Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:279–293 279 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from NEUROLOGY AND MEDICINE Neurology and the liver E A Jones, K Weissenborn Neurological syndromes commonly occur in pathy associated with increased portal- patients with liver disease. A neurological syn- systemic shunting in the absence of drome associated with a liver disease may be a unequivocal evidence of hepatocellular complication of the disease, it may be induced insuYciency—for example, shunting second- by a factor that also contributes to the ary to a congenital portal-systemic shunt, disease—for example, alcohol—or it may have extrahepatic portal hypertension or portal no relation to the presence of the liver disease. hypertension due to hepatic fibrosis (for exam- Neurological deficits associated with liver ple, schistosomiasis). disease may aVect the CNS, the peripheral Subclinical hepatic encephalopathy is the nervous system, or both. This review focuses term applied to a patient with chronic liver dis- on syndromes characterised by altered CNS ease (for example, cirrhosis) when routine function associated with structural liver dis- neurological examination is normal, but appli- eases. Space does not permit consideration of cation of psychometric or electrophysiological peripheral neuropathies associated with liver tests discloses abnormal brain function that disease (for example, xanthomatous peripheral can be reversed by eVective treatment for neuropathy), diseases of childhood that aVect hepatic encephalopathy.8 the liver and CNS (for example, Reye’s Fulminant hepatic failure and subfulminant syndrome), or neurological consequences of (or late onset) hepatic failure are terms used copyright. hepatic lesions characterised by specific en- when the syndrome of acute liver failure is zyme deficiencies (for example, congenital complicated by hepatic encephalopathy within hyperammonaemias, the porphyrias, kern- one to several weeks of the first evidence of liver icterus, galactosaemia, and Zellweger’s syn- disease or the development of jaundice.910 drome (cerebrohepatorenal syndrome)). Hepatic encephalopathy occurring in a That there is a relationship between the patient with cirrhosis may be either acute or functional status of the liver and that of the chronic. The acute form in such a patient is brain has been known for centuries.1 The most usually associated with a clearly identifiable widely recognised aspect of this relation is that precipitating factor and usually resolves when hepatocellular failure may be complicated by the precipitating factor is removed or cor- the behavioural syndrome of hepatic encepha- rected. Failure to find a precipitating factor lopathy, in which neurotransmission in the may imply that a decrease in overall hepatocel- http://jnnp.bmj.com/ brain is altered.23 Recently, it has been lular function has taken place. The term suggested that two other behavioural complica- chronic hepatic encephalopathy (or chronic tions of liver disease, scratching due to pruritus portal-systemic encephalopathy) is often ap- in cholestatic patients45 and profound fatigue plied to a patient with cirrhosis and substantial in patients with chronic cholestasis,67may also Department of portal-systemic shunting, who has hepatic Gastrointestinal and be associated with altered neurotransmission in encephalopathy that is persistent or episodic, Liver Diseases, the brain. with or without complete resolution of en- Academic Medical cephalopathy between episodes. on September 24, 2021 by guest. Protected Center, 1105 AZ Hepatic encephalopathy It has been conventional to classify hepatic Amsterdam, The DEFINITIONS AND CLASSIFICATION encephalopathy as a reversible metabolic en- Netherlands E A Jones The term hepatic encephalopathy refers to the cephalopathy. This definition excludes rare syndrome of neuropsychiatric disturbances neurodegenerative disorders associated with Neurologische Klinik, that may arise as a complication of acute, suba- chronic liver disease and extensive portal Medizinische cute, or chronic hepatocellular failure. The systemic shunting (see Degenerative disorders Hochschule Hannover, syndrome is associated with increased portal- section). However, this widely accepted 30623 Hannover, systemic shunting of gut derived constituents classification of hepatic encephalopathy may Germany 11 12 K Weissenborn of portal venous blood, due to their impaired need reappraisal. It is probably useful to extraction by the failing liver and, in most classify cerebral oedema and raised intracranial Correspondence to: instances, their passage through intrahepatic pressure (ICP) occurring in patients with Dr E A Jones, Academisch and/or extrahepatic portal-systemic venous fulminant hepatic failure separately from he- Medisch Centrum, Department of collateral channels. patic encephalopathy. However, these compli- Gastrointestinal and Liver The term portal-systemic encephalopathy is cations of fulminant hepatic failure contribute Diseases, Room C2–330, often used interchangeably with hepatic en- to encephalopathy, occur together with hepatic Meibergdreef 9, 1105 AZ Amsterdam Zuidoost, The cephalopathy, but portal-systemic encephalo- encephalopathy, and may share pathogenic fac- Netherlands. pathy can be defined to include encephalo- tors with hepatic encephalopathy (for example, 280 Jones, Weissenborn J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.279 on 1 September 1997. Downloaded from Table 1 The clinical stages of hepatic encephalopathy pathognomonic, of liver failure; it may occur in hypoxia, hypercapnia, uraemia, heart failure, or Stage Mental state sedative overdosage. I Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, untidiness, slurred speech, irritability, DIFFERENTIAL DIAGNOSIS reversal of sleep rhythm II Drowsiness, lethargy, gross deficits in ability to perform mental tasks, The diVerential diagnosis of hepatic encepha- obvious personality changes, inappropriate behaviour, intermittent lopathy includes alcohol intoxication and with- disorientation (usually for time), lack of sphincter control drawal syndromes, Wernicke’s encephalopathy, III Somnolent but rousable, unable to perform mental tasks, persistent disorientation with respect to time and/or place, amnesia, occasional fits KorsakoV’s syndrome, intoxication with of rage, speech present but incoherent, pronounced confusion sedative/hypnotic drugs, other metabolic en- IV Coma, with (IVA) or without (IVB) response to painful stimuli cephalopathies (for example, hypernatraemia From Adams and Foley13 with modifications. or hyponatraemia, uraemia, hyperglycaemia or hypoglycaemia, hypercapnia), Wilson’s disease, raised ammonia concentrations) (see Fulmi- consequences of head trauma (for example, nant hepatic failure section). subdural haematoma) and organic intracranial lesions. Delirium tremens (DTs) may occur in CLINICAL FEATURES a patient with underlying alcoholic liver The term encephalopathy covers a wide range disease. It is important, therefore, to distin- of neuropsychiatric disturbances ranging from guish this syndrome from hepatic encephalopa- minimal changes in personality or altered sleep thy. In contrast to asterixis associated with pattern to deep coma13 (table 1). The earliest hepatic encephalopathy, patients with DTs clinical signs of hepatic encephalopathy (stage have a rapid postural and action tremor. 1) are often subtle psychiatric and behavioural Furthermore, the manifestations of DTs, changes that may be more apparent to the including delirium, suggest cortical excitation patient’s family and close friends than to the rather than the presumed cortical inhibition neurologist.14 15 These changes are primarily that seems to characterise hepatic encepha- due to mild impairment of intellectual function lopathy. Benzodiazepines are commonly given that reflect predominantly bilateral forebrain, in the management of DTs. Patients with parietal, and temporal dysfunction. In early chronic liver disease have increased sensitivity stages of hepatic encephalopathy the presence to the neuroinhibitory eVects of these drugs.20 of pronounced intellectual impairment may be Other CNS complications of alcoholism, such masked by relatively well preserved verbal as Wernicke’s encephalopathy and KorsakoV’s ability.16 17 Whether patients with subclinical psychosis, are also not dependent on the devel- copyright. hepatic encephalopathy should be considered opment of alcoholic liver disease. unfit to drive a car is uncertain.17 18 As encephalopathy progresses, intellectual abili- DIAGNOSIS ties deteriorate overtly (with deterioration of When patients, with and without known liver performance at school or work), motor func- disease, present with neuropsychiatric symp- tion becomes impaired, and consciousness toms or neurological signs, it is necessary to ask decreases. With further progression coma one of the following questions: (1) Does this ensues. Neurological signs vary with progres- patient have hepatic encephalopathy? or (2) sion of hepatic encephalopathy. Hypertonia, Could this patient have hepatic encephalopa- hyperreflexia, and positive Babinski signs may thy? There are two components to making a be elicited and tend to precede the occurrence diagnosis of hepatic encephalopathy: one is to of hypotonia and diminished deep tendon determine that subclinical or overt encepha- http://jnnp.bmj.com/ reflexes in late