The importance of hepatic encephalopathy: Pre-transplant and post-transplant

Field: Medicine (Health Sciences)

This issue of Liver Transplantation features an interesting article by Sotil et al.1 that further substantiates the clinical significance of hepatic encephalopathy (HE) and its potential effect on patient functioning in the years following liver transplantation (LTX). With the implementation of the Model for End-Stage Liver Disease (MELD) system of organ allocation, HE was not included in the MELD score for prioritizing patients for LTX because it was not found to influence short-term survival.2 However, Sotil et al. suggest that beyond the prediction of survival, pre-LTX HE has important implications for persisting neurological deficits post-LTX. Their point is well taken. Transplant outcomes have largely moved beyond mere survival to improving patient quantity and quality of life. In this context, the importance of HE cannot be overemphasized. Diagnosing HE is essential to improving treatment and prognosticating about the potential for recovery following LTX. Clinicians, patients, and families alike need to be aware of the signs and symptoms of HE in order to prepare for LTX and the post-LTX recovery. Although the current study by Sotil et al. highlights the critical issue of the persistence of post-LTX cognitive impairment, it additionally raises the yet unanswered question of whether early identification and treatment could prevent or at least minimize these persisting effects. Several key points on HE deserve further discussion. As proposed by Ferenci et al.3 in the 2002 final report of the working party on HE, every effort should be made to better define and quantify the degree of HE. This is especially important for patients undergoing evaluation for listing for LTX and for patients on the waiting list for LTX. HE is a complex neuropsychiatric syndrome characterized by a constellation of signs and symptoms, which can include alteration of consciousness (up to and including stupor or coma), cognitive impairment, confusion/disorientation, affective/emotional dysregulation, psychosis, behavioral disturbances, bioregulatory disturbances, and disturbances of the motor system represented by asterixis, extrapyramidal symptoms, tremor, increased tendon reflexes, increased muscle tone, ataxic gait, bradykinesia, slurred speech, or incoordination. Although Sotil et al.1 relied on the diagnosis of overt HE, the current definition of HE emphasizes that it reflects a continuum of symptoms, with subclinical HE lying at the minimal end of the spectrum.3 Although gross disorientation and bizarre behavior (eg, lack of restraint, inappropriate behavior, psychotic symptoms, and nocturnal ramblings) are easily identifiable, minimal symptoms can manifest as slight deficits in attention and personality or mood changes most often noticed only by family or those who know the patient well. Thus, in addition to clinical interviews of the patient and family about such subtle changes, subclinical HE by definition will be revealed only by psychometric testing. Neuropsychological tests of psychomotor speed, praxis, concentration, and attention, such as the Number Connection tests (A and B) and the Digit Symbol and Block Design tests from the Wechsler Adult Intelligence Scale–Revised, which were used in Sotil et al.'s study post-LTX, are commonly used to identify pre-LTX subclinical HE. HE, hepatic encephalopathy; LTX, liver transplantation; MELD, Model for End-Stage Liver Disease. In a previous editorial on HE in Liver Transplantation, Thornton and Mullen4 state "the concept that a syndrome as complicated as HE can be measured by a single point in time may be flawed." Episodic encephalopathy needs to be differentiated from persistent encephalopathy, and both need to be differentiated from minimal encephalopathy. This would require repeated, periodic reassessment, perhaps at defined intervals. For episodic or persistent encephalopathy, the West Haven criteria, which grade HE from I to IV, as well as the Glasgow coma scale have been widely used. However, as these scales do not fully reflect the progression of HE symptoms, recent scales to assess the severity of HE across a continuum are being developed.5 Persistent HE is rare and is observed predominantly in patients with extensive portocaval collateral circulation or after surgical or transjugular portosystemic stent shunting procedures.6 Whether surgical or radiological closure of a dominant shunt should be considered to manage severe or persistent HE remains controversial. As defined by the working party, "HE is a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease."1 Thus, establishing the persistence of symptoms is essential to differentiating between the typically fluctuating course of HE and more persisting cognitive impairments that may indicate preexisting dementia or a static cognitive deficit. Persisting cognitive deficits may reflect the neurologic sequelae of underlying brain pathology. This distinction may be difficult to determine and requires a good historical accounting of the patient's cognitive course by the treating clinicians, patient, and family members. Cognitive symptoms that predate the onset of liver disease may be most informative of a potentially non-HE origin. In dementia, the symptoms typically are not of acute onset and do not fluctuate as significantly as in HE, and patients may be more likely to have memory loss with aphasia, apraxia, or agnosia in addition to the disordered executive functioning seen in HE (ie, personality changes and disinhibition). Risk factors for persisting cognitive deficits should be elicited (eg, advanced age, family history of dementia, hypertension, diabetes, stroke, prior head trauma, and significant alcohol exposure). Those with preexisting cognitive deficits are at increased risk of HE and may have both. Unfortunately, cognitive testing is not specific to HE, and many symptoms of minimal HE and dementia overlap. Electroencephalograms are not very sensitive to the identification of minimal HE and also may not distinguish HE from early dementia. Nonspecific findings such as mild slowing of the background frequency can be present in both disorders. Computed tomography and magnetic resonance imaging abnormalities (edema, atrophy, volume loss, and small-vessel disease) may identify structural changes in patients with advanced liver disease, but these findings can also be observed in those not overtly encephalopathic.7 Newer neurophysiological imaging technologies (eg, functional magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography) may provide important information on neuronal functioning and even on the biological mechanisms underpinning HE8 but have not been widely tested and are not used clinically for the diagnosis of HE. Optimal treatment of HE with subsequent neuropsychological retesting may aid in the identification of those deficits that may be more persistent. It is also essential to rule out other medical disorders, some potentially reversible, that may be contributing to pre-LTX mental status changes. For example, in Sotil et al.'s cohort,1 24% of those with overt HE also required a kidney transplant versus none of the non-HE group.1 In addition to cognitive impairment from uremic encephalopathy, it is well established that renal function is important for ammonia metabolism in patients with cirrhosis. In a study by Kalaitzakis and Bjornsson,9 in which they prospectively evaluated for the presence of cognitive dysfunction using the West Haven criteria and 2 psychometric tests, they found that cognitive dysfunction was related to serum creatinine and the glomerular filtration rate. They concluded that renal impairment was related to cognitive impairment in patients with cirrhosis and might be implicated in the pathogenesis of HE. The identification of HE is important because its symptoms directly affect patient quality and quantity of life both pre-LTX and post-LTX. Minimal HE predicts overt HE, and fulminant HE is associated with intracranial hypertension, seizures, cerebral edema, and death pre-transplant.3 Subclinical HE is equally important, as it is often clinically missed, can affect up to 60% of patients with cirrhosis, and can impair patient occupational and social functioning and safety.6 For example, one study found that 85% of patients with subclinical HE were either of questionable fitness or unfit to drive on psychometric testing of driving capacity.10 In addition, although the authors reported on the persisting effects of overt HE post-LTX, subclinical HE is also associated with persisting cognitive deficits post-LTX.7 The determination of HE (ostensibly reversible) versus persisting cognitive deficits, while not exact, will aid both clinicians and patients alike in preparing for post-LTX recovery and/or possible further cognitive complications. Patients with preexisting brain lesions (eg, small-vessel disease and prior damage from alcohol, stroke, or trauma), which may be contributing to pre-LTX cognitive impairments, may also have higher sensitivity to central nervous system insults in the perioperative period. Advanced age is also associated with decreased central nervous system homeostatic reserve, increased sensitivity to neuronally active medications, and impaired adaptability,11 which make the older brain more vulnerable to central nervous system insults. A simple model of 4 preoperative variables (alcoholic or metabolic etiology, MELD > 15, mechanical ventilation, and nonelective transplantation) reportedly identifies patients at a higher risk for post-LTX neurological complications.12 Thus, although the effects of HE may be expected to resolve, albeit slowly over time post-LTX, additional insults (eg, respiratory failure, intraoperative events, hypertension or hypotension, calcineurin-inhibiting immunosuppressive medications, and infections including hepatitis C virus) may add to existing cognitive deficits and slow or limit the maximal potential cognitive recovery post-LTX. Therefore, the prediction of recovery from HE needs to be informed by knowledge of the degree and persistence of HE, other comorbid medical disorders, the presence of preexisting possibly irreversible cognitive deficits, and the potential for additional post-LTX insults. This awareness is especially pertinent given the progressive trend toward a current recipient population that is older, has higher MELD scores and poorer renal functioning, and is increasingly requiring combined liver/kidney transplantation in comparison with the recipient population in the last decade.13 The uncertain contribution of severe or persisting HE to irreversible cognitive impairment and whether such patients should be given a higher priority (i.e. MELD exception) in hopes of preventing such damage have not been established. In the meantime, ongoing, standardized evaluations and aggressive treatment of HE symptoms during the pre-LTX phase are an endeavor that every liver transplant program should strive to undertake. Such standardized assessments will provide the necessary data on the course of pre-LTX HE, will inform the development of more effective treatment algorithms, and will eventually lead to a more precise understanding of the contribution of HE to post-LTX outcomes. Only then can prospective studies disentangle these complex issues and provide clinical guidelines for the treatment and recovery of LTX patients with pre-LTX cognitive deficits.