Hepatic encephalopathy (HE) refers to the changes that occur in the brain of people with advanced, sudden, or chronic liver disease. This is a reversible syndrome. Though the exact mechanism of disease development and progression remains unknown, it is directly linked to liver dysfunction. Generally, the role of the liver is to filter toxins from your blood. In a person with liver disease, the liver does not perform the desired function, this can lead to the build-up of neurotoxins, impaired neurotransmission, changes in brain energy metabolism, and alterations of the blood-brain barrier; all of which contribute to the development of HE.2
Clinically HE displays a wide spectrum of neurological and psychiatric manifestations. In some cases, patients exhibit cognitive impairment and altered levels of consciousness that may progress to coma and death. Though the disease is potent, even mild HE reduces health-related quality of life and is a risk factor for bouts of severe HE. It is reversible however, it cannot be directly treated. Successful treatment of the underlying liver disease is essential to treating HE.1
Types of hepatic encephalopathy
According to the American Association for the Study of Liver Disease (AASLD), HE should be classified according to the progression stage of the underlying liver disease. Based on this, the following classifications have been made:
Type A (acute)
Brought on by acute liver failure without underlying chronic liver disease. It displays liver dysfunction in patients with no pre-existing liver disease. The incidence of acute liver failure is low however, its mortality rate is high as it is attributed to fast progression to HE.
Type B (bypass)
Associated with a portosystemic shunting. This is when there is an abnormal blood vessel connection between the portal vascular system and systemic circulation leading to a progressive deterioration of liver function.3 This is without the presence of an intrinsic liver disease.
Type C (Chronic)
This subtype is the consequence of cirrhosis, which is the scarring of the liver caused by long-term liver damage. The scarring prevents the liver from functioning properly, leaving it permanently damaged.
Causes of hepatic encephalopathy
The exact pathogenesis (the manner of development) of HE is not well known however, various abnormalities have been attributed to the onset of HE. The consensus also seems to be that these abnormalities exhibit comorbidity.
Molecular biological techniques indicate that the excess accumulation of ammonia may alter the expression of certain genes coding for key brain proteins that are essential for energy production, structure, and cell communication.8
Blood-brain barrier (BBB) alterations
One of the diagnostic symptoms of HE is brain oedema, where the entry of water into the brain causes swelling. This can arise through two processes:9
- Vasogenic oedema- BBB breakdown leads to an influx of water into the brain
- Cytotoxic oedema- Cellular alterations in the BBB, not a breakdown, alter the osmotic gradients, leading to an influx of water into the brain
A normally functioning liver clears ammonia (a neurotoxin), preventing it from entering systemic circulation.2 Patients with liver disease fail to clear this ammonia and the shunting of blood vessels increases blood ammonia levels. Hyperammonemia in the brain is positively correlated to the development and severity of HE. Hyperammonemia induces processes such as swelling of astrocytes, brain oedema, and impaired neurological performance.
Chronic hyperammonemia affects signal transductions within the brain. In particular, the impairment of the glutamate-cGMP pathway is associated with the altered learning and cognitive deficits observed in HE patients.7
Glutamine metabolism impairment
85% of ammonia in astrocytes is transformed into the amino acid glutamine.7 The hyperammonemia associated with CLD leads to increased astrocyte glutamine which is responsible for astrocyte swelling- brain edema.
Signs and symptoms of hepatic encephalopathy
HE produces a wide spectrum of neurological and psychiatric manifestations which can loosely be categorised according to the stage of HE progression.
- Forgetfulness/Poor concentration
- Personality/mood changes
- Disturbances in sleep-wake cycle
- Worsening of small hand movement
- Severe confusion
- Severe personality changes
- Slurred speech
- Unusual movements/shaking of hands
- Extreme anxiety
- Slow movement
Diagnosis of hepatic encephalopathy
HE is a treatable condition. Your healthcare provider will evaluate the following to confirm your diagnosis of hepatic encephalopathy:
- Evaluation of your symptoms
- Evaluate if you have any underlying liver conditions
- Evaluate if you might have any other factors that could be contributing to your symptoms
Some of the tests your healthcare provider might run to diagnose you are:
- Blood tests: To check your liver function or ammonia levels
- Doppler ultrasound: To look at the blood flow through your liver
- EEG test: To measure your brain activity
- Imaging tests: CT scan or MRI to look at the brain
Management and treatment for hepatic encephalopathy
The treatment for HE is predominantly focused on addressing the underlying liver disease and the precipitating (triggering) reversible factors. However, this is a list of the current strategies:
- Nonabsorbable disaccharides: Lactulose reduces the concentration of ammoniagenic substrates in the colon by lowering colonic pH 5
- Non-absorbable antibiotics: Oral non-absorbable antibiotics such as Neomycin and Rifaximin have been used to inhibit the growth of or kill susceptible ammoniagenic bacterial species.6 These are used for patients who don’t respond to non-absorbable disaccharides
Correction of precipitating factors
- Gastrointestinal bleeding: Due to the high protein content, the nitrogenous load of the blood there is increased, thereby increasing the intestinal ammonia production. Treatment is focussed on restoring the lack of isoleucine which protects the inhibitory effect of ammonia in neuronal cells 6
- Constipation: Enemas are beneficial in expelling ammonia-producing gut bacteria through cleansing or colonic acidification 6
Severe HE treatment
In the case of severe HE which can cause cerebral oedema and progression to coma stages, the following therapies are adopted:6
- Early ventilation
- Renal support
- Treatment of causes of acute liver injury
- Antiepileptic Drugs
- In extreme cases, liver transplantations for liver failure may be required
- Alcohol Use
- Consumption of drugs that affect the nervous system (sleeping pills, antidepressants)
How can I prevent hepatic encephalopathy?
The primary way to prevent HE is to lead a lifestyle that eliminates the risk factors for liver disease and the precipitating factors of HE.
How common is hepatic encephalopathy?
HE occurs in up to 50% of cirrhotic patients.4
When should I see a doctor?
If you have liver disease and start to notice symptoms associated with impaired thinking, altered hand movements, mood changes, and constipation it is a good idea to consult your doctor.
Hepatic encephalopathy (HE) is a reversible syndrome associated with a decline in cognitive and nervous system function exclusively in patients who are suffering from liver failure/disease. The symptoms exhibited depend on the type of liver failure-induced; some of them are confusion, disturbed sleep patterns, slurred speech, extreme anxiety, slowed movement etc. If you experience any of the HE symptoms, please visit your healthcare provider. Your healthcare provider will diagnose if you have HE by conducting a few tests like blood test and Doppler ultrasound to determine the condition of your liver and order image tests and EEG tests to determine the condition of your brain. HE is reversible but cannot be treated directly. It can only be reversed by treating the underlying condition that is responsible for HE. Based on the results of the diagnostic tests, the treatments offered involve a combination of ammonia-lowering strategies and correction of precipitating factors that contribute to the treatment.
- D’amico G, Morabito A, Pagliaro L, Marubini E, The Liver Study Group of “V. Cervello” Hospital. Survival and prognostic indicators in compensated and decompensated cirrhosis. Digest Dis Sci. 1986 May 1 [cited 2023 Jun 27];31(5):468–75. Available from: https://doi.org/10.1007/BF01320309
- Ferenci P. Hepatic encephalopathy. Gastroenterology Report. 2017 May [cited 2023 Jun 27];5(2):138–47. Available from: https://academic.oup.com/gastro/article-lookup/doi/10.1093/gastro/gox013
- Nardelli S, Riggio O, Gioia S, Puzzono M, Pelle G, Ridola L. Spontaneous porto-systemic shunts in liver cirrhosis: Clinical and therapeutical aspects. WJG. 2020 Apr 21 [cited 2023 Jun 27];26(15):1726–32. Available from: https://www.wjgnet.com/1007-9327/full/v26/i15/1726.htm
- Bohra A, Worland T, Hui S, Terbah R, Farrell A, Robertson M. Prognostic significance of hepatic encephalopathy in patients with cirrhosis treated with current standards of care. WJG. 2020 May 14 [cited 2023 Jun 27];26(18):2221–31. Available from: https://www.wjgnet.com/1007-9327/full/v26/i18/2221.htm
- Cash WJ, McConville P, McDermott E, McCormick PA, Callender ME, McDougall NI. Current concepts in the assessment and treatment of Hepatic Encephalopathy. QJM. 2010 Jan 1 [cited 2023 Jun 27];103(1):9–16. Available from: https://academic.oup.com/qjmed/article-lookup/doi/10.1093/qjmed/hcp152
- Wright G, Chattree A, Jalan R. Management of hepatic encephalopathy. International Journal of Hepatology. 2011 [cited 2023 Jun 27];2011:1–10. Available from: http://www.hindawi.com/journals/ijh/2011/841407/
- Ochoa-Sanchez R, Rose CF. Pathogenesis of hepatic encephalopathy in chronic liver disease. Journal of Clinical and Experimental Hepatology. 2018 Sep [cited 2023 Jun 27];8(3):262–71. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0973688318306480
- Butterworth RF. Hepatic encephalopathy. Alcohol Res Health. 2003 [cited 2023 Jun 27];27(3):240–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668878/
- Michinaga S, Koyama Y. Pathogenesis of brain edema and investigation into anti-edema drugs. Int J Mol Sci. 2015 Apr 30 [cited 2023 Jun 27];16(5):9949–75. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463627/