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Severe Liver Injury and Its Impact on the Brain

October/November 2015

Hepatitis C virus (HCV) infects the liver. Once the immune system detects HCV-infected liver cells, it tries to destroy those cells and restrict the spread of HCV within the liver. However, in many cases the immune system does not vanquish HCV and this viral infection becomes established or chronic. Despite this initial failure, the immune system continues to attempt to contain the infection. The ongoing struggle between HCV and the immune system causes inflammation within the liver. Due to this ongoing inflammation and infection, healthy liver cells are gradually replaced with useless scar tissue and the liver becomes increasingly dysfunctional. Eventually, when scar tissue has encompassed most of the liver, cirrhosis has occurred. This greatly increases the risk for serious complications, including liver failure, liver cancer and death.


Cirrhosis and the Brain -- A Spectrum of Symptoms

One complication that occurs in cirrhosis is HE (hepatic encephalopathy). This problem can occur when unfriendly bacteria in the gut produce excessive levels of substances that can cause inflammation in the brain. These substances include ammonia and chemical signals used by brain cells. Since the liver is dysfunctional, toxins produced by bacteria are not removed from the blood and persist in the body.

HE represents a spectrum of issues, from mild to severe. In the early stages there may be sleep disturbances, anxiety, impaired concentration and problems with memory and thinking clearly. As HE grows worse, caregivers and family members notice that, in some cases, affected patients become irritable.

In later stages of HE, there can be changes in personality, persistent confusion, inappropriate behaviour and loss of connection to the present (patients may not know the day, week, month or season).

In the most extreme cases of HE, people can sleep most of the time (and it can be difficult to wake them up), speech becomes slurred and the patient can eventually go into a coma.


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Mild Forms of HE

In the mild or very early stage of HE -- called minimal HE (MHE) or covert HE (CHE) -- a person's ability to carry out routine tasks can be affected and their quality of life can be degraded. Furthermore, emerging research suggests that episodes of CHE appear to be linked to a future risk for decreased survival in some people.


Some Risk Factors

If the cause of CHE is related to underlying HCV infection of the liver, getting treatment for HCV can help resolve CHE. If liver injury and cirrhosis arise because of alcoholism, quitting alcohol can help.

Factors that can trigger an episode of CHE include the following:

  • serious infections other than HCV
  • intestinal bleeding
  • constipation
  • less-than-ideal levels of electrolytes (sodium, potassium) in the blood
  • too high a dose of a diuretic (a drug that increases urination) -- this can inadvertently cause a loss of electrolytes


The Difficulty of Recognition and Diagnosis

Researchers estimate that up to 80% of people with cirrhosis can develop CHE. Yet there is no simple, quick test to help doctors diagnose CHE. In part, this is because CHE's initial effects can be subtle and may require extensive neuropsychological testing to unmask. Such testing is not routinely done and there is no consensus among specialists as to the ideal group of tests to use when assessing CHE. However, someone who may be experiencing CHE should always discuss this condition with their doctor(s). As with many health-related issues, treating a problem in its early stages can often be simpler and may even reverse the condition. Measuring levels of ammonia in the blood has not been found to help predict or diagnose CHE.


After a Diagnosis

Once a diagnosis of CHE has been made, there may be several treatment options that can be discussed with your care providers, such as the following:


Non-Absorbable Sugars

A substance such as lactulose, an artificial form of sugar, is sometimes useful in treating CHE or HE. Lactulose is not absorbed, but once swallowed it goes to the intestine. From there, it helps to pull ammonia and other toxic products produced by bacteria from the blood into the intestine, where they can be released into the stool. Clinical trials have generally found that most people with overt HE (and in some cases, CHE) improve after treatment with lactulose. However, lactulose can have side effects, including nausea, gas, abdominal cramps and diarrhea. Due to these side effects some patients may not be able to tolerate lactulose over the long-term.


Antibiotics

Rifaximin (Zaxine) is an antibiotic that is very poorly absorbed. This poor absorption helps the antibiotic concentrate in the intestines, where it can reduce the growth of unfriendly bacteria, causing their production of toxins to decrease. This antibiotic has generally been well tolerated in clinical trials, although headache may be a side effect. In clinical trials, rifaximin resulted in improvement in CHE and HE. Some doctors prescribe both lactulose and rifaximin for treating CHE and HE. The cost of rifaximin is not covered by all provincial and territorial drug formularies. Ask your doctor or nurse for the latest information about coverage of this drug in your region.


Probiotics (Friendly Bacteria)

There have been small clinical trials of probiotics for HE and CHE. Probiotics can change the balance of bacteria in the intestines, increasing the proportion of friendly bacteria. This can result in decreased levels of ammonia and other substances. However, the ideal mixture and dose of bacteria for treating CHE is not known. Although there are many different combinations of probiotics available over the counter, it is always best to discuss the possible use of these with your doctor. His/her advice and monitoring will be essential in managing CHE and any complications that could possibly occur.


LOLA (L-Ornithine-L-Aspartate)

Two amino acids (L-ornithine and L-aspartate) have been tested in cases of HE and CHE. In theory, these amino acids should activate the body's mechanisms for breaking down ammonia. Controlled clinical trials with LOLA have produced mixed results. However, researchers noticed that six months after participants had stopped one study of LOLA, only 5% of participants who received LOLA had developed overt HE vs. 38% of participants who received placebo. This finding is intriguing and raises the possibility that LOLA might have some potential benefit. As with any other possible intervention for CHE, your doctor's advice and approval should always be sought.


For the Future

More research is needed in the following areas:

  • developing simple, quick tests to help unmask CHE
  • getting doctors to agree about which tests to use when assessing a person for the presence of CHE
  • better treatments or combinations of treatment for CHE
  • determining the timing of treatment for CHE
  • ways to prevent the development of CHE


Resource

Understanding Cirrhosis of the Liver: First steps for the newly diagnosed -- Canadian Association of Hepatology Nurses (CAHN), CATIE


References

  1. Henderson PK, Herrera JL. Should we treat minimal/covert hepatic encephalopathy, and with what? Clinics in Liver Disease. 2015 Aug;19(3):487-95.
  2. Flamm SL. Covert hepatic encephalopathy: who should be tested and treated. Clinics in Liver Disease. 2015 Aug;19(3):473-85.
  3. Bajaj JS. Diagnosing minimal hepatic encephalopathy: from the ivory tower to the real world. Gastroenterology. 2015; in press.
  4. Ampuero J, Simón M, Montoliú C, et al. Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis. Gastroenterology. 2015; in press.
  5. Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nature reviews. Gastroenterology & Hepatology. 2013 Sep;10(9):522-8.


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This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.

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