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 1,2 Minimal/ Covert HE 2
Spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction and/or porto-systemic shunting Denotes subtle neuropsychometric or neuropsychological 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

Recurrent episodes of HE have a negative impact on the patient’s quality of life 5

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 10

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. 11
  • 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. 12
  • Bacterial translocation may be increased in cirrhosis and increased systemic exposure to bacteria and bacterial toxins could potentially contribute to HE. 13

 

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. 2

Grading of Hepatic Encephalopathy 2,14-19



Temporal and clinical detection of HE subtypes

Covert (minimal) 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. 2,20

Episodic or Recurrent HE

Episodic HE or Recurrent HE:
Remains clinically undetectable in between HE episodes. 2,20

Episodic HE:
Denotes an isolated bout of HE. 2,20

Recurrent HE:
Denotes bouts of HE that occur with a time interval of 6 months or less. 2,20


 

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 the current 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. 21 PHES is highly sensitive and specific (96% and 100% respectively) for determining covert HE. 22

Please note that different versions of the PHES/paper and pencil tests are available with local population-based normative values. Validated versions of the PHES are available in Germany, Italy, Spain, India, Korea and China. Please check for local versions of these tests where appropriate.

The LiverSync® app also allows patients with advanced liver disease and at risk of developing HE to regularly test their brain function and detect any early signs of change through tests including trail-making, line drawing and block design, amongst others. Download from the AppStore or from Google Play (please note that this is not currently available in all countries).


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. 22

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


GL-HEP-XIF-2000170    April 2021
You have reached the TARGAXAN® (rifaximin-α) website developed by Norgine to provide you with information about TARGAXAN®
Please select an option below:
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard (United Kingdom) or www.hpra.ie (Ireland)

Adverse events should also be reported to Medical Information at Norgine Pharmaceuticals Ltd on 01895 826606 or Email: medinfo@norgine.com

Product under licence from Alfasigma S.p.A. TARGAXAN is a registered trademark of the Alfasigma group of companies, licensed to the Norgine group of companies

NORGINE and the sail logo are registered trademarks of the Norgine group of companies

Date of preparation: May 2020 Job Code: UKE-HEP-XIF-2000012 © 2019 Norgine

Privacy Policy
Seven UK participating centres agreed a standardised data collection pro-forma. Patients with chronic liver disease who were treated with rifaximin-α for secondary prevention of overt hepatic encephalopathy (OHE) were included.* Details of all causes of HE and emergency hospital admissions were requested at 3, 6 and 12 months before and after rifaxamin-α initiation. Clinical data were recorded at baseline, at 3, 6 and 12 months before and after rifaximin-α initiation.
87% of patients (n=282) were taking concomitant lactulose.
*Some patients included were on 3 x 400 mg daily as this was prior to the launch of the K licensed dose of XIFAXAN® 550 mg twice a day.

External Link
You are now leaving the Norgine sponsored website and entering an external website.
Norgine is not responsible for the content of external websites

Please confirm you wish to follow this link.

External Link
You are now leaving the Norgine sponsored website and entering an external website.
Norgine is not responsible for the content of external websites

Please confirm you wish to follow this link.

External Link
You are now leaving the Norgine sponsored website and entering an external website.
Norgine is not responsible for the content of external websites

Please confirm you wish to follow this link.

External Link
You are now leaving the Norgine sponsored website and entering an external website.
Norgine is not responsible for the content of external websites

Please confirm you wish to follow this link.

An observational study including 127 patients from the Netherlands. Conducted between September 2015 to May 2018.
AIM: To assess hospital resource use, bacterial infections and adverse events in the 6 months before and after rifaximin-α initiation in patients with overt hepatic encephalopathy.

External Link
You are now leaving the Norgine sponsored website and entering an external website.
Norgine is not responsible for the content of external websites

Please confirm you wish to follow this link:

Costing Details

Inpatient costs were estimated in UK£ at 2013/14 prices from published NHS sources at a mean cost of £513(€569.43)* per day for non-elective admissions for liver disease.1

Rifaximin-α drug costs were calculated from the price published in the British National Formulary of £259(€287.75)* for 56 550mg tablets2, giving an annual drug treatment cost per patient of £3,379(€3750.69)* for the licensed dose of 550mg twice daily.

Please note that costs from this study were based on UK NHS sources and the UK BNF and have been calculated by using GBP to Euro conversion rate mentioned below. These prices may differ from local EU prices of XIFAXAN®.
*Values in Euros converted from values in Pound Sterling at an exchange rate of £1:€1.11 (correct as 03.11.20).

References

  1. NHS reference costs. Available at: www.gov.uk/government/publications/nhs-reference-costs-2013-to-2014, 2013-14
  2. Joint Formulary Committee. British National Formulary. Available at: https://bnf.nice.org.uk/medicinal-forms/rifaximin.html
A retrospective, observational, multicentre study including 145 patients from 11 UK NHS centres. Conducted from Aug 2014 to Jun 2015.
AIM: To compare resource use in the 6 and 12 months before and after rifaximin-α initiation in UK patients with HE.
INCLUSION CRITERIA: Clinical diagnosis of HE. HE diagnosed prior to rifaximin-α initiation. Initiated on rifaximin-α at least 12 months prior data collection.
EXCLUSION CRITERIA: Rifaximin-α initiated at other hospitals. Medical records unavailable.

Details of hospitalisations and hospital visits were extracted from NHS Trust electronic databases. Analysis included only alive patients at the end of 6 and 12 month periods.
IMPRESS study was sponsored and funded by Norgine

Rifaximin-α initiation dose was 1100mg/day (licensed dose) in 30%, 1200 mg/day in 64%, and other doses in 6% of patients, respectively.
This study included patients started on rifaximin-a prior to the launch of XIFAXAN® 550mg bd. 82% of patients (n=119) were taking concomitant lactulose at baseline.

An observational study including 127 patients from the Netherlands. Conducted between September 2015 to May 2018.
AIM: To assess hospital resource use, bacterial infections and adverse events in the 6 months before and after rifaximin-α initiation in patients with overt hepatic encephalopathy.

The study was sponsored by the Foundation for Liver and Gastrointestinal Research Rotterdam (SLO) to which an educational grant was provided by Norgine B.V., Amsterdam, the Netherlands.


Rifaximin-α initiation dose was 1100 mg per day (licensed dose) and was raised to 1650 mg per day in 11 patients due to recurrence of overt hepatic encephalopathy while on 1100 mg per day. 97.6% of patients (n=124) were taking concomitant lactulose at baseline.


* Optional use of lactulose (~90% patients in 'All rifaximin-α' group received concomitant lactulose).

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. Vilstrup H, et al. J Hepatol 2014;60:715-735
  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. Clayton M. Guide to: hepatic encephalopathy. October 2016
  11. Shawcross DL, et al. J Hepatol 2011;54:640-649
  12. Coltart I, et al. Arch Biochem Biophys 2013;536:189-196
  13. Weist R, Lawson M and Geuking M. J Hepatol 2014;60:197-209
  14. Sidhu S, et al. Am J Gastroenterol 2011;106:307-316
  15. Dyspraxia foundation UK. Available at: http://dyspraxiafoundation.org.uk/
  16. Weissenborn K. Neurochem Res 2015;40:265-273
  17. Hepatic Encephalopathy – American Liver Association. Available at: 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. Bajaj J S, et al. Aliment Pharmacol Ther 2010;31:537-547
  21. Nabi E, Bajaj JS. Current Gastroenterology Reports 2014;16(1):362
  22. Patidar KR, Bajaj JS. Clinical Gastroenterology and Hepatology 2015;13(12):2048-2061