17th February 2017

Hepatic encephalopathy (HE)

HE is the occurrence of confusion, altered level of consciousness and potentially coma due to the influence on the brain of toxic compounds that accumulate in the blood due to the inability of the cirrhotic liver to remove them from the blood, as would occur in healthy individuals. 1

Overt HE 1 Minimal/ Covert HE 2
Spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction and/or porto-systemic shunting Denotes subtle neuro-psychometric or neuro-psychological abnormalities without clinical evidence of mental change

The impact of hepatic encephalopathy (HE) on patients

  • Up to 45% of patients with cirrhosis are affected by overt HE 3
  • Each overt HE episode is likely to leave patients with cumulative cognitive impairment that affects memory and learning ability 4
  • Recurrent overt HE episodes have detrimental effects on physical activity, fatigue and emotional function 5
  • Compared with those without, patients with previous bouts of overt HE had a significantly worsened vitality, social and physical functioning 6

The risk of death increases with each overt HE episode 7

  • Hazard ratio (HR) for death for HE+ vs. HE- = 2.28 (95% CI 1.82-2.87)
  • No p value available
  • Data was selected between 1998-2012
Kaplan-Meier plot for survival of patients with liver disease from diagnosis of HE relative to matched liver disease control (N=778)

Kaplan-Meier plot for survival of patients with liver disease from diagnosis of HE relative to matched liver disease control
Adapted from Morgan et al. 2014 7


Pathophysiology

Ammonia is considered by many to be central in the pathogenesis of hepatic encephalopathy (HE).

Normal Individuals 8 Cirrhotic Patients 8,9
  • In normal individuals, ammonia is produced in the gut from protein metabolism and in the kidneys from glutamine metabolism.
  • The majority of ammonia is converted in the liver to glutamine and urea and subsequently excreted in the urine.
  • Muscle also detoxifies some ammonia by conversion to glutamine.
  • The capacity of the liver to metabolise ammonia is reduced due to decreased liver function.
  • Portal hypertension and portal-systemic shunting increase systemic exposure to ammonia.
  • The capacity of the muscle to metabolise ammonia is decreased due to reduced muscle mass (sarcopenia).
  • In the brain, astrocytes synthesise glutamine from ammonia and glutamate, and the ensuing osmotic change causes astrocytes to swell, which may lead to cerebral oedema.

Pathogenesis of HE
Adapted from Clayton, M. Guide to: hepatic encephalopathy, October 2016

Ammonia levels correlate poorly with clinical severity suggesting that other factors are also involved in the pathogenesis of HE.

Infection and Inflammation

  • Two important factors are infection and systemic inflammation. 10
  • Inflammatory mediators, such as nitric oxide and cytokines produced by infection or hepatocyte necrosis, lead to further increases in cerebral blood flow and delivery of ammonia to the brain. 11
  • Bacterial translocation may be dysregulated in cirrhosis and increased systemic exposure to bacteria and bacterial toxins could potentially contribute to HE 12

Diagnosis

HE may often go unrecognised unless it is severe. 1 HE should be regarded as a continuum ranging from unimpaired cognitive function and intact consciousness through to coma. 13

Grading of Hepatic Encephalopathy 13-19

Adapted from EASL/AASLD Guidelines 2014

Temporal and clinical detection of HE subtypes

Covert HE


Covert HE:
Denotes neuro-psychometric or neuro-psychological abnormalities without clinical evidence of mental change, but with subtle alterations in attention, psychomotor speed, working memory and visuospatial ability. Patients remain below the clinical detection level. 2,13

Episodic or Recurrent HE


Episodic HE or Recurrent HE:
Remains clinically undetectable in between HE episodes. 2,13

Episodic HE:
Denotes an isolated bout of HE. 2,13

Recurrent HE:
Denotes bouts of HE that occur with a time interval of 6 months or less. 2,13

Testing cognitive function

Click on each heading to find out more

Psychometric hepatic encephalopathy score (PHES) / Paper & Pencil tests:
The Psychometric Hepatic Encephalopathy Score (PHES) is known as the ‘gold standard’ pencil-and-paper test battery for the psychometric evaluation of patients with HE. This battery measures psychomotor speed and precision, visual perception, visuo-spatial orientation, visual construction, concentration, attention and memory, is simple to perform and can be completed in less than 20 minutes. 20 PHES is highly sensitive and specific (96% and 100% respectively) for determining covert HE. 21

Inhibitory control test (ICT):
This is a computerised test that assesses attention, response inhibition and working memory. Patients are shown a series of letters and are asked to respond to target sequences (X and Y, Y and X) while not responding to lures (X and X, Y and Y). This test is easy to administer and is reliable for the diagnosis of minimal HE. However training and specalised equipment are required. 21

Critical flicker (fusion) frequency (CFF) test:
The clicker flicker frequency (CFF) test measures cortical function, and correlates well with those of psychometric tests. Here patients are shown light pulses at an initial frequency of 60Hz and gradually reduced by 0.1Hz per second. Patients are asked to identify the time of which of the light begins to flicker.
CFF can be affected by medications, age, and equipment used. However, even with its limitations, the CFF is a simple, valid, and effective tool that can be used to diagnose covert HE. 21
Image supplied by nevoLAB

Imaging:
Electroencephalography (EEG) examination can detect changes in cortical cerebral activity across the spectrum of HE without patient cooperation or risk of a learning effect. However, it is nonspecific and may be influenced by accompanying metabolic disturbances, such as hyponatremia as well as drugs. 13 In patients with cirrhosis with increasing deterioration in neuropsychiatric status, there is an initial slowing in frequency with increasing amplitude, the amplitude then decreases. 1
UK/XIF5/0719/0520    DOP: October 2019

References

  1. Morgan M. Chapter 8: Hepatic Encephalopathy in Patients with Cirrhosis. In: Dooley JS, Lok A, Burroughs A, Heathcote J, editors. Sherlock’s Diseases of the Liver and Biliary System. 12th ed. London: Blackwell Publishing Ltd; 2011. p.121-51
  2. Bajaj J S, et al. Aliment Pharmacol Ther 2010;31:537–547
  3. Poordad FF. Aliment Pharmacol Ther 2006; 25 (Suppl 1):3-9
  4. Bajaj J S, et al. Gastroenterology 2010;138:2332-2340
  5. Sanyal A, et al. Aliment Pharmacol Ther 2011;34:853-861
  6. Moscucci F, et al. Liver Int 2011;31(10):1505-10
  7. Morgan et al. Mortality Associated with Hepatic Encephalopathy in Patients with Severe Liver Disease. Abstract poster presented at EASL-ILC London 2014
  8. Shawcross D, Jalan R. Lancet 2005; 365: 431-433
  9. Olde Damink SW,  et al. Hepatology 2002; 36: 1163-71
  10. Shawcross DL, et al.  J Hepatol 2011; 54: 640-649
  11. Coltart I, et al. Arch Biochem Biophys 2013; 536: 189-196
  12. Weist R, Lawson M and Geuking M. J Hepatol 2014; 60: 197-209
  13. EASL/AASLD Guidelines. J Hepatol 2014 
  14. Sidhu S, et al. Am J Gastroenterol. 2011;106:307–316
  15. Dyspraxia foundation UK, http://dyspraxiafoundation.org.uk/
  16. Weissenborn K. Neurochem Res. 2015;40:265
  17. Hepatic Encephalopathy - American Liver Association, he123.liverfoundation.org 
  18. Montagnese S, et al. Metab Brain Dis. 2012;27:567–572
  19. Bajaj J, et al. Am J Gastroenterol. 2011;106:1646–1653
  20. Nabi E, Bajaj JS. Current Gastroenterology Reports. 2014;16(1):362
  21. Patidar KR, Bajaj JS. Clinical Gastroenterology and Hepatology. 2015;13(12):2048-2061