FEATURE HEPATOLOGY 053
DIAGNOSIS AND MANAGEMENT OF HEPATIC ENCEPHALOPATHY
By: Professor Simon D. Taylor-Robinson, The London Clinic, London, United Kingdom
INTRODUCTION Hepatic encephalopathy (HE) is a serious and potentially fatal complication of both acute and chronic liver disease, arising because of hepatocellular failure, cirrhosis and/or portal-systemic shunting. It reflects a broad spectrum of neuropsychiatric abnormalities, encompassing a range of defects in psychomotor, locomotive, cognitive, emotional, and behavioural functions. HE is recognised as being either overt (OHE), or minimal (MHE). While OHE can be diagnosed using bedside clinical tests, MHE is clinically invisible and requires psychometric testing. The rising prevalence of end-stage viral hepatitis related liver disease, coupled with the growing problem of alcoholic and non-alcoholic fatty liver disease, has significantly increased the burden of disease from cirrhosis. Therefore, recognition and appropriate management of the manifestations of decompensating cirrhosis (including HE), is essential. HE is associated with a substantial societal burden due to its impact on survival, quality of life, and daily functioning, including an impaired ability to drive, leaving patients especially vulnerable to road traffic accidents.
NOMENCLATURE According to international consensus guidelines HE is classified into type A (due to acute liver failure), B (due to portosystemic bypass) or C (due to cirrhosis). Of these, type C is the most frequently encountered.
PATHOPHYSIOLOGY The pathogenesis of HE has not yet been fully elucidated. It is accepted that a hyperammoniaemic state, combined with an inflammatory response leads to varying degrees of cerebral oedema, which is thought to account for the symptoms observed. However, the molecular mechanisms leading to these changes continue to be disputed.
Ammonia
The metabolism of nitrogen-containing compounds releases ammonia. Ammonia is toxic and is therefore metabolised to urea, which can be easily excreted via the kidneys. However, liver failure can impair urea cycle function. Subsequently, the brain becomes a significant ‘ammonia sink’. Astrocytes are a site of conversion for ammonia to glutamine, and as ammonia concentration increases, intracellular glutamine levels rise. Glutamine is an osmolyte and draws water into the astrocyte, causing it to swell, leading to cerebral oedema.
GABA/Benzodiazepine GABA is the major inhibitory neurotransmitter in the brain. Benzodiazpeines act on the GABA receptor complex to cause neuroinhibition. HE results in an accumulation of endogenous benzodiazepines, which augments GABA-ergic transmission. Intestinal flora can contribute to the increased GABA-ergic tone seen in these patients by providing precursors, which are converted into natural benzodiazepines in the brain.
Branched chain amino acids Branched chain amino acids (BCAA), such as leucine, isoleucine and valine, and aromatic amino acids (AAA), such as phenylalanine, tryptophan and tyrosine, are competitively taken up across the blood brain barrier. In liver failure, skeletal muscle is used as an ammonia sink to detoxify ammonia, through conversion to glutamine. This results in a fall in BCAA levels. Therefore, higher levels of AAA enter the brain, where they act as substrates for the synthesis of neuroactive substances, such as tryptophan and serotonin, which are harmful in excess.
INVESTIGATION OF HE A detailed history is essential to determine the aetiology of the underlying liver disease, in order to ascertain whether hepatocellular failure is a result of ALF or CLD. HE during an episode of ALF can progress quickly to coma and death from cerebral oedema. CLD by contrast, tends to be characterised by a chronic fluctuating encephalopathy, and in this situation, it may be possible to elicit specific clinical signs. Jaundice and ascites may be present in conjunction with HE, reflecting decompensated chronic liver disease. Although asterixis is not specific to HE, it is commonly seen in CLD potentially as a result of disturbance to the basal ganglia. Patients who are not able to raise their hands up to demonstrate adequately a ‘flapping tremor’, can be assessed by the examiner passively dorsiflexing the patient’s wrists or gripping the hands. Asterixis is confirmed by an oscillatory grip, which fluctuates between tight and loose.
MANAGEMENT OF HE The approach to diagnosis of HE initially requires the exclusion of other conditions which can mimic HE, and the identification of potential precipitating factors, principally sepsis, GI bleeds, drugs and constipation (see box 1). The assessments used to diagnose HE broadly encompass five categories: clinical assessment scales, neuropsychometric tests, which comprise ‘paper and pencil’ tests and computerised tests, neurophysiological assessments, brain imaging, and measurement of blood ammonia levels. OHE is typically graded using clinical scales; the most widely used being the West Haven criteria (see box 2). However, the most reproducible stages of assessment tend to be above grade 2. By contrast, diagnosis of MHE requires specialised neuropsychometric
tests, as these patients tend to have cognitive dysfunction in the absence of clinical features indicative of OHE. Neuropsychometric testing focuses on attention span, short-term memory, and executive functioning as these cognitive domains tend to be impaired in MHE. The psychometric HE score (PHES) is a 5-part bedside test, which can be performed easily in the clinical setting (see figure 1). It has a high specificity for detection of MHE, and has been internationally endorsed as the ‘gold standard’ for diagnosis of MHE in Europe. Of the computerised assessments, the system designed by the Cognitive Drug Research (CDR), Goring-on-Thames, UK, has been shown to correlate well with the PHES test, and is used in the UK. However, it is not as suitable for the bedside as the PHES test. Neurophysiological tests range from a simple EEG to advanced techniques of evoked potentials. A reduced level of neural electrical
www.lifesciencesmagazines.com
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84