Last Updated on December 11, 2019
Hepatic encephalopathy is a spectrum of neural and behavioral symptoms like changes in personality, cognitive impairment and depression of consciousness in patients with the liver disorder [in absence of any brain lesion – encephalopathy means disease of brain per se, hepatic means pertaining to liver.]
It is most commonly associated with cirrhosis and liver failure. It is also seen after portosystemic shunts.
The development of hepatic encephalopathy is considered negative for patient survival.
Hepatic encephalopathy, accompanying the acute onset of severe hepatic synthetic dysfunction, is the hallmark of acute liver failure such as acute fulminant viral hepatitis, toxic hepatitis and Reye’s syndrome.
While acute hepatic encephalopathy is generally a sign of terminal liver failure, chronic hepatic encephalopathy may occur as a constant feature or recurrently. Recurrent type is more common.
Hepatic encephalopathy has been labeled as
- Type A – associated with Acute liver failure
- Type B with portal-systemic Bypass and no intrinsic hepatocellular disease.
- Type C associated with Cirrhosis
- Episodic
- Persistent
- Minimal
Two broad categories of hepatic encephalopathy are covert or minimal and overt.
It is estimated that up to 50 percent of people with cirrhosis have subtle [covert] signs of hepatic encephalopathy and approximately 30% of patients end-stage liver have significant encephalopathy [covert].
Up to 50% of the patients who undergo portosystemic shunt surgery have overt encephalopathy.
Hepatic encephalopathy was regarded as a reversible condition conventionally but a recent study showed that patients are left with residual cognitive impairment.
Pathogenesis of Hepatic Encephalopathy
Image Credit: Researchgate
The exact mechanism of encephalopathy in liver damage is not clear. Various theories have been proposed for the formation
Astrocyte function disorder
Astrocytes are star-shaped glial cells in the brain and spinal cord. These perform the following functions
- Support the neurons
- Regulate the blood-brain barrier
- Maintain electrolyte homeostasis
- Providing nutrients and neurotransmitter precursors to the neurons.
- Detoxification of chemicals, including ammonia.
In liver failure, neurotoxic substances, including ammonia and manganese, enter the brain leading to structural changes in the astrocytes including swelling leading to increased intracranial pressure.
The neurotoxins include
- Short-chain fatty acids
- Mercaptans
- False neurotransmitters like tyramine, octopamine, and beta-phenylethanolamines
- Manganese
- Ammonia
- Gamma-aminobutyric acid
Ammonia hypothesis
Ammonia is produced in the gastrointestinal and detoxified in the liver by conversion to urea.
Increased levels of ammonia are seen in liver disease due to
- A decrease in the number of working liver
- Shunting carried ammonia-containing blood away from the liver to the systemic circulation.
Ammonia has multiple neurotoxic effects and appears to play a role in hepatic encephalopathy in patients with cirrhosis.
However, about 10% of patients with significant encephalopathy have normal serum ammonia levels
GABA Receptor Complex
GABA is a neuroinhibitory substance that is dealt with in the brain by the GABA receptor complex. It also contains binding sites for GABA, benzodiazepines, and barbiturates.
The neuronal GABA receptor complex contains a binding site for neurosteroids which are thought to play a key role in hepatic encephalopathy. Neurosteroids are endogenous or exogenous steroids that rapidly alter neuronal excitability
Common Precipitants of Hepatic Encephalopathy
Certain conditions precipitate hepatic encephalopathy. These are
- Renal failure
- Decreased clearance of urea, ammonia
- Gastrointestinal bleeding
- Increases ammonia and nitrogen absorption
- Bleeding may predispose to decreased perfusion of the kidney causing impairment of function
- Blood transfusions may result in mild hemolysis and result in elevated blood ammonia levels.
- Infection
- Impair renal function
- Increasing catabolism and blood ammonia levels.
- Constipation
- Increases intestinal production and absorption of ammonia.
- Drugs
- Opiates
- Benzodiazepines
- Antidepressants
- Antipsychotics
- Diuretic therapy
- Decreased serum potassium levels and alkalosis may facilitate the conversion of NH4+ to NH3.
- Dietary protein overload
- Rare cause
Clinical Presentation
Because hepatic encephalopathy is a spectrum, the presentation depends on the stage of hepatic encephalopathy.
In case of minimal or grade I hepatic encephalopathy, the patient is almost normal but an examination would reveal probing could reveal
- Impaired complex and sustained attention
- Decreased short term memory and concentration in mental testing
There is a normal function on standard mental status testing but abnormal psychometric testing.
Disorientation and asterixis are characteristic of grade 2 hepatic encephalopathy.
The symptoms are graded into grades of increasing severity as follows [West Haven classification]
Grade 0
- Minimal hepatic encephalopathy
- Also called covert hepatic encephalopathy or subclinical hepatic encephalopathy
- No detectable changes in personality or behavior
- Minimum changes in brain functions
Grade 1
- Symptoms are mild
- Lack of awareness
- Shortened attention span
- Mildly decreased cognitive abilities like addition or subtraction or mental tasks
- Changes in sleep – hypersomnia, insomnia
- Mood changes – euphoria, depression, or irritability
Grade 2
- Lethargy or apathy
- Drowsiness
- Disorientation
- Inappropriate behavior
- Slurred speech
- Notable asterixis [a type of negative myoclonus characterized by irregular lapses of posture of various body parts]
- Deficient to perform mental tasks
- Personality changes
- Inappropriate behavior,
- Intermittent disorientation especially of time
Grade 3
- Sleepy but can be woken
- Unable to perform mental tasks
- Disoriented about time and place;
- Marked confusion
- Loss of memory
- Occasional fits of rage
- Incomprehensible speech
Grade 4
- Coma with or without response to painful stimuli
Grades 0 and 1 hepatic encephalopathies are said to be covert and patients with grades 2 through 4 hepatic encephalopathies are said to be overt.
Some patients with hepatic encephalopathy have a sweet musty aroma of the breath. It is called fetor hepaticus and is thought to be due to exhalation of mercaptans.
The examination may reveal increased ventilation and decreased body temperature.
Extrapyramidal symptoms like tremor, bradykinesia, cog-wheel rigidity, and shuffling gait are known to occur in patients with portosystemic shunting. These are thought to be due to increased manganese deposition in the basal ganglia.
Diagnostic Studies
The tests would reveal severely deranged liver functions tests or LFTs.
An elevated blood ammonia level is the classic laboratory abnormality and aids in diagnosis.
EEG reveals high-amplitude low-frequency waves and triphasic waves but these findings are not exclusive and could be present in other encephalopathies.
CT and MRI are used to rule out local lesions of the brain.
MRI may demonstrate hyperintensity of the globus pallidus on T1-weighted images. This finding is seen commonly in hepatic encephalopathy and is thought to be due to increased manganese deposition in this portion of the brain.
Differential Diagnosis
- Intracranial lesions
- Subdural hematoma
- Intracranial bleeding
- Stroke
- Tumors
- Infections
- Meningitis
- Encephalitis,
- Intracranial abscess
- Metabolic encephalopathy
- Hypoglycemia
- Electrolyte imbalance
- Lack of oxygen to the brain
- Increased carbon dioxide in brain
- Uremia, anoxia, hypercarbia, and uremia
- Hyperammonemia from other causes
- Ureterosigmoidostomy
- Urea cycle disorders
- Toxic encephalopathy
- Alcohol intake
- Wernicke encephalopathy
- Sedative drugs
- Antidepressants
- antipsychotic drugs
- Salicylates
- Organic brain syndrome
- Post seizure encephalopathy
Treatment of Hepatic Encephalopathy
General Approach
Hepatic encephalopathy results from failure of the liver acutely or due to long-standing disease. The development of hepatic encephalopathy is a negative factor.
Though it can be controlled in some cases, the ultimate fate lies with the correction of liver functions. Some acute failures may reverse and in chronic cirrhosis cases, options like liver transplant may improve the status of liver function.
That apart, the treatment of hepatic encephalopathy depends on the mental status changes. Also, the non-hepatic causes of the altered mental function should be ruled out.
Correction of Trigger Factors
Look out for dehydration, metabolic disturbances, gastrointestinal bleeding, infection, and constipation. If present, the issue should be addressed.
Any medicine that affects the central nervous system should be stopped. Benzodiazepines as sedatives should be avoided. Haloperidol should be used instead.
Patients of alcohol withdrawal are on benzodiazepines and in these cases, stopping these drugs may not be possible.
Those who have severe encephalopathy (ie, grade 3 or 4) should be monitored in ICU.
They should also undergo prophylactic endotracheal intubation to decrease the risk of respiration.
The following steps are taken for decreasing increased ammonia levels.
For Decreasing Intestinal Ammonia Production
Diet
Classically protein intake was restricted as ammonia is formed by protein breakdown. While it could be justified in a severe flare of symptoms, it is not advised in chronic cases.
These patients with mild chronic hepatic encephalopathy can tolerate about 60-80 g of protein per day.
Cathartics
Lactulose and lactitol are disaccharides that cannot be absorbed by the gastrointestinal system. Intestinal bacteriae degrade them to lactic acid and other organic acids.
Lactulose inhibits intestinal ammonia production. Following are the mechanisms suggested.
- Lactulose is converted to lactic acid and acetic acid. This acidification of the gut lumen favors the conversion of ammonia (NH3) to ammonium (NH4+) which are not absorbed.
- Reduces the bacterial load of the gut by acting as cathartic.
- Reduces ammoniagenic coliform bacteria due to acidification.
Lactulose is given orally, 30 mL in one or two doses. The patient should have 2-4 loose stools per day. The dose may be increased as tolerated.
In the case of diarrhea, abdominal cramping, or bloating, the patient is advised to reduce the dose.
Severe diarrhea, electrolyte disturbances, and hypovolemia are common side effects of lactulose.
In severe cases, high doses of lactulose are given in hospital settings.
It can be given as enema in unconscious patients as well.
Antibiotics
Antibiotics are given to decrease ammoniagenic bacteriae in the colon. Antibiotics used are
- Neomycin
- Metronidazole
- Vancomycin
- Oral quinolones
- Rifaximin – a nonabsorbable derivative of rifampin,
L-ornithine L-aspartate (LOLA)
LOLA is a stable salt of the two constituent amino acids and can be given orally or intravenous.
L-ornithine stimulates the urea cycle which decreases ammonia
Both l-ornithine and l-aspartate increase the glutamate level which is converted to glutamine using ammonia.
Other Drugs
- Zinc administration decreases increased ammonia levels
- Sodium benzoate,
- Interacts with glycine to form hippurate
- Renal excretion of hippurate results in the loss of ammonia ions
- Phenylbutyrate/Phenylacetate
- Given as sodium salts or glycerol salts [glycerol phenylbutyrate]
- Phenylbutyrate is converted to phenylacetate in the body
- Phenylacetate forms phenylacetylglutamine by interacting with glutamine which is excreted in the urine.
- L-carnitine is found to improve symptoms in cirrhosis.
For Sleep Disturbances
- Hydroxyzine 25 mg at bedtime
Prevention of Hepatic Encephalopathy
Hepatic encephalopathy is associated with liver disease. Therefore its prevention means efforts to prevent liver diseases or prevent progression or slow progression to cirrhosis if the liver gets affected.
Not all liver diseases are preventable. But the ones which commonly affect the liver can be prevented by
- Healthy lifestyle
- Alcohol moderation
- Avoiding fat-rich diet
- Discard high-risk behavior like sharing needles
- Maintain proper hygiene
- Getting vaccinated against disease like hepatitis B
Prognosis
Chronic hepatic encephalopathy has better recovery rates than those of acute encephalopathy.
Early treatment is associated with better recovery.