation97 needs further validation. The dosing of lactulose should be initiated98 when the three first elements of the four-pronged approach are completed, with 25 mL of lactulose syrup every 1-2 hours until at least two soft or loose bowel movements per day are produced. Subsequently, the dosing is titrated to maintain two to three bowel movements per day. This dose reduction should be implemented. It is a misconception that lack of effect of smaller amounts of lactulose is remedied by much larger doses. There is a danger for overuse of lactulose leading to complications, such as aspiration, dehydration, hypernatremia, and severe perianal skin irritation, and overuse can even precipitate HE.99 Rifaximin has been used for the therapy of HE in a number of trials100 comparing it with placebo, other antibiotics, nonabsorbable disaccharides, and in dose-ranging studies. These trials showed effect of rifaximin that was equivalent or superior to the compared agents with good tolerability. Long-term cyclical therapy over 3-6 months with rifaximin for patients with OHE has also been studied in three trials (two compared to nonabsorbable disaccharides and one against neomycin) showing equivalence in cognitive improvement and ammonia lowering. A multinational study101 with patients having two earlier OHE bouts to maintain remission showed the superiority of rifaximin versus placebo (in the background of 91% lactulose use). No solid data support the use of rifaximin alone. Many drugs have been used for treatment of HE, but data to support their use are limited, preliminary, or lacking. However, most of these drugs can safely be used despite their limited proven efficacy. An updated meta-analysis of eight randomized, controlled trials (RCTs) indicated that oral BCAA-enriched formulations improve the manifestations of episodic HE whether OHE or MHE.102, 130 There is no effect of IV BCAA on the episodic bout of HE.127 These agents, through their metabolism, a