Hepatic and Pancreatic Encephalopathy

Keywords

acute liver failure, hepatic encephalopathy, cirrhosis-related parkinsonism, hepatic myelopathy, pancreatic encephalopathy

Hepatic Encephalopathy

Definition

The term hepatic encephalopathy (HE) refers to any type of cerebral dysfunction that is due to liver insufficiency and/or portosystemic shunting and is detectable by either clinical, neuropsychologic or neurophysiologic means. Three types of HE are differentiated based on the underlying cause: type A occurs in patients with acute liver failure, type B in patients with portosystemic shunting in the absence of liver dysfunction, and type C in patients with cirrhosis. Episodic, recurrent and chronic progressive forms have been described.

Clinical Features

HE is characterized by alterations of cognition, motor function, and consciousness in various combinations. The most commonly used grading system that distinguishes grades of HE (I-IV) based on degree of alteration in consciousness is the West Haven system ( Table 12-1 ). Motor symptoms can be detected in all grades, but with increasing frequency and severity in grades II and III ( Fig. 12-1 ). The most characteristic motor findings are extrapyramidal and cerebellar symptoms, including hypomimia, hypo- and bradykinesia, rigidity, tremor, dysarthria, dysdiadochokinesia, and ataxia. Hyperreflexia and pyramidal signs are observed predominantly in patients with grade III and IV encephalopathy. Asterixis (flapping tremor), a form of negative myoclonus, may be present in the absence of any alteration of consciousness or cognition, but is observed most frequently in patients with grade II or III disease.

Table 12-1

West Haven Criteria for Grading of Clinically Overt Hepatic Encephalopathy

From Ferenci P, Lockwood A, Mullen K, et al: Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716, 2002, with permission.

Grade I	Trivial lack of awareness, shortened attention span, impaired performance of addition, euphoria or anxiety
Grade II	Lethargy or apathy, minimal disorientation for time and place, inappropriate behavior
Grade III	Somnolence to semistupor but responsiveness to verbal stimuli, confusion, gross disorientation
Grade IV	Coma

Difficulties in writing and speech disturbances are some of the first symptoms of HE. In the early phases, tremulous writing, omission of single letters, reversal of order, and misspellings are common. With later stages of HE, letters become superimposed and lines of writing converge. Patients become unable to sign their names or to move the pencil from left to right. Speech, initially monotonous and slowed, becomes slurred and unintelligible with associated dysphasia in later stages of the illness.

Personality changes and alterations of mood may be the first symptoms of HE and are generally first observed by relatives or friends. As the disease progresses, patients may become uninhibited and bizarre due to increasing difficulties in visual perception and disorientation, illusions and hallucinations. Mood alterations including euphoria and depression are common and may exhibit rapid fluctuations.

Chronic Progressive Hepatic Encephalopathy

The chronic progressive (or persistent) form of HE has predominantly been observed in patients with extensive portosystemic shunting that developed either spontaneously or after transjugular intrahepatic portosystemic stent shunting (TIPPS) or other shunting procedures. Data regarding the prevalence of this subtype of HE are sparse. Cirrhosis-related parkinsonism and hepatic myelopathy are the best-characterized manifestations of this form of HE. In a prospective study of 214 patients with cirrhosis awaiting liver transplantation, cirrhosis-related parkinsonism was found in 4 percent and hepatic myelopathy in 2 percent of patients. The parkinsonian patients show hypomimia, hypokinesia, tremor, and rigidity similar to patients with idiopathic Parkinson disease (PD), but typically they do not develop the characteristic shuffling gait of PD and have predominant involvement of their upper limbs. Moreover, symptoms develop faster and are symmetric more often. Tremor occurs predominantly with action; a parkinsonian rest tremor is observed less commonly. The extrapyramidal symptoms may be associated with cerebellar and corticospinal deficits.

Some patients present with a combination of cirrhosis-related parkinsonism and hepatic myelopathy. The myelopathy is characterized by a rapidly progressive spastic paraparesis without accompanying sensory deficits or disturbances of bladder or bowel functions. After only a few months of progressive disability, most patients with hepatic myelopathy either depend upon an assistive device or are confined to a wheelchair. For unknown reasons most patients with hepatic myelopathy are men, whereas cirrhosis-related parkinsonism is equally prevalent in men and women.

Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy is considered the mildest form of HE and is defined as cerebral dysfunction detectable only by neuropsychologic or neurophysiologic means in the absence of clinically overt symptoms of encephalopathy. The concept of minimal HE was developed in the 1970s when it became obvious that some patients who were considered unimpaired clinically nevertheless had significant deficits in attention, visual perception, and motor speed and accuracy on neuropsychometric tests ; some only showed slowing of the electroencephalogram (EEG). These observations led to this early stage of HE being added to established grading systems.

The prevalence of minimal HE ranges between 30 and 60 percent of patients with HE. Variations in prevalence estimates are due to differences in methods used for diagnosis and population differences regarding underlying liver disorders.

It has been suggested that minimal and grade I HE should be merged into a new class termed “covert HE” as grade I HE may only be apparent to clinicians with experience in neurologic assessment. More detailed clinical examination of HE patients yields a higher number with grade I HE and fewer with minimal HE. In one study, among patients initially thought to be clinically unimpaired, bradykinesia, tremor, and hyperactive muscle stretch reflexes were detected in about 30 percent when examined in detail, and 50 percent of these patients showed eye movement abnormalities indicating cerebellar dysfunction.

Encephalopathy in Acute Liver Failure

In diagnosing acute liver failure (ALF), the presence of HE is a prerequisite in patients with jaundice, coagulopathy, and no preexisting liver disease. Thus, HE is present by definition in all patients with ALF. In contrast, clinically overt HE is prevalent in 10 to 14 percent of all cirrhotic patients, and in about 20 percent of patients with decompensated cirrhosis. The risk of developing recurrent HE is 40 percent within 1 year.

In contrast to HE in patients with liver cirrhosis, HE with ALF may be complicated by significant brain edema (25 to 35% in grade III; 65 to 75% in grade IV). Currently there seems to be a decline in the prevalence of brain edema in patients with ALF for unclear reasons. An analysis of the case records of 3,305 patients with ALF or acute liver injury from King’s College Hospital, London, between 1973 and 2008 showed that the proportion of patients with intracranial hypertension fell from 76 percent in the period from 1984 to 1988 to 20 percent in 2004 to 2008. Multivariate analysis showed an association of intracranial hypertension with younger age, female gender, and elevated international normalized ratio (INR).

ALF patients usually present initially as restless, agitated, and irritable, whereas HE in patients with cirrhosis usually begins with psychomotor slowing. With increasing grade of HE, clinical presentations are more similar, as depressed consciousness predominates. Extrapyramidal symptoms are not typically observed in patients with ALF, but signs of corticospinal tract dysfunction are present. Seizures are a frequent complication of ALF, but occur only rarely in patients with cirrhosis.

Diagnosis of Forms of Hepatic Encephalopathy

The diagnosis of HE can only be made after exclusion of other possible causes of brain dysfunction, as the symptoms are not specific. Hyponatremia, hypo- or hyperglycemia, uremia, diabetes mellitus, and renal dysfunction are frequent in patients with cirrhosis and may resemble HE. Other important disorders to distinguish are septic encephalopathy and Wernicke encephalopathy. In a neuropathologic study of the brains of 32 patients with cirrhosis who died with HE, cerebellar lesions suggestive of Wernicke encephalopathy were observed in 50 percent; the diagnosis of Wernicke encephalopathy was made in 9 patients, whereas in only 2 patients had the diagnosis been made clinically.

Due to altered coagulation, intracranial hemorrhage must be considered in the differential diagnosis of HE, and brain imaging should be obtained in all patients, usually with noncontrast computed tomography (CT). Magnetic resonance imaging (MRI) requires much more cooperation than CT, and thus is not practical in agitated patients.

Hepatic encephalopathy may occasionally present with focal neurologic symptoms such as dysphasia or hemiparesis. Of 10 observed focal presentations of HE, only 2 were due to intracranial hemorrhage.

Cirrhosis-Related Parkinsonism

In patients with cirrhosis who develop clinical signs of extrapyramidal motor dysfunction, the differential diagnosis includes acquired hepatocerebral degeneration or an independent neurodegenerative disease. The course of the disease and the symptom combination may help to differentiate between these entities.

The clinical features of cirrhosis-related parkinsonism resemble those of patients with PD. As discussed earlier, however, symptoms in PD are more often asymmetric, develop more slowly, may be associated with early gait abnormalities, are not accompanied by cerebellar or corticospinal deficits, and respond well to dopaminergic drugs.

More difficult is the distinction from multiple system atrophy (MSA), which combines extrapyramidal symptoms with cerebellar and pyramidal deficits and thereby can resemble cirrhosis-related parkinsonism. MSA likewise shows rapid progression and often a poor response to dopaminergic agents. In contrast to patients with cirrhosis-related parkinsonism, however, patients with MSA characteristically show severe autonomic dysfunction and many show alterations of the basal ganglia, midbrain, and cerebellum on MRI. Single-photon emission computed tomography (SPECT) in patients with cirrhosis-related parkinsonism shows a decreased binding capacity of striatal dopamine receptors and the dopamine transporter similar to the findings in MSA but different from those in PD, in which there is decreased availability of the transporter but not of the receptors.

Hepatic Myelopathy

A diagnosis of hepatic myelopathy can be based on the clinical findings of myelopathy and exclusion of other possible causes through MRI and cerebrospinal fluid analysis, both of which are normal in hepatic myelopathy.

Minimal Hepatic Encephalopathy

The diagnosis of minimal HE depends on the results of neuropsychologic or neurophysiologic examinations in the setting of a normal clinical examination. Debate about the most useful method for diagnosing minimal HE is ongoing. Currently the PSE Syndrome Test, Inhibition Control Test, critical flicker frequency analysis, and automated EEG analysis are the most frequently used methods. A combination of the number connection tests A and B and either the digit symbol test or the block design test, or both, are used as an alternative. Working groups commissioned to elaborate an expert recommendation for diagnosing minimal HE agreed on the PSE Syndrome Test as valuable, objective, and reliable. For the United States, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been recommended as an alternative, because it is a valid, objective, and reliable test battery, and there are no US norms for the PSE Syndrome Test. However, the RBANS has only rarely be used for diagnosing minimal HE, and thus data regarding its suitability for this purpose are sparse.

The PSE Syndrome Test is a battery of five paper-pencil tests: the number connection tests A and B, the digit symbol test, the serial dotting test, and the line-tracing test. The latter is evaluated by measuring the time needed to perform the test and the number of errors that occur. Thus, six subtest results are scored compared to normative values. A sum score termed the portosystemic hepatic encephalopathy score (PHES) is generated ranging between+6 and−18 points; scores lower than−4 are considered pathologic. The PHES correlates significantly with cerebral glucose utilization at rest in patients with minimal HE. It is a reliable predictor of the risk of developing overt HE as well as of mortality.

The critical flicker frequency is a psychophysiologic test that has been used in the past for the assessment of central nervous system drug effects. It was recommended for diagnosing minimal HE in 2002. Light pulses are presented to the subject in decreasing frequency (usually from 60 Hz downwards), and the subject has to react as soon as the impression of fused light switches to flickering light. The critical flicker frequency depends on the experimental setting—the color and luminance of the stimuli, distance between the light source and the subject’s eye, visual angle, and subject age. The assessment requires intact binocular vision and absence of red-green blindness. Normative data have to be elaborated for the specific equipment used. The results correlate with the portosystemic hepatic encephalopathy score and can predict the development of overt HE. Of note, scores in patients with alcoholic cirrhosis are lower than in patients with cirrhosis due to other causes. The results may be affected by propofol given during endoscopy, though only temporarily.

The Inhibitory Control Test (ICT) has been recommended for diagnosing minimal HE as well. It is freely available online ( www.hecme.tv ) and is a test of attention and response inhibition. Results depend on age and education and are compared with normative values.

The Continuous Reaction Time Test (CRT) requires a simple reaction to a series of 500-Hz tones. With developing HE, not only reaction time but especially the variability of reaction times increases. The reaction time variability is represented by the so-called CRT index, which is calculated from the 50th reaction time percentile/(90th−10th percentile). Recently it was shown that the CRT index does not depend on age or sex, and is more sensitive for cerebral dysfunction in patients with liver cirrhosis than the critical flicker frequency test.

The EEG has been used for diagnosing HE for decades after the observation that the amount of theta and delta activity increases with increasing grade of HE. This initially is associated with an increase in amplitude and the appearance of triphasic waves, followed in later stages by a decrease in amplitude, a discontinuous pattern, and finally isoelectricity in patients with coma ( Fig. 12-2 ). Occasionally it is unaltered in spite of clinically overt HE. Quantitative EEG analysis shows a decrease in the mean dominant frequency and an increase in theta and delta activity in only 15 to 30 percent of patients with cirrhosis having no clinical signs of HE, and in up to 40 percent of patients with clinically overt HE. Thus EEG appears more appropriate for serially following the progression of HE than for diagnosis.