Hepatic encephalopathy
Hepatic encephalopathy is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stages, it can result in a coma.
Hepatic encephalopathy can occur in those with acute or chronic liver disease. Episodes can be triggered by alcoholism, infections, gastrointestinal bleeding, constipation, electrolyte problems, or certain medications. The underlying mechanism is believed to involve the buildup of ammonia in the blood, a substance that is normally removed by the liver. The diagnosis is typically based on symptoms after ruling out other potential [|causes]. It may be supported by blood ammonia levels, an electroencephalogram, or computer tomography of the brain.
Hepatic encephalopathy is possibly reversible with treatment. This typically involves supportive care and addressing the triggers of the event. Lactulose is frequently used to decrease ammonia levels. Certain antibiotics and probiotics are other potential options. A liver transplant may improve outcomes in those with severe disease.
More than 40% of people with cirrhosis develop hepatic encephalopathy. More than half of those with cirrhosis and significant HE live less than a year. In those who are able to get a liver transplant, the risk of death is less than 30% over the subsequent five years. The condition has been described since at least 1860.
Signs and symptoms
The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability. EEG can reveal a slowing of alpha waves. The first stage of hepatic encephalopathy is characterised by an inverted sleep-wake pattern. The second stage is marked by lethargy and personality changes. The third stage is marked by worsened confusion. The fourth stage is marked by a progression to coma.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 ; this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. In the third stage, neurological examination may reveal clonus and positive Babinski sign. Coma and seizures represent the most advanced stage; cerebral edema leads to death.
Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice, ascites, and peripheral oedema. The tendon reflexes may be exaggerated, and the plantar reflex may be abnormal, namely extending rather than flexing in severe encephalopathy. A particular smell on an affected person's breath 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 triggered by an additional cause, and identifying these triggers can be important to treat the episode effectively.| Type | Causes |
| Excessive nitrogen load | Consumption of large amounts of protein, gastrointestinal bleeding e.g. from esophageal varices, kidney failure, constipation |
| Electrolyte or metabolic disturbance | Hyponatraemia and hypokalaemia —these are both common in those taking diuretics, often used for the treatment of ascites; furthermore alkalosis, hypoxia, dehydration |
| Drugs and medications | Sedatives such as benzodiazepines, narcotics, antipsychotics, alcohol intoxication, Valproic Acid |
| Infection | Pneumonia, urinary tract infection, spontaneous bacterial peritonitis, other infections |
| Others | Surgery, progression of the liver disease, additional cause for liver damage |
| 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. This is used in the treatment of refractory ascites, bleeding from esophageal varices and hepatorenal syndrome. TIPS-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.
Pathogenesis
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% are metabolised through the urea cycle and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocytes 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. The most important waste product is ammonia. This small molecule crosses the blood–brain barrier and is absorbed and metabolised by the astrocytes, 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 system and the energy supply to other brain cells is decreased. This can be thought of as an example of brain edema of the "cytotoxic" type.Despite numerous studies demonstrating the central role of ammonia, ammonia levels do not 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, 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. Loss of glutamate transporter gene expression has been attributed to acute liver failure. Benzodiazepine-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system. An imbalance between aromatic amino acids and branched-chain amino acids has been described; this would lead to the generation of false neurotransmitters. 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 cytokines and bacterial lipopolysaccharide on astrocytes.
Diagnosis
Investigations
The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease or a portosystemic shunt, as its symptoms are similar to those encountered in other encephalopathies. To make the distinction, abnormal liver function tests and/or ultrasound suggesting liver disease are required, and ideally a liver biopsy. The symptoms of hepatic encephalopathy may also arise from other conditions, such as bleeding in the brain and seizures. A CT scan of the brain may be required to exclude bleeding in the brain, and if seizure activity is suspected an electroencephalograph 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 people, but not all hyperammonaemia is associated with encephalopathy. A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when brain swelling may be visible. Other neuroimaging modalities, such as magnetic resonance imaging, 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 lobes 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. This requires blood tests, usually a chest X-ray, and urinalysis. If there is ascites, a diagnostic paracentesis may be required to identify spontaneous bacterial peritonitis.
Classification
West Haven criteria
The severity of hepatic encephalopathy is graded with the West Haven Criteria, based on the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and dependence on therapy.- Grade 0 - No obvious changes other than a potentially mild decrease in intellectual ability and coordination
- Grade 1 - Trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired performance of addition or subtraction
- Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality change; inappropriate behaviour
- Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation
- Grade 4 - Coma
Types
- Type A describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema
- Type B is caused by portal-systemic shunting without associated intrinsic liver disease
- Type C occurs in people with cirrhosis - this type is subdivided in episodic, persistent and minimal encephalopathy