Hepatic encephalopathy
Encyclopedia
Hepatic encephalopathy is the occurrence of confusion
, altered level of consciousness
and coma
as a result of liver failure
. In the advanced stages it is called hepatic coma or coma hepaticum. It may ultimately lead to death.
It is caused by accumulation in the bloodstream of toxic substances that are normally removed by the liver
. The diagnosis of hepatic encephalopathy requires the presence of impaired liver function and the exclusion of an alternative explanation for the symptoms. Blood test
s (ammonia
levels) may assist in the diagnosis. Attacks are often precipitated by an intercurrent problem, such as infection
or constipation
.
Hepatic encephalopathy is reversible with treatment. This relies on suppressing the production of the toxic substances in the intestine
and is most commonly done with the laxative lactulose
or with non-absorbable antibiotic
s. In addition, the treatment of any underlying condition may improve the symptoms. In particular settings, such as acute liver failure, the onset of encephalopathy may indicate the need for a liver transplant
.
ing. It is experienced as forgetfulness, mild confusion and irritability. More severe encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night), marked irritability, tremor
, difficulties with coordination and trouble writing.
More severe forms of hepatic encephalopathy lead to a worsening level of consciousness, from lethargy to somnolence
and eventually coma. In the intermediate stages, a characteristic jerking movement of the limbs is observed (asterixis
, "liver flap" due to its flapping character); this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. Coma and seizure
s represent the most advanced stage; cerebral oedema
(swelling of the brain tissue) leads to death.
Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice
(yellow discolouration of the skin and the whites of the eyes), ascites
(fluid accumulation in the abdominal cavity), and peripheral oedema
(swelling of the legs due to fluid build-up in the skin). The tendon reflex
es may be exaggerated, and the plantar reflex
may be abnormal, namely extending rather than flexing (Babinski's sign) in severe encephalopathy. A particular smell (foetor hepaticus
) may be detected.
Hepatic encephalopathy may also occur after the creation of a transjugular intrahepatic portosystemic shunt
(TIPSS). This is used in the treatment of refractory ascites
, bleeding from oesophageal varices and hepatorenal syndrome
. TIPSS-related encephalopathy occurs in about 30% of cases, with the risk being higher in those with previous episodes of encephalopathy, higher age, female sex and liver disease due to causes other than alcohol.
A classification of hepatic encephalopathy was introduced at the World Congress of Gastroenterology
1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause.
The term minimal encephalopathy (MHE) is defined as encephalopathy that does not lead to clinically-overt cognitive dysfunction, but can be demonstrated with neuropsychological studies. This is still an important finding, as minimal encephalopathy has been demonstrated to impair quality of life
and increase the risk of involvement in road traffic accidents.
There are various explanations why liver dysfunction or portosystemic shunting might lead to encephalopathy. In healthy subjects, nitrogen
-containing compounds from the intestine
, generated by gut bacteria
from food, are transported by the portal vein to the liver, where 80–90% is metabolised
and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocyte
s (liver cells) are incapable of metabolising the waste products or because portal venous blood bypasses the liver through collateral circulation
or a medically constructed shunt. Nitrogenous waste products accumulate in the systemic circulation
(hence the older term "portosystemic encephalopathy"). The most important waste product is ammonia
(NH3). This small molecule crosses the blood-brain barrier
and is absorbed and metabolised by the astrocyte
s, a population of cells in the brain that constitutes 30% of the cerebral cortex
. Astrocytes use ammonia when synthesising glutamine from glutamate. The increased levels of glutamine lead to an increase in osmotic pressure in the astrocytes, which become swollen. There is increased activity of the inhibitory γ-aminobutyric acid
(GABA) system, and the energy supply to other brain cells is decreased. This can be thought of as an example of brain oedema of the "cytotoxic" type.
Despite numerous studies demonstrating the central role of ammonia, ammonia levels don't always correlate with the severity of the encephalopathy; it is suspected that this means that more ammonia has already been absorbed into the brain in those with severe symptoms whose serum levels are relatively low. Other waste products implicated in hepatic encephalopathy include mercaptans (substances containing a thiol group), short-chain fatty acids and phenol
.
Numerous other abnormalities have been described in hepatic encephalopathy, although their relative contribution to the disease state is uncertain. Benzodiazepine
-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system. An imbalance between aromatic amino acids
(phenylalanine, tryptophan and tyrosine) and branched-chain amino acids
(leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitter
s (such octopamine
and 2-hydroxyphenethylamine
). Dysregulation of the serotonin
system, too, has been reported. Depletion of zinc
and accumulation of manganese
may play a role. Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokine
s and bacterial lipopolysaccharide
on astrocytes.
. To make the distinction, abnormal liver function tests
and/or ultrasound
suggesting liver disease are required, and ideally liver biopsy
. The symptoms of hepatic encephalopathy may also arise from other conditions, such as cerebral haemorrhage and seizure
s (both of which are more common in chronic liver disease). A CT scan of the brain may be required to exclude haemorrhage, and if seizure activity is suspected an electroencephalograph
(EEG) study may be performed. Rarer mimics of encephalopathy are meningitis
, encephalitis
, Wernicke's encephalopathy
and Wilson's disease
; these may be suspected on clinical grounds and confirmed with investigations.
The diagnosis of hepatic encephalopathy is a clinical one, once other causes for confusion or coma have been excluded; no test fully diagnoses or excludes it. Serum ammonia levels are elevated in 90% of patients, but not all hyperammonaemia (high ammonia levels) is associated with encephalopathy. A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when cerebral oedema may be visible. Other neuroimaging
modalities, such as magnetic resonance imaging
(MRI), are not currently regarded as useful, although they may show abnormalities. Electroencephalography shows no clear abnormalities in stage 0, even if minimal HE is present; in stages I, II and III there are triphasic waves over the frontal lobe
s that oscillate at 5 Hz, and in stage IV there is slow delta wave
activity. However, the changes in EEG are not typical enough to be useful in distinguishing hepatic encephalopathy from other conditions.
Once the diagnosis of encephalopathy has been made, efforts are made to exclude underlying causes (such as listed above in "causes"). This requires blood test
s (urea and electrolytes, full blood count, liver function tests), usually a chest X-ray
, and urinalysis
. If there is ascites, diagnostic paracentesis
(removal of a fluid sample with a needle) may be required to identify spontaneous bacterial peritonitis
(SBP).
(RBANS) and PSE-Syndrom-Test may be used for this purpose. The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as the number connection test.
due to decreased protective reflexes such as the gag reflex
. This can lead to respiratory arrest
. Transferring the patient to a higher level of nursing care, such as an intensive care unit
, is required and intubation
of the airway is often necessary to prevent life-threatening complications (e.g., aspiration or respiratory failure). Placement of a nasogastric tube
permits the safe administration of nutrients and medication.
The treatment of hepatic encephalopathy depends on the suspected underlying cause (types A, B or C) and the presence or absence of underlying causes. If encephalopathy develops in acute liver failure (type A), even in a mild form (grade 1–2), it indicates that a liver transplant may be required, and transfer to a specialist centre is advised. Hepatic encephalopathy type B may arise in those who have undergone a TIPSS procedure; in most cases this resolves spontaneously or with the medical treatments discussed below, but in a small proportion of about 5%, occlusion
of the shunt is required to address the symptoms.
In hepatic encephalopathy type C, the identification and treatment of alternative or underlying causes is central to the initial management. Given the frequency of infection as the underlying cause, antibiotics are often administered empirically
(without knowledge of the exact source and nature of the infection). Once an episode of encephalopathy has been effectively treated, a decision may need to be made on whether to prepare for a liver transplant.
Dietary supplementation with branched-chain amino acids has shown improvement of encephalopathy and other complications of cirrhosis. Some studies have shown benefit of administration of probiotic
s ("healthy bacteria").
s that are not absorbed from the digestive tract. They are thought to improve the generation of ammonia by bacteria, render the ammonia inabsorbable by converting it to ammonium (NH4), and increase transit of bowel content through the gut. Doses of 15-30 ml are administered three times a day; the result is aimed to be 3–5 soft stools a day, or (in some settings) a stool pH
of <6.0.
Lactulose may also be given by enema
, especially if encephalopathy is severe. More commonly, phosphate enemas are used. This may relieve constipation, one of the causes of encephalopathy, and increase bowel transit.
A 2004 review by the Cochrane Collaboration
concluded that there was insufficient evidence to determine whether lactulose and lactitol are of benefit of hepatic encephalopathy, but it remains the first-line treatment for type C hepatic encephalopathy. In acute liver failure, it is unclear whether lactulose is beneficial. Furthermore, it may lead to bloating
and as such interfere with a liver transplant procedure if required.
and metronidazole
were previously used as a treatment for hepatic encephalopathy. Again, the rationale of their use was the fact that ammonia and other waste products are generated and converted by intestinal bacteria, and killing of these bacteria would reduce the generation of these waste products. Neomycin was chosen because of its low intestinal absorption
, as neomycin and similar aminoglycoside
antibiotics may cause hearing loss and renal failure
if used extensively. Later studies showed that neomycin was indeed absorbed enterally, with resultant complications. Metronidazole, similarly, was abandoned because prolonged use could cause a peripheral neuropathy
(nerve damage), and many experience gastrointestinal side effects.
A safer and probably more effective antibiotic is rifaximin, a nonabsorbable antibiotic from the rifamycin
class. This is thought to work in a similar way, but without the complications attached to neomycin and metronidazole. The use of rifaximin is supported by better evidence
than lactulose. Due to more widespread experience, it is only used as a second-line treatment if lactulose is not effective or poorly tolerated. When added to lactulose, the combination of the two may be more effective than each component separately. Rifaximin is more expensive than lactulose, but the cost may be offset by reduced hospital admissions for encephalopathy.
and L-aspartate
(LOLA) is used to increase the generation of urea
through the urea cycle
, a metabolic pathway
that removes ammonia by turning it into the neutral substance urea
. It may be combined with lactulose and/or rifaximin if these alone are ineffective at controlling symptoms.
is determined largely by other markers of liver failure, such as the levels of albumin
(a protein produced by the liver), the prothrombin time
(a test of coagulation
, which relies on proteins produced in the liver), the presence of ascites
and the level of bilirubin
(a breakdown product of hemoglobin
which is conjugated and excreted by the liver). Together with the severity of encephalopathy, these markers have been incorporated into the Child-Pugh score
; this score determines the one- and two-year survival and may assist in a decision to offer liver transplantation.
In acute liver failure, the development of severe encephalopathy strongly predicts short-term mortality, and is almost as important as the nature of the underlying cause of the liver failure in determining the prognosis. Historically widely used criteria for offering liver transplantation, such as King's College Criteria
, are of limited use and recent guidelines discourage excessive reliance on these criteria. The occurrence of hepatic encephalopathy in patients with Wilson's disease (hereditary copper accumulation) and mushroom poisoning indicates an urgent need for a liver transplant.
(ca. 460–370 BCE). Celsus
and Galen
(first and third century respectively) both recognised the condition. Many modern descriptions of the link between liver disease and neuropsychiatric symptoms were made in the eighteenth and nineteenth century; for instance, Giovanni Battista Morgagni
(1682–1771) reported in 1761 that it was a progressive condition.
In the 1950s, several reports enumerated the numerous abnormalities reported previously, and confirmed the previously enunciated theory that metabolic impairment and portosystemic shunting are the underlying mechanism behind hepatic encephalopathy, and that the nitrogen-rich compounds originate from the intestine. Many of these studies were done by Professor Dame Sheila Sherlock
(1918–2001), then at the Royal Postgraduate Medical School
in London
and subsequently at the Royal Free Hospital
. The same group investigated protein restriction and neomycin.
The West Haven
classification was formulated by Prof Harold Conn and colleagues at Yale University
while investigating the therapeutic efficacy of lactulose.
Mental confusion
Confusion of a pathological degree usually refers to loss of orientation sometimes accompanied by disordered consciousness and often memory Confusion (from Latin confusĭo, -ōnis, noun of action from confundere "to pour together", also "to confuse") of a pathological degree usually refers to loss...
, altered level of consciousness
Altered level of consciousness
An altered level of consciousness is any measure of arousal other than normal. Level of consciousness is a measurement of a person's arousability and responsiveness to stimuli from the environment. A mildly depressed level of consciousness may be classed as lethargy; someone in this state can be...
and coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
as a result of liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
. In the advanced stages it is called hepatic coma or coma hepaticum. It may ultimately lead to death.
It is caused by accumulation in the bloodstream of toxic substances that are normally removed by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. The diagnosis of hepatic encephalopathy requires the presence of impaired liver function and the exclusion of an alternative explanation for the symptoms. Blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s (ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
levels) may assist in the diagnosis. Attacks are often precipitated by an intercurrent problem, such as infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
or constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
.
Hepatic encephalopathy is reversible with treatment. This relies on suppressing the production of the toxic substances in the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
and is most commonly done with the laxative lactulose
Lactulose
Lactulose is a synthetic, non-digestible sugar used in the treatment of chronic constipation and hepatic encephalopathy, a complication of liver disease. It is a disaccharide formed from one molecule each of the simple sugars fructose and galactose...
or with non-absorbable antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s. In addition, the treatment of any underlying condition may improve the symptoms. In particular settings, such as acute liver failure, the onset of encephalopathy may indicate the need for a liver transplant
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
.
Signs and symptoms
The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testNeuropsychological test
Neuropsychological tests are specifically designed tasks used to measure a psychological function known to be linked to a particular brain structure or pathway. Tests are used for research into brain function and in a clinical setting for the diagnosis of deficits. They usually involve the...
ing. It is experienced as forgetfulness, mild confusion and irritability. More severe encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night), marked irritability, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, difficulties with coordination and trouble writing.
More severe forms of hepatic encephalopathy lead to a worsening level of consciousness, from lethargy to somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
and eventually coma. In the intermediate stages, a characteristic jerking movement of the limbs is observed (asterixis
Asterixis
Asterixis is a tremor of the wrist when the wrist is extended , sometimes said to resemble a bird flapping its wings. This motor disorder is characterized by jerking movements and is associated with various encephalopathies due especially to faulty metabolism...
, "liver flap" due to its flapping character); this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. Coma and seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s represent the most advanced stage; cerebral oedema
Cerebral edema
Cerebral edema or cerebral œdema is an excess accumulation of water in the intracellular or extracellular spaces of the brain.-Vasogenic:Due to a breakdown of tight endothelial junctions which make up the blood-brain barrier...
(swelling of the brain tissue) leads to death.
Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
(yellow discolouration of the skin and the whites of the eyes), ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
(fluid accumulation in the abdominal cavity), and peripheral oedema
Peripheral edema
Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...
(swelling of the legs due to fluid build-up in the skin). The tendon reflex
Tendon reflex
Tendon reflex may refer to:*A stretch reflex, when the stretch is created by a blow upon a muscle tendon. This is the usual definition of the term...
es may be exaggerated, and the plantar reflex
Plantar reflex
The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In normal adults the plantar reflex causes a downward response of the hallux...
may be abnormal, namely extending rather than flexing (Babinski's sign) in severe encephalopathy. A particular smell (foetor hepaticus
Fetor hepaticus
Fetor hepaticus or foetor hepaticus , also known as breath of the dead, is a condition seen in portal hypertension where portosystemic shunting allows mercaptans to pass directly into the lungs. It is a late sign in liver failure. Other possible causes are the presence of ammonia and ketones in the...
) may be detected.
Causes
In a small proportion of cases, the encephalopathy is caused directly by liver failure; this is more likely in acute liver failure. More commonly, especially in chronic liver disease, hepatic encephalopathy is caused or aggravated by an additional cause, and identifying these causes can be important to treat the episode effectively.| Type | Causes |
|---|---|
| Excessive nitrogen load |
Consumption of large amounts of protein Protein Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of... , gastrointestinal bleeding e.g. from esophageal varices Esophageal varices In medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus... (blood is high in protein, which is reabsorbed from the bowel), renal failure Renal failure Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood... (inability to excrete nitrogen-containing waste products such as urea Urea Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group.... ), constipation Constipation Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation... |
| Electrolyte or metabolic disturbance Electrolyte disturbance Electrolytes play a vital role in maintaining homeostasis within the body. They help to regulate myocardial and neurological function, fluid balance, oxygen delivery, acid-base balance and much more. Electrolyte imbalances can develop by the following mechanisms: excessive ingestion; diminished... |
Hyponatraemia (low sodium Sodium Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride... level in the blood) and hypokalaemia (low potassium Potassium Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are... levels)—these are both common in those taking diuretic Diuretic A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :... s, often used for the treatment of ascites; furthermore alkalosis Alkalosis Alkalosis refers to a condition reducing hydrogen ion concentration of arterial blood plasma . Generally, alkalosis is said to occur when pH of the blood exceeds 7.45. The opposite condition is acidosis .-Causes:... (decreased acid level), hypoxia Hypoxia (medical) Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise... (insufficient oxygen levels), dehydration Dehydration In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism... |
| Drugs and medications |
Sedative Sedative A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement.... s such as benzodiazepine Benzodiazepine A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring... s (often used to suppress alcohol withdrawal Alcohol withdrawal syndrome -Protracted withdrawal:A protracted alcohol withdrawal syndrome occurs in many alcoholics where withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is also sometimes referred to... or anxiety disorder Anxiety disorder Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are... ), narcotic Narcotic The term narcotic originally referred medically to any psychoactive compound with any sleep-inducing properties. In the United States of America it has since become associated with opioids, commonly morphine and heroin and their derivatives, such as hydrocodone. The term is, today, imprecisely... s (used as painkillers or drugs of abuse) and sedative antipsychotic Antipsychotic An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s... s, alcohol intoxication Alcoholic beverage An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption... |
| Infection | Pneumonia Pneumonia Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes... , urinary tract infection Urinary tract infection A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli... , spontaneous bacterial peritonitis Spontaneous bacterial peritonitis Spontaneous bacterial peritonitis is the development of peritonitis despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension , usually as a result of cirrhosis of the liver... , other infections |
| Others | Surgery Surgery Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical... , progression of the liver disease, additional cause for liver damage (e.g. alcoholic hepatitis Alcoholic hepatitis Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. While distinct from cirrhosis, it is regarded as the earliest stage of alcoholic liver disease. Symptoms are jaundice, ascites , fatigue and hepatic encephalopathy... , hepatitis A Hepatitis A Hepatitis A is an acute infectious disease of the liver caused by the hepatitis A virus , an RNA virus, usually spread the fecal-oral route; transmitted person-to-person by ingestion of contaminated food or water or through direct contact with an infectious person... ) |
| Unknown | In 20–30% of cases, no clear cause for an attack can be found |
Hepatic encephalopathy may also occur after the creation of a transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt
A Transjugular Intrahepatic Portosystemic Shunt is an artificial channel within the liver that establishes communication between the inflow portal vein and the outflow hepatic vein...
(TIPSS). This is used in the treatment of refractory ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
, bleeding from oesophageal varices and hepatorenal syndrome
Hepatorenal syndrome
Hepatorenal syndrome is a life-threatening medical condition that consists of rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure...
. TIPSS-related encephalopathy occurs in about 30% of cases, with the risk being higher in those with previous episodes of encephalopathy, higher age, female sex and liver disease due to causes other than alcohol.
West Haven Criteria
The severity of hepatic encephalopathy is graded with the West Haven Criteria; this is based on the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy.- Grade 1 - Trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired performance of addition or subtraction
- Grade 2 - Lethargy or apathyApathyApathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
; minimal disorientation for time or place; subtle personality change; inappropriate behaviour - Grade 3 - SomnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
to semistuporStuporStupor is the lack of critical cognitive function and level of consciousness wherein a sufferer is almost entirely unresponsive and only responds to base stimuli such as pain. This is often mistaken for delirium and treated with Haldol and or other anti-psychotic drugs...
, but responsive to verbal stimuli; confusion; gross disorientation - Grade 4 - ComaComaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
(unresponsive to verbal or noxious stimuli)
Types
Gastroenterology
Gastroenterology is the branch of medicine whereby the digestive system and its disorders are studied. The name is a combination of three Ancient Greek words gaster , enteron , and logos...
1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause.
- Type A (=acute) describes hepatic encephalopathy associated with acute liver failure
- Type B (=bypassBypass (surgical)In medicine, a vascular bypass generally means an alternate or additional route for blood flow, which is created in bypass surgery, e.g. coronary artery bypass surgery by moving blood vessels or implanting synthetic tubing. Vessels frequently used for the bypass are large veins taken from the...
) is caused by portal-systemic shunting without associated intrinsic liver disease - Type C (=cirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
) occurs in patients with cirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
- this type is subdivided in episodic, persistent and minimal encephalopathy
The term minimal encephalopathy (MHE) is defined as encephalopathy that does not lead to clinically-overt cognitive dysfunction, but can be demonstrated with neuropsychological studies. This is still an important finding, as minimal encephalopathy has been demonstrated to impair quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
and increase the risk of involvement in road traffic accidents.
Pathogenesis
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
-containing compounds from the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
, generated by gut bacteria
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....
from food, are transported by the portal vein to the liver, where 80–90% is metabolised
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s (liver cells) are incapable of metabolising the waste products or because portal venous blood bypasses the liver through collateral circulation
Collateral circulation
Collateral circulation is when an area of tissue or an organ has a number of different pathways for blood to reach it. This is often as a result of anastamoses - branches formed between adjacent blood vessels....
or a medically constructed shunt. Nitrogenous waste products accumulate in the systemic circulation
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...
(hence the older term "portosystemic encephalopathy"). The most important waste product is ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
(NH3). This small molecule crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and is absorbed and metabolised by the astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s, a population of cells in the brain that constitutes 30% of the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
. Astrocytes use ammonia when synthesising glutamine from glutamate. The increased levels of glutamine lead to an increase in osmotic pressure in the astrocytes, which become swollen. There is increased activity of the inhibitory γ-aminobutyric acid
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(GABA) system, and the energy supply to other brain cells is decreased. This can be thought of as an example of brain oedema of the "cytotoxic" type.
Despite numerous studies demonstrating the central role of ammonia, ammonia levels don't always correlate with the severity of the encephalopathy; it is suspected that this means that more ammonia has already been absorbed into the brain in those with severe symptoms whose serum levels are relatively low. Other waste products implicated in hepatic encephalopathy include mercaptans (substances containing a thiol group), short-chain fatty acids and phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
.
Numerous other abnormalities have been described in hepatic encephalopathy, although their relative contribution to the disease state is uncertain. Benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system. An imbalance between aromatic amino acids
Aromatic amino acids
Aromatic amino acids are amino acids that include an aromatic ring.Examples include:* Among 20 standard amino acids: phenylalanine, tryptophan, and tyrosine* Others: thyroxine-See also:* Aromatic L-amino acid decarboxylase...
(phenylalanine, tryptophan and tyrosine) and branched-chain amino acids
Branched-chain amino acids
A branched-chain amino acid is an amino acid having aliphatic side-chains with a branch...
(leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s (such octopamine
Octopamine
Octopamine is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic and dopaminergic systems. It is also found naturally in numerous plants, including bitter orange. Biosynthesis of the D--enantiomer of octopamine is by β-hydroxylation of...
and 2-hydroxyphenethylamine
2-Hydroxyphenethylamine
2-Hydroxyphenethylamine is an amine. It is similar in structure to ephedrine and phenylpropanolamine.- References :...
). Dysregulation of the serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
system, too, has been reported. Depletion of zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
and accumulation of manganese
Manganese
Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature , and in many minerals...
may play a role. Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and bacterial lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
on astrocytes.
Diagnosis
Investigations
The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease (types A and C) or a portosystemic shunt (type B), as it leads to similar symptoms to other encephalopathiesEncephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
. To make the distinction, abnormal liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
and/or ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
suggesting liver disease are required, and ideally liver biopsy
Liver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
. The symptoms of hepatic encephalopathy may also arise from other conditions, such as cerebral haemorrhage and seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s (both of which are more common in chronic liver disease). A CT scan of the brain may be required to exclude haemorrhage, and if seizure activity is suspected an electroencephalograph
Electroencephalography
Electroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
(EEG) study may be performed. Rarer mimics of encephalopathy are meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
, Wernicke's encephalopathy
Wernicke's encephalopathy
Wernicke encephalopathy is a syndrome characterised by ataxia, ophthalmoplegia, confusion, and impairment of short-term memory.It is caused by lesions in the medial thalamic nuclei, mammillary bodies, periaqueductal and periventricular brainstem nuclei, and superior cerebellar vermis, often...
and Wilson's disease
Wilson's disease
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease...
; these may be suspected on clinical grounds and confirmed with investigations.
The diagnosis of hepatic encephalopathy is a clinical one, once other causes for confusion or coma have been excluded; no test fully diagnoses or excludes it. Serum ammonia levels are elevated in 90% of patients, but not all hyperammonaemia (high ammonia levels) is associated with encephalopathy. A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when cerebral oedema may be visible. Other neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
modalities, such as magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI), are not currently regarded as useful, although they may show abnormalities. Electroencephalography shows no clear abnormalities in stage 0, even if minimal HE is present; in stages I, II and III there are triphasic waves over the frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
s that oscillate at 5 Hz, and in stage IV there is slow delta wave
Delta wave
A delta wave is a high amplitude brain wave with a frequency of oscillation between 0–4 hertz. Delta waves, like other brain waves, are recorded with an electroencephalogram and are usually associated with the deepest stages of sleep , also known as slow-wave sleep , and aid in characterizing the...
activity. However, the changes in EEG are not typical enough to be useful in distinguishing hepatic encephalopathy from other conditions.
Once the diagnosis of encephalopathy has been made, efforts are made to exclude underlying causes (such as listed above in "causes"). This requires blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s (urea and electrolytes, full blood count, liver function tests), usually a chest X-ray
Chest X-ray
In medicine, a chest radiograph, commonly called a chest X-ray , is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures...
, and urinalysis
Urinalysis
A urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...
. If there is ascites, diagnostic paracentesis
Paracentesis
Paracentesis is a medical procedure involving needle drainage of fluid from a body cavity, most commonly the peritoneal cavity in the abdomen.A related procedure is thoracocentesis, which is needle drainage of the chest cavity...
(removal of a fluid sample with a needle) may be required to identify spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis is the development of peritonitis despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension , usually as a result of cirrhosis of the liver...
(SBP).
Minimal HE
The diagnosis of minimal hepatic encephalopathy requires neuropsychological testing by definition. Older tests include the "numbers connecting test" A and B (measuring the speed at which one could connect randomly dispersed numbers 1–20), the "block design test" and the "digit-symbol test". In 2009 an expert panel concluded that neuropsychological test batteries aimed at measuring multiple domains of cognitive function are generally more reliable than single tests, and tend to be more strongly correlated with functional status. Both the Repeatable Battery for the Assessment of Neuropsychological StatusRepeatable Battery for the Assessment of Neuropsychological Status
The Repeatable Battery for the Assessment of Neuropsychological Status is a neuropsychological assessment initially introduced in 1998. It consists of ten subtests which give five scores, one for each of the five domains tested...
(RBANS) and PSE-Syndrom-Test may be used for this purpose. The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as the number connection test.
Treatment
Those with severe encephalopathy (stages 3 and 4) are at risk of obstructing their airwayAirway
The pulmonary airway comprises those parts of the respiratory system through which air flows, conceptually beginning at the nose and mouth, and terminating in the alveoli...
due to decreased protective reflexes such as the gag reflex
Gag reflex
The pharyngeal reflex or gag reflex is a reflex contraction of the back of the throat, evoked by touching the soft palate or sometimes the back of the tongue. It prevents something from entering the throat except as part of normal swallowing and helps prevent choking...
. This can lead to respiratory arrest
Respiratory arrest
Respiratory arrest is the cessation of breathing. It is a medical emergency and it usually is related to or coincides with a cardiac arrest. Causes include opiate overdose, head injury, anaesthesia, tetanus, or drowning...
. Transferring the patient to a higher level of nursing care, such as an intensive care unit
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
, is required and intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
of the airway is often necessary to prevent life-threatening complications (e.g., aspiration or respiratory failure). Placement of a nasogastric tube
Nasogastric intubation
Nasogastric intubation is a medical process involving the insertion of a plastic tube through the nose, past the throat, and down into the stomach.-Uses:...
permits the safe administration of nutrients and medication.
The treatment of hepatic encephalopathy depends on the suspected underlying cause (types A, B or C) and the presence or absence of underlying causes. If encephalopathy develops in acute liver failure (type A), even in a mild form (grade 1–2), it indicates that a liver transplant may be required, and transfer to a specialist centre is advised. Hepatic encephalopathy type B may arise in those who have undergone a TIPSS procedure; in most cases this resolves spontaneously or with the medical treatments discussed below, but in a small proportion of about 5%, occlusion
Vascular occlusion
Vascular occlusion is a sudden blockage of a blood vessel, usually with a clot. It differs from thrombosis in that it can be used to describe any form of blockage, not just one formed by a clot. When it occurs in a major vein, it can, in some cases, cause deep vein thrombosis. The condition is...
of the shunt is required to address the symptoms.
In hepatic encephalopathy type C, the identification and treatment of alternative or underlying causes is central to the initial management. Given the frequency of infection as the underlying cause, antibiotics are often administered empirically
Empiric therapy
Empiric therapy is a medical term referring to the initiation of treatment prior to determination of a firm diagnosis. It may be thought of as taking the initiative against an anticipated and likely cause of infectious disease. It is most often used when antibiotics are given to a person before the...
(without knowledge of the exact source and nature of the infection). Once an episode of encephalopathy has been effectively treated, a decision may need to be made on whether to prepare for a liver transplant.
Diet
In the past, it was thought that consumption of protein even at normal levels increased the risk of hepatic encephalopathy. This has been shown to be incorrect. Furthermore, many people with chronic liver disease are malnourished and require adequate protein to maintain a stable body weight. A diet with adequate protein and energy is therefore recommended.Dietary supplementation with branched-chain amino acids has shown improvement of encephalopathy and other complications of cirrhosis. Some studies have shown benefit of administration of probiotic
Probiotic
Probiotics are live microorganisms thought to be beneficial to the host organism. According to the currently adopted definition by FAO/WHO, probiotics are: "Live microorganisms which when administered in adequate amounts confer a health benefit on the host"...
s ("healthy bacteria").
Lactulose/lactitol
Lactulose and lactitol are disaccharideDisaccharide
A disaccharide or biose is the carbohydrate formed when two monosaccharides undergo a condensation reaction which involves the elimination of a small molecule, such as water, from the functional groups only. Like monosaccharides, disaccharides form an aqueous solution when dissolved in water...
s that are not absorbed from the digestive tract. They are thought to improve the generation of ammonia by bacteria, render the ammonia inabsorbable by converting it to ammonium (NH4), and increase transit of bowel content through the gut. Doses of 15-30 ml are administered three times a day; the result is aimed to be 3–5 soft stools a day, or (in some settings) a stool pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of <6.0.
Lactulose may also be given by enema
Enema
An enema is the procedure of introducing liquids into the rectum and colon via the anus. The increasing volume of the liquid causes rapid expansion of the lower intestinal tract, often resulting in very uncomfortable bloating, cramping, powerful peristalsis, a feeling of extreme urgency and...
, especially if encephalopathy is severe. More commonly, phosphate enemas are used. This may relieve constipation, one of the causes of encephalopathy, and increase bowel transit.
A 2004 review by the Cochrane Collaboration
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
concluded that there was insufficient evidence to determine whether lactulose and lactitol are of benefit of hepatic encephalopathy, but it remains the first-line treatment for type C hepatic encephalopathy. In acute liver failure, it is unclear whether lactulose is beneficial. Furthermore, it may lead to bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
and as such interfere with a liver transplant procedure if required.
Antibiotics
The antibiotics neomycinNeomycin
Neomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951...
and metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
were previously used as a treatment for hepatic encephalopathy. Again, the rationale of their use was the fact that ammonia and other waste products are generated and converted by intestinal bacteria, and killing of these bacteria would reduce the generation of these waste products. Neomycin was chosen because of its low intestinal absorption
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
, as neomycin and similar aminoglycoside
Aminoglycoside
An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...
antibiotics may cause hearing loss and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
if used extensively. Later studies showed that neomycin was indeed absorbed enterally, with resultant complications. Metronidazole, similarly, was abandoned because prolonged use could cause a peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
(nerve damage), and many experience gastrointestinal side effects.
A safer and probably more effective antibiotic is rifaximin, a nonabsorbable antibiotic from the rifamycin
Rifamycin
The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis mediterranei or artificially. They are a subclass of the larger family Ansamycin...
class. This is thought to work in a similar way, but without the complications attached to neomycin and metronidazole. The use of rifaximin is supported by better evidence
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...
than lactulose. Due to more widespread experience, it is only used as a second-line treatment if lactulose is not effective or poorly tolerated. When added to lactulose, the combination of the two may be more effective than each component separately. Rifaximin is more expensive than lactulose, but the cost may be offset by reduced hospital admissions for encephalopathy.
LOLA
A preparation of L-ornithineOrnithine
Ornithine is an amino acid that plays a role in the urea cycle.-Role in urea cycle:L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen....
and L-aspartate
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
(LOLA) is used to increase the generation of urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
through the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
, a metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
that removes ammonia by turning it into the neutral substance urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
. It may be combined with lactulose and/or rifaximin if these alone are ineffective at controlling symptoms.
Epidemiology and prognosis
In those with cirrhosis, the risk of developing hepatic encephalopathy is 20% per year, and at any time about 30–45% of people with cirrhosis exhibit evidence of overt encephalopathy. The prevalence of minimal hepatic encephalopathy detectable on formal neuropsychological testing is 60–80%; this increases the likelihood of developing overt encephalopathy in the future. Once hepatic encephalopathy has developed, the prognosisPrognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
is determined largely by other markers of liver failure, such as the levels of albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
(a protein produced by the liver), the prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
(a test of coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
, which relies on proteins produced in the liver), the presence of ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
and the level of bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
(a breakdown product of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
which is conjugated and excreted by the liver). Together with the severity of encephalopathy, these markers have been incorporated into the Child-Pugh score
Child-Pugh score
In medicine , the Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly cirrhosis...
; this score determines the one- and two-year survival and may assist in a decision to offer liver transplantation.
In acute liver failure, the development of severe encephalopathy strongly predicts short-term mortality, and is almost as important as the nature of the underlying cause of the liver failure in determining the prognosis. Historically widely used criteria for offering liver transplantation, such as King's College Criteria
King's College Criteria
The King's College Criteria or the King's College Hospital criteria were devised in 1989 to determine if there were any early indices of poor prognosis in patients with acute liver failure. Acute liver failure is defined as the onset of encephalopathy or coagulopathy within 26 weeks of a patient...
, are of limited use and recent guidelines discourage excessive reliance on these criteria. The occurrence of hepatic encephalopathy in patients with Wilson's disease (hereditary copper accumulation) and mushroom poisoning indicates an urgent need for a liver transplant.
History
The occurrence of disturbed behaviour in people with jaundice may have been described in antiquity by Hippocrates of CosHippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...
(ca. 460–370 BCE). Celsus
Aulus Cornelius Celsus
Aulus Cornelius Celsus was a Roman encyclopedist, known for his extant medical work, De Medicina, which is believed to be the only surviving section of a much larger encyclopedia. The De Medicina is a primary source on diet, pharmacy, surgery and related fields, and it is one of the best sources...
and Galen
Galen
Aelius Galenus or Claudius Galenus , better known as Galen of Pergamon , was a prominent Roman physician, surgeon and philosopher...
(first and third century respectively) both recognised the condition. Many modern descriptions of the link between liver disease and neuropsychiatric symptoms were made in the eighteenth and nineteenth century; for instance, Giovanni Battista Morgagni
Giovanni Battista Morgagni
Giovanni Battista Morgagni was an Italian anatomist, celebrated as the father of modern anatomical pathology.-Education:...
(1682–1771) reported in 1761 that it was a progressive condition.
In the 1950s, several reports enumerated the numerous abnormalities reported previously, and confirmed the previously enunciated theory that metabolic impairment and portosystemic shunting are the underlying mechanism behind hepatic encephalopathy, and that the nitrogen-rich compounds originate from the intestine. Many of these studies were done by Professor Dame Sheila Sherlock
Sheila Sherlock
Professor Dame Sheila Patricia Violet Sherlock, Mrs. James, DBE, MD, FRCP, FRCP Ed, FRS was a British physician, hepatologist and teacher.-Early life:...
(1918–2001), then at the Royal Postgraduate Medical School
Royal Postgraduate Medical School
The Royal Postgraduate Medical School was an independent medical school, based primarily at Hammersmith Hospital in west London. In 1988, the school merged with the Institute of Obstetrics & Gynaecology, and in 1997 became part of the Imperial College School of Medicine.-History:The medical school...
in London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...
and subsequently at the Royal Free Hospital
Royal Free Hospital
The Royal Free Hospital is a major teaching hospital in Hampstead, London, England and part of the Royal Free Hampstead NHS Trust....
. The same group investigated protein restriction and neomycin.
The West Haven
West Haven, Connecticut
West Haven is a city in New Haven County, Connecticut, United States. According to 2006 Census Bureau estimates, the population of the city is 52,721.-History:...
classification was formulated by Prof Harold Conn and colleagues at Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
while investigating the therapeutic efficacy of lactulose.