Overview
Hepatic encephalopathy (hepaticencepHalopathy, HE) used to be called hepatic coma (hepaticcoma), which is a syndrome of central nervous system dysfunction caused by severe liver disease and based on metabolic disorders, whose main clinical manifestations are impaired consciousness, behavioral disorders and coma. Portal shunt encephalopathy (porto-systemicencepHabpathy, PSE) emphasizes portal hypertension, the presence of collateral circulation between the portal vein and the vena cava, thus allowing a large amount of portal blood to bypass the liver and flow into the body circulation, as the main mechanism for the development of encephalopathy. Subclinical or latent hepatic encephalopathy (subclinicalorlatentHE) refers to hepatic encephalopathy without obvious clinical manifestations and biochemical abnormalities, which can only be diagnosed with fine intelligence tests and/or electrophysiological tests.
Diagnosis】
The main diagnoses of hepatic encephalopathy are based on.
(i) severe liver disease and/or extensive portal collateral circulation.
② mental disturbance, lethargy or coma.
③ Triggers of hepatic encephalopathy.
(iv) Significant hepatic impairment or elevated blood ammonia. Flutter-like tremor and typical EEG changes have important reference value.
Subclinical hepatic encephalopathy can be detected by routine simple intelligence tests in patients with cirrhosis.
Hepatic encephalopathy with psychiatric symptoms as the only prominent manifestation can easily be misdiagnosed as psychosis, therefore any patient with psychosis should be alerted to the possibility of hepatic encephalopathy. Hepatic coma should also be differentiated from other diseases that can cause coma, such as diabetes mellitus, hypoglycemia, uremia, cerebrovascular accident, brain infection, and sedation overdose. Further history of liver disease, examination of liver and spleen size, liver function, blood ammonia, and electroencephalogram will help in the diagnosis and differential diagnosis.
Therapeutic measures
There is no specific treatment for hepatic encephalopathy, treatment should be comprehensive measures.
(a) eliminate the causes of certain factors can trigger or aggravate hepatic encephalopathy. When cirrhosis, the half-life of drugs in the body is prolonged, the contour is reduced, the sensitivity of the brain of patients with encephalopathy increases, and most cannot tolerate anesthesia, pain relief, sleeping, sedation and other types of drugs, such as improper use, can appear drowsy, until coma. When patients are manic or have convulsions, morphine and its derivatives, paracetamol, chloral hydrate, pethidine and fast-acting barbiturates are prohibited, Valium and scopolamine can be used in reduced doses (1/2 or 1/3 of the usual dose) and the number of doses can be reduced. Antihistamines such as fenugreek and paracetamol can sometimes be used as a substitute for Valium. Infection and upper gastrointestinal bleeding must be controlled promptly, and rapid and massive potassium diuresis and ascites discharge must be avoided. Pay attention to the correction of water, electrolytes and acid-base balance imbalance.
(B) Reduce the generation and absorption of intestinal toxins 1. Abstain from protein for a few days at the beginning of the diet. Supply 1200-1600 calories and sufficient vitamins daily, carbohydrates as the main food, coma can not eat through the nasogastric tube for food. Fat can delay the emptying of the stomach should be used sparingly. The best nasal feeding solution is 25% sucrose or glucose solution, which produces 1 calorie of heat per ml, and 3-6g of essential amino acids per day. When the stomach cannot be emptied, nasal feeding should be stopped and replaced by deep intravenous cannula with 25% glucose solution to maintain nutrition. In the process of massive glucose infusion, hypokalemia, heart failure and cerebral edema must be alerted. The tendency of different sources of protein to cause coma varies, and it is generally believed that meat protein has the greatest effect on encephalopathy, followed by cow’s milk protein and plant protein the least, so it is best to correct the patient’s negative nitrogen balance with plant protein. Plant proteins contain less methionine and aromatic amino acids and more branched chain amino acids, and can increase fecal nitrogen excretion. In addition, vegetable protein contains non-absorbable fiber, which is fermented by intestinal bacteria to produce acid to facilitate the elimination of ammonia, and is conducive to laxation, so it is suitable for patients with hepatic encephalopathy.
2, enema or diarrhea to remove the intestinal accumulation of food, blood or other nitrogenous substances, saline or weak acidic solution (such as dilute acetic acid solution) enema, or oral or nasal feed 25% magnesium sulfate 30 ~ 60ml diarrhea. For acute portal shunt encephalopathy coma patients with lactulose 500ml with water 500ml enema as the first treatment, especially useful.
3, inhibition of bacterial growth oral neomycin 2 ~ 4g / day or optional balomycin, kanamycin, ampicillin have good effect. A few of patients taking neomycin for a long time have hearing or kidney function impairment, so neomycin should not be taken for more than one month. Oral metronidazole 0.2g, 4 times a day, has the same efficacy as neomycin and is suitable for those with poor renal function.
Lactulose (β-galactosidofructose) is broken down by bacteria in the colon into lactic acid and acetic acid after oral administration, making the intestinal lumen acidic and thus reducing the formation and absorption of ammonia. For patients who are contraindicated to use neomycin or need long-term treatment, lactulose or lactosorbide is the drug of choice. Lactulose has syrup and powder, daily dose 30-100ml or 30-100g in three oral doses, starting with small doses to regulate to 2-3 times daily fecal excretion, fecal pH 5-6 is appropriate. Side effects are fullness, abdominal cramps, nausea, vomiting, etc. Lactosanol (1actitol, β-galactosido-sorbitol) is a disaccharide similar to lactulose, can be made into tablets or syrups, easy to preserve, metabolism and efficacy with lactulose, daily dose of 30g, divided into three oral doses. In recent years, it is found that lactose is used to treat hepatic encephalopathy in the colon of people with lactase deficiency, which also reduces the pH of stool and ammonia content after acid production by bacterial fermentation, with the same effect as lactulose, but cheaper.
(iii) Promote the metabolism of toxic substances to eliminate and correct the disorder of amino acid metabolism.
1.Ammonia-lowering drugs
(1) Potassium glutamate (6.3g/20ml per stick, containing 34mmol of potassium) and sodium glutamate (5.75g/20ml per stick, containing 34mmol of sodium), 4 sticks each time, added to glucose solution for intravenous infusion, 1 to 2 times a day. The ratio of potassium and sodium glutamate depends on the concentration of serum potassium and sodium and the condition. Use less potassium agent when urine is low and use sodium agent cautiously when ascites and edema are obvious.
②Arginine 10-20g is added to glucose solution once a day in a sedative drip. This drug can promote urea synthesis, and the drug is acidic, which is suitable for patients with high blood pH. Ammonia-lowering drugs are effective in chronic recurrent portal shunt encephalopathy and ineffective in acute hepatic coma due to severe hepatitis.
(3) Sodium benzoate can combine with residual intestinal nitrogen such as glycine or glutamine to form mauric acid, which is excreted via the kidneys, thus lowering blood ammonia. It is comparable to lactulose in the treatment of acute portal shunt encephalopathy. The dose is 5g orally twice daily.
④Phenylacetic acid combines with intestinal glutamine to form non-toxic marenesic acid excreted via the kidneys, which also reduces blood ammonia concentration.
⑤Ornithine-α-ketoglutarate and ornithine menthylate both have significant ammonia-lowering effects.
2.Branched-chain amino acids orally or by intravenous infusion of an amino acid mixture based on branched-chain amino acids can theoretically correct the imbalance of amino acid metabolism and inhibit the formation of pseudoneurotransmitters in the brain, but the efficacy on portal shunt encephalopathy is controversial. Branched-chain amino acids have less coma-causing effect than general consumption of protein, and if patients cannot tolerate protein food, the intake of sufficient amount of mixture rich in branched-chain amino acids is effective and safe to restore the positive nitrogen balance of patients.
3.GABA/BZ receptor antagonists GABA receptor antagonists have been bicuculline, weak tranquilizer receptor antagonists for flumazenil (flumazenil). The dose of flumazenil application has a wide range. It has been reported that 45% of patients with fulminant hepatic failure encephalopathy and 78% of patients with cirrhosis had significant improvement in symptoms and somatic evoked potentials (SEP) with flumazenil 15 mg IV drip for more than 3 hours, but the symptoms recurred after a few hours of discontinuation. Another group reported flumazenil at a dose of 0.2 mg intravenously, and if there was no improvement in EEG after 3 minutes, the dose was increased to 0.4 mg, then 0.8 mg, 1 to 2 mg, and up to a total dose of 9.6 mg in one case, with improvement in 71% of 14 patients. The dose used in our hospital was 0.5mg plus 10ml of 0.9% saline pushed in 5 minutes, followed by 1.0mg in 250ml saline drip for 30 minutes, which showed great improvement in the symptoms of cirrhosis with hepatic encephalopathy.
(iv) Liver transplantation is a recognized effective treatment for many chronic liver diseases that have no other satisfactory treatment to reverse. Due to improved and standardized transplantation procedures, advances in donor liver preservation methods and surgical techniques, and the use of anti-rejection, low-toxicity immunosuppressive agents, patient survival after transplantation has improved significantly (see chapter on liver transplantation).
(V) Other symptomatic treatment
1. Correct the imbalance of water, electrolytes and acid-base balance. The total amount of daily fluid intake should not exceed 2500 ml. In patients with cirrhotic ascites, the amount of fluid intake should be controlled (generally about 1000 ml of urine) to avoid aggravating coma due to hemodilution and low blood sodium. Timely correction of potassium deficiency and alkalosis, potassium chloride supplementation for potassium deficiency; alkalosis with arginine salt solution intravenous drip.
2.Protect brain cell function by lowering the intracranial temperature with ice cap to reduce energy consumption and protect brain cell function.
3.Keep the airway open for deep coma, tracheotomy should be made to give oxygen.
4.Prevent and treat cerebral edema by intravenous injection of hypertonic glucose, mannitol and other dehydrating agents to prevent and treat cerebral edema.
5.Prevent hemorrhage and shock, intravenous vitamin K1 or blood transfusion to correct shock, hypoxia and prenephrotic uremia.
6, peritoneal or renal dialysis If azotemia is the cause of hepatic encephalopathy, peritoneal or hemodialysis may be useful.
[Etiology].
Most hepatic encephalopathy is caused by all types of cirrhosis (post-hepatitis cirrhosis is most common), also including surgical portal shunts for the treatment of portal hypertension in cirrhosis, if even subclinical hepatic encephalopathy is counted, hepatic encephalopathy can occur in up to 70% of patients with cirrhosis, and a small proportion of encephalopathy is seen in the acute or fulminant hepatic failure stage of severe viral hepatitis, toxic hepatitis and drug-related liver disease. More rare causes include primary hepatocellular carcinoma, acute fatty liver during pregnancy, and severe biliary tract infections.
Hepatic encephalopathy, especially portal shunt encephalopathy, often has obvious causative factors, commonly including upper gastrointestinal bleeding, massive potassium diuresis, ascites discharge, high protein diet, sleeping and sedative drugs, narcotics, constipation, uremia, surgery, infection, etc.
Pathogenesis]
The pathogenesis of hepatic encephalopathy is not fully understood so far. The pathophysiological basis for hepatic encephalopathy is believed to be hepatocellular failure and the presence of surgically caused or naturally formed collateral shunts between the portal veins. Many toxic metabolites, mainly from the intestinal tract, are not detoxified and cleared by the liver and enter the circulation via the collateral branches, crossing the blood-brain barrier and reaching the brain, causing brain dysfunction. The metabolic disorders in the body in hepatic encephalopathy are multifaceted, and the occurrence of encephalopathy may be the result of a combination of factors, but the metabolic disorders of nitrogenous substances including proteins, amino acids, ammonia, thiols, and the accumulation of inhibitory neurotransmitters may play a major role. Disorders of glucose and water and electrolyte metabolism as well as hypoxia can interfere with energy metabolism in the brain and exacerbate encephalopathy. Abnormal fat metabolism, especially an increase in short-chain fatty acids, also plays an important role. In addition, increased brain sensitivity in patients with chronic liver disease is also an important factor. There are many hypotheses about the pathogenesis of hepatic encephalopathy, among which the ammonia toxicity theory is the most researched and well documented.
(A) ammonia toxicity caused by disorders of ammonia metabolism is an important pathogenesis of hepatic encephalopathy, especially portal shunt encephalopathy, and the encephalopathy related to ammonia toxicity is also called nitrogenous encephalopathy (nitrogenousencephalopathy).
1, ammonia formation and metabolism of blood ammonia mainly from the intestinal tract, kidney and skeletal muscle generated ammonia, but the gastrointestinal tract is the main portal of ammonia into the body. The normal human gastrointestinal tract can produce 4g of ammonia per day, most of which is produced by the decomposition of urea diffused from the blood circulation to the intestine by urease of intestinal bacteria, and a small portion is produced by the decomposition of protein in food by amino acid oxidase of intestinal bacteria. Ammonia is absorbed in the intestine mainly as nonionic ammonia (NH3) diffused into the intestinal mucosa, and its absorption rate is much higher than that of ionic ammonia (NH4+). Free NH3 is toxic and can cross the blood-brain barrier; NH4+ exists in the form of salts, which are relatively non-toxic and cannot cross the blood-brain barrier. interconversion of NH3 and NH4+ is influenced by changes in the pH gradient. As the reaction equation shows, when pH > 6 in the colon, NH3 is diffused into the blood in large quantities; when pH < 6, NH4 is transferred from the blood to the intestinal lumen and excreted with the feces. The kidney produces ammonia by breaking down glutamine in the renal blood stream into ammonia by glutaminase in the renal tubular epithelium. When the renal tubular filtrate is alkaline, a large amount of NH3 is absorbed into the renal vein, which increases blood ammonia; when it is acidic, a large amount of ammonia enters the renal tubular lumen to combine with acid and is excreted in the urine as ammonium salts (e.g., NH4Cl), which is an important way for the kidney to excrete strong acids. In addition, skeletal muscle and cardiac muscle can also produce ammonia during exercise.
The main pathways of ammonia removal by the body are: (1) the vast majority of ammonia from the intestine is converted to urea in the liver via the ornithine metabolic ring; (2) the brain, liver, kidney and other tissues use and consume ammonia to synthesize glutamate and glutamine under the energy supply of adenosine triphosphate (ATP) (α-ketoglutarate ten NH3→ glutamate, glutamate ten NH3→ glutamine); (3) the kidney is the main site of ammonia excretion, in addition to excretion of large amounts of urea, in addition to the excretion of acid, but also in the form of NH4+ to exclude a large amount of ammonia; (4) excessive blood ammonia can be exhaled from the lungs in small amounts.
2, the causes of increased blood ammonia in hepatic encephalopathy increased blood ammonia is mainly due to excessive production and/or metabolic clearance. Excessive production of blood ammonia can be exogenous, such as excessive intake of nitrogen-containing food or drugs from outside the body, which is converted into ammonia in the intestine; it can also be endogenous, such as prenephrosis and nephrogenic azotemia, when a large amount of urea in the blood diffuses into the intestinal lumen and is converted into ammonia, which then enters the blood. After gastrointestinal bleeding, the blood that stays in the intestine decomposes into ammonia, which does not come from outside the body and should be endogenous, but the process of ammonia production is similar to that of ingesting nitrogen-containing food. In short, in liver failure, the liver’s ability to synthesize ammonia into urea is diminished, and when portal shunt exists, ammonia from the intestine enters the body circulation directly without liver detoxification, causing the blood ammonia to increase.
3.Factors affecting ammonia toxicity Many factors that induce hepatic encephalopathy can affect the amount of blood ammonia entering brain tissue and/or change the sensitivity of brain tissue to ammonia.
(1) Hypokalemic alkalosis: eating less, vomiting, diarrhea, diuretic excretion of potassium, discharge of ascites, secondary aldosteronism, etc. can all lead to hypokalemia. Hypokalemia causes malfunction of acid-base balance, which alters the intra- and extracellular distribution of ammonia. The loss of potassium from the extracellular fluid is replenished by the removal of intracellular potassium, which is exchanged with the extracellular fluid by the entry of sodium and hydrogen into the cells, thus reducing [H+] in the extracellular fluid and facilitating the entry of NH3 into brain cells to produce toxic effects. Furthermore, potassium and hydrogen excretion through the kidneys are negatively correlated. In hypokalemia, urinary potassium excretion decreases while hydrogen ion excretion increases, leading to metabolic alkalosis, thus promoting NH3 to cross the blood-brain barrier and enter the cells to produce toxic effects. Most patients with portal shunt encephalopathy have elevated blood ammonia, which can be normalized when the blood ammonia is lowered; many cases of fulminant hepatic failure have normal blood ammonia even though they are in deep coma. In addition, in patients with cirrhosis who have encephalopathy due to sedation, sleeping or narcotic drugs, the blood ammonia can also be normal or slightly high, these are non-nitrogenous encephalopathy, accounting for about 1/3 of all encephalopathies.
(2) Increased ammonia production in the intestine when excessive nitrogen-containing food or drugs are ingested, or when the upper gastrointestinal tract bleeds (about 20g of protein per 100ml of blood).
(3) Hypovolemia and hypoxia: seen in upper gastrointestinal bleeding, massive discharge of ascites, diuresis, etc. Shock and hypoxia can lead to pre-renal azotemia, which increases blood ammonia. Hypoxia in brain cells can reduce the brain’s tolerance to ammonia toxicity.
(4) Constipation: prolongs the contact time of ammonia-containing, amines and other toxic derivatives with the colonic mucosa, which facilitates the absorption of toxic substances.
(5) Infection: increases tissue catabolism thereby increasing ammonia production, water loss can exacerbate prerenal azotemia, hypoxia and hyperthermia increase ammonia toxicity.
(6) Hypoglycemia: glucose is an important fuel for energy production in the brain, energy is reduced in hypoglycemia, the brain de-ammonia activity is stalled and ammonia toxicity is increased.
(7) Other: sedative and sleeping drugs can directly inhibit the brain and respiratory center, causing hypoxia. Anesthesia and surgery increase the functional burden of liver, brain and kidney.
4, ammonia toxic effects on the central nervous system brain cells are extremely sensitive to ammonia. Normal human skeletal muscle, liver and brain tissue can take up too much ammonia in the blood (50%, 24% and 7.5%, respectively), and in cirrhosis of the liver, ammonia uptake is often reduced due to muscle depletion, and due to the portal shunt and the liver to reduce ammonia uptake, so the brain is subjected to a larger ammonia load. It is generally believed that the toxic effect of ammonia on the brain is to interfere with brain energy metabolism and cause a decrease in the concentration of high-energy phosphate compounds. High ammonia levels may inhibit pyruvate dehydrogenase activity, thereby affecting acetyl coenzyme A production and interfering with the tricarboxylic acid cycle in the brain. On the other hand, the detoxification of ammonia in the brain involves the combination of ammonia with α-ketoglutarate to glutamate and glutamate with ammonia to glutamine, and these reactions require the consumption of large amounts of coenzyme, ATP, α-ketoglutarate and glutamate, and the production of large amounts of glutamine. The lack of α-ketoglutarate, an important intermediate product in the tricarboxylic acid cycle, leaves brain cells with insufficient energy supply to maintain normal function. Glutamate is an important excitatory neurotransmitter in the brain, and its absence increases brain inhibition.
(ii) Synergistic toxic effects of ammonia, thiols and short-chain fatty acids Methyl mercaptan is a product of methionine metabolism by bacteria in the gastrointestinal tract, and methyl mercaptan and its derivative dimethyl sulfoxide, both of which can cause confusion, disorientation, lethargy and coma in experimental animals. The mechanism of hepatic encephalopathy in patients with cirrhosis who consume methionine may be related to these two metabolites. Hepatic odor may be the odor of methyl mercaptan and dimethyl disulfide volatilization. In patients with severe liver disease, the blood concentration of methyl mercaptan is increased, more significantly in those with encephalopathy. Short-chain fatty acids (mainly valeric, capric and octanoic acids), which are formed when long-chain fatty acids are broken down by bacteria, can induce experimental hepatic encephalopathy and are also significantly increased in the plasma and cerebrospinal fluid of patients with hepatic encephalopathy.
In experimental animals with liver failure, the use of any of the three toxic substances, ammonia, thiols and short-chain fatty acids alone, in small amounts, is not sufficient to induce hepatic encephalopathy, but if used in combination, they can cause brain symptoms even at the same dose. For this reason, it has been suggested that the synergistic toxic effects of ammonia, thiols and short-chain fatty acids on the central nervous system may have an important place in the pathogenesis of hepatic encephalopathy.
(iii) Pseudoneurotransmitters The conduction of nerve impulses is accomplished through transmitters. Neurotransmitters are divided into two categories: excitatory and inhibitory, and the two are in physiological balance when normal. Excitatory neurotransmitters include dopamine and norepinephrine in catecholamines, acetylcholine, glutamate and menadione, etc.; inhibitory neurotransmitters are formed only in the brain.
The aromatic amino acids in food, such as tyrosine and phenylalanine, are converted into tyramine and phenylethylamine respectively by the action of enterobacterial decarboxylase. In normal times, these two amines are cleared by monoamine oxidase in the liver, but in liver failure, clearance is impaired, and these two amines can enter brain tissue and form amines (β-hydroxytyramine) and phenylethylamine, respectively, in the brain by the action of βhydroxylase. The latter two are chemically similar to the normal neurotransmitter norepinephrine, but cannot transmit nerve impulses or have weak effects, hence the term pseudoneurotransmitter. When pseudoneurotransmitters are taken up by brain cells and replace normal transmitters in synapses, nerve conduction is impaired and excitatory impulses do not reach the cerebral cortex normally, resulting in abnormal inhibition; impairment of consciousness and coma occur.
So far, the above theory of pseudoneurotransmitters has not been fully confirmed.
(iv) GABA/Bz receptors γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain, produced by intestinal bacteria, which can bypass the liver and enter the body circulation during portal shunt and liver failure. In recent years, in animal models of fulminant liver failure and hepatic encephalopathy, increased blood concentrations of GA-BA were found, as well as increased permeability of the blood-brain barrier and a significant increase in GABA receptors in postsynaptic neurons of the brain. This receptor not only binds to GABA, but also binds to barbiturates and benzodiazepines (BZs) at different sites on the receptor surface, so it is called the GABA/BZ complex receptor. The binding of either GABA or any of these drugs to the receptor promotes chloride conduction into postsynaptic neurons and causes neurotransmission inhibition, at which point the instrumentally recorded visual evoked potentials (VEPs) are identical to those in animal models of encephalopathy caused by galactosamine. Plasma GABA concentrations in patients with hepatic encephalopathy paralleled the degree of encephalopathy. A small number of patients treated with GABA receptor antagonists or weak tranquilizer receptor antagonists showed a reduction in symptoms and a return to normal VEP, more evidence that hepatic encephalopathy is due to an increase in the inhibitory transmitter GABA.
(v) Imbalance of amino acid metabolism Plasma amino acid measurements revealed that plasma aromatic amino acids (e.g. phenylalanine, tyrosine, tryptophan) increased and branched chain amino acids (e.g. valine, leucine, isoleucine) decreased in patients with cirrhosis loss of compensation, and the metabolism of the two groups of amino acids was unbalanced. In normal people, the aromatic amino acids are metabolized and broken down in the liver, and the breakdown decreases in liver failure, so the blood concentration increases. Normally, branched-chain amino acids are mainly metabolized and broken down in skeletal muscle but not in the liver, but insulin has the effect of promoting the entry of these amino acids into muscle. In hepatic failure, the inactivation of insulin in the liver decreases and the blood concentration increases, thus promoting the entry of branched-chain amino acids into muscle tissue in large quantities, so the blood concentration decreases, and finally the gram-molecule ratio of branched-chain amino acids to aromatic amino acids decreases from the normal 3 to 3.5 to 1 or lower. The above two groups of amino acids are in competition and repulsion with each other to enter the brain through the blood-brain barrier to exchange with glutamine. A decrease in branched-chain amino acids increases the entry of aromatic amino acids into the brain, the latter further forming pseudoneurotransmitters as described previously. Increased serum free tryptophan in patients with cirrhosis due to impaired hepatic metabolism and reduced plasma albumin levels can lead to increased serum free tryptophan, and the increased tryptophan in the brain can derive 5-hydroxytryptamine, which is an inhibitory transmitter for certain neurons in the central nervous system, has antagonistic effects on norepinephrine, and may also be associated with coma. Arginine, glutamate and menthol by themselves or their derivatives have a reversing effect on experimental hepatic encephalopathy caused by ammonia intoxication, and have a hypnotic effect on comatose patients with cirrhosis.
[Pathological changes
Patients with hepatic encephalopathy due to acute liver failure often have no obvious anatomical abnormalities in the brain, but 38-50% have cerebral edema, which may be a secondary change of the syndrome. In patients with chronic hepatic encephalopathy, there may be hypertrophy and increase of protoplasmic astrocytes in the gray matter of the brain and cerebellum as well as in the subcortical tissues, and in those with longer disease duration, there is thinning of the cerebral cortex, disappearance of neurons and nerve fibers, and lamellar necrosis in the deep cortex, and even the cerebellum and the base may be involved.
Clinical manifestations
The clinical manifestations of hepatic encephalopathy are often inconsistent depending on the nature of the original liver disease, the severity of the liver cell damage and the causative factors. Acute hepatic encephalopathy is common in fulminant hepatitis, with massive hepatocellular necrosis and acute liver failure, with no obvious cause. Chronic hepatic encephalopathy is mostly a portal shunt encephalopathy, due to massive portal collateral circulation and chronic liver failure, mostly seen in patients with cirrhosis and/or after portal shunt surgery, with chronic recurrent episodes of miosis and coma as the prominent manifestation, often with a large amount of protein food, upper gastrointestinal bleeding, infection, discharge of ascites, massive potassium diuresis and other triggers. The hepatic encephalopathy seen in the end stage of cirrhosis starts slowly, with a gradual deepening of coma and finally death.
In order to observe the dynamic changes of encephalopathy and facilitate early diagnosis and management and analysis of the efficacy, hepatic encephalopathy is generally divided into four stages from mild mental changes to deep coma according to the degree of impaired consciousness, neurological manifestations and electroencephalographic changes.
Phase I (prodromal phase) Mild personality changes and behavioral disorders, such as euphoria and excitement or indifference, inappropriate clothing or open defecation. The patient’s response is still accurate, but the spitting is slurred and slow, and there may be fluttering tremor (flappingtremor or asterixis), also known as hepatic tremor: the patient is asked to extend both arms flat, the elbow joint is fixed, the palm of the hand is extended dorsally, and when the fingers are separated, the hand is seen to be deflected laterally, and there are sharp and irregular fluttering tremors of the metacarpophalangeal joint, wrist joint, and even the elbow and shoulder joints. The patient was asked to hold the doctor’s hand tightly for one minute, and the doctor could feel the patient shaking. Most of the EEGs are normal. This phase lasts for several days or weeks, and sometimes the symptoms are not obvious and easily ignored.
The second stage (pre-coma) is dominated by confusion, sleep disturbance, and behavioral disorders. The symptoms of the first stage are aggravated, orientation and comprehension are diminished, the concept of time, place and person is confused, and simple calculations and mental compositions (such as building blocks, arranging pentagrams with matchsticks, etc.) cannot be completed. Slurred speech, dysgraphia, and abnormal demeanor are also common. There are mostly sleep time inversions, daytime sleepiness and nighttime wakefulness, and even hallucinations, fear, and mania, while being seen as general psychosis. Patients in this stage have obvious neurological signs, such as hyperactive tendon reflexes, increased muscle tone, ankle spasms and positive Babinski’s sign. Fluttering tremor is present in this stage, and there are characteristic abnormalities in the EEG. Patients may develop involuntary movements and movement disorders.
In the third stage (lethargic stage), lethargy and confusion are predominant, and various neurological signs persist or worsen, and most of the time, the patient is in a lethargic state but can be awakened. The patient can answer questions upon awakening, but often has confusion and hallucinations. Fluttering tremor can still be elicited. Myotonia is increased and passive movements of the extremities are often resistant. Cone cord signs are often positive, and the EEG has abnormal waveforms.
Stage IV (coma phase) has complete loss of consciousness and cannot be aroused. In superficial coma, there is still a response to painful stimuli and uncomfortable positions, and tendon reflexes and muscle tone are still hyperactive; fluttering tremor cannot be elicited because the patient is uncooperative. In deep coma, various reflexes disappear, muscle tone decreases, pupils are often dilated, and paroxysmal convulsions, ankle clonus, and hyperventilation may occur. EEG is obviously abnormal.
The demarcation of the above stages is not very clear, and the clinical manifestations of the first and second stages may overlap, and the degree may progress or recede when the disease progresses or improves with treatment. A small number of patients with chronic hepatic encephalopathy have hypo-intelligence, ataxia, positive pyramidal signs or paraplegia due to organic damage in different parts of the central nervous system, and these manifestations may exist temporarily or become permanent.
Patients with subclinical or occult hepatic encephalopathy are considered healthy and participate in normal social activities due to the absence of any clinical manifestations. There is a risk of traffic accidents when driving various means of transportation, so Western countries have paid great attention to it in recent years, and it has been suggested that subclinical hepatic encephalopathy should be classified as stage 0 in clinical staging.
Hepatic encephalopathy with severe hepatic impairment often has obvious jaundice, bleeding tendency and liver odor, and is easily complicated by various infections, hepatorenal syndrome and cerebral edema, which makes the clinical manifestation more complicated.
Auxiliary tests
(A) blood ammonia normal people fasting venous blood ammonia for 40 ~ 70 & mu;g/dl, arterial blood ammonia content for venous blood ammonia 0.5 ~ 2 times. Fasting arterial blood ammonia is more stable and reliable. Patients with chronic hepatic encephalopathy, especially portal shunt encephalopathy, tend to have increased blood ammonia. In encephalopathy due to acute liver failure, the blood ammonia is mostly normal.
(B) EEG examination EEG not only has diagnostic value, but also has certain prognostic significance. The typical change is a slowing of the rhythm, mainly the appearance of universal waves of 4-7 times per second, some also appear 1 to 3 times per second δ waves. In coma, symmetrical high amplitude waves appear simultaneously on both sides.
(iii) Evoked potentials are externally recordable potentials, which are synchronized firing responses generated by various external stimuli transmitted to the neuronal network of the brain via sensory apparatus. They are classified as visual evoked potentials (VEP), auditory evoked potentials (AEP), and repulsive evoked potentials (SEP) depending on the sensory stimulus. It has been found that the evoked potentials recorded by stimulating experimental rats or rabbits with hepatic encephalopathy have specific changes according to the superficiality of the disease. This technique was later used to study patients with hepatic encephalopathy. Initially, VEP was thought to provide an objective and accurate diagnosis of different degrees of hepatic encephalopathy, including subclinical encephalopathy, with greater sensitivity than any other method. Recent studies have concluded that the VEP test varies too much from person to person and from time to time, lacks specificity and sensitivity, and is not as effective as simple psychological or intelligence tests.
(iv) Simple intelligence tests are currently considered the most useful for the diagnosis of early hepatic encephalopathy, including subclinical encephalopathy. The test includes writing, word formation, drawing, building blocks, building a pentagram with a matchstick, etc. The test used as a routine is the number connection test, whose results are easy to measure and facilitate follow-up.
Prevention
Actively prevent and treat liver disease. Patients with liver disease should avoid all triggers of hepatic encephalopathy. Closely observe patients with liver disease, promptly detect the prodromal phase and pre-conscious manifestations of hepatic encephalopathy and provide appropriate treatment.
[Prognosis].
The prognosis is better for those with clear causative factors that can be easily eliminated (e.g., bleeding, potassium deficiency, etc.). The prognosis of portal shunt encephalopathy due to high protein intake is better if the liver function is good, shunt surgery has been performed, and the prognosis of portal shunt encephalopathy is better. Patients with ascites, jaundice, and bleeding tendencies suggest very poor liver function and their prognosis is poor. The prognosis for hepatic encephalopathy due to fulminant liver failure is the worst.