Inability to convert ammonia to urea results in elevated ammonia levels in the blood. This can result in a condition called hepatic encephalopathy, which is a neurological syndrome characterized by alterations in mental status and behavior.
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By Liz Highleyman.
Encephalopathy is a general name for brain dysfunction, which may be cause by factors including infectious diseases and toxins. (Bovine spongiform encephalopathy, or mad cow disease, has been in the news lately, as has encephalitis due to West Nile virus.) Chronic hepatitis C patients with advanced liver disease may develop hepatic encephalopathy, also called portal-systemic encephalopathy.
This condition occurs when a heavily damaged liver is unable to filter toxins from the blood or when blood flow through the liver is blocked. The condition may occur in people with either acute fulminant hepatitis or long-term chronic liver disease. Few patients with chronic hepatitis C develop full-blown hepatic encephalopathy; however, some degree of brain impairment may occur in as many as three-quarters of those (estimated at 10-25 percent) who develop advanced liver cirrhosis. Hepatic encephalopathy is distinct from the more common “brain fog” that often experienced by people with HCV.
Causes of Hepatic Encephalopathy
The liver carries out many important bodily functions including filtering toxic metabolic byproducts from the blood. Normally blood coming from the intestines flows through the liver, where it undergoes detoxification. In people with decompensated cirrhosis—when the damaged liver is unable to carry out its normal metabolic processes or when blood bypasses the liver—these toxins can build up in the bloodstream.
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Blood may bypass or be shunted around the liver when blood flow through the liver is blocked by scar tissue (causing portal hypertension) or when an artificial shunt is surgically inserted (a procedure sometimes done to control bleeding varices or ascites).
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High levels of toxins can affect the central nervous system (the brain and spinal cord), although how they do so is not well understood. Increased levels of ammonia are believed to be most responsible for hepatic encephalopathy. Ammonia is a byproduct of the digestion of proteins by bacteria in the intestines; normally ammonia is metabolized into urea by the liver and excreted by the kidneys as urine. High levels of ammonia appear to alter the balance of neurotransmitters (chemicals that carry messages between neurons) in the brain.
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This theory is supported by the fact that reducing ammonia usually improves encephalopathy symptoms; however, some people with hepatic encephalopathy do not have elevated blood ammonia levels. Other toxins that may contribute to hepatic encephalopathy include short chain fatty acids and mercaptans. Toxins may interfere with energy metabolism in the brain and alter the function of cell membranes, making the protective blood-brain barrier more permeable. In addition, they may enhance the activity of gamma-aminobutyric acid (GABA)—a chemical that inhibits neural transmission—and may lead to the accumulation of “false” neurotransmitters. In addition, hepatic encephalopathy can lead to changes in a type of brain cell called astrocytes.
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Various precipitating factors can bring on hepatic encephalopathy. Any condition that leads to a buildup of nitrogenous waste products in the blood (azotemia) can exacerbate the condition. Consuming large amounts of protein in the diet can worsen symptoms, as can gastrointestinal bleeding (because blood in the intestines is broken down into protein components).
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Other possible culprits include electrolyte imbalance, alkalosis (high blood pH), dehydration, constipation, bile duct obstruction, and kidney dysfunction.
Infections—for example, sepsis, bacterial peritonitis, or urinary tract infections—are often associated with hepatic encephalopathy. Drugs that depress the central nervous system—such as barbiturates, opiates, and benzodiazepine tranquilizers—can magnify symptoms. People with hepatic encephalopathy should stop taking depressants drugs, and such drugs should be used with caution in anyone with advanced liver disease.Hepatic Encephalopathy Symptoms and DiagnosisSymptoms of hepatic encephalopathy can range from barely perceptible changes to hepatic coma.Symptoms-Cognitive.Cognitive dysfunction may include lack of concentration, irritability, impaired short-term memory, confusion, disorientation, slowed reaction times, and dementia. Some people experience personality, mood, or behavior changes. Motor symptoms can range from muscle tremors to asterixis (flapping of the hands when they are held out in front of the body) to altered reflexes. Changes in consciousness may occur, progressing from decreased alertness and daytime sleepiness to lethargy and stupor...
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The severity of hepatic encephalopathy is measured on a five-point scale..
Grade 0 is indicated by minimal changes in memory, concentration, intellectual function, and coordination.
Grade 1 is characterized by increasing confusion and disorientation, forgetfulness, impaired intellectual function, decreased attention, agitation, lack of coordination, and disturbed sleep patterns (often day-night reversal). .
Grade 2 involves drowsiness, disorientation, loss of ability to perform mental tasks, personality and behavior changes, and increased motor symptoms such as asterixis.
Grade 3 is characterized by lethargy, somnolence (sleeping), loss of mental function, profound confusion, amnesia, aggression, asterixis, and hyperactive reflexes.
Grade 4 is indicated by coma. In the coma stage, respiratory or cardiovascular failure may occur.
Symptomatic hepatic encephalopathy indicates serious liver disease and may be accompanied by other signs of decompensated cirrhosis such as jaundice, ascites, bleeding varices, and gynecomastia (enlarged breasts in men).
Patients with acute, fulminant liver failure often have life-threatening brain swelling (cerebral edema), but this does not usually occur in people with encephalopathy due to chronic hepatitis.Hepatic encephalopathy is diagnosed on the basis of clinical symptoms. Subclinical encephalopathy may be detected by neurological testing before the patient notices any symptoms. Family and friends may report mental or personality changes before the patients is aware of them. Elevated blood ammonia is common in people with hepatic encephalopathy, but ammonia level is not well correlated with severity of symptoms. Some people have a characteristic sweet, musty breath odor called fetor hepaticus. In the later stages, patients typically exhibit brain wave changes as measured by an EEG. Positron emission tomography (PET), CT scans, magnetic resonance imagery, and spinal taps may also be used to assist diagnosis.
Many of the symptoms of hepatic encephalopathy also occur in people with other types of brain disease or damage (for example, meningitis, alcohol or drug overdose, stroke, head trauma), so doctors should be careful to rule out other possible causes.What about “Brain Fog”?Hepatic encephalopathy should not be confused with “brain fog”—the mild lack of concentration, forgetfulness, or absent-mindedness that is common in people with chronic hepatitis C and those receiving HCV treatment.
Several studies have shown some degree of cognitive impairment, memory problems, and reduced concentration in people with hepatitis C who do not have advanced disease. The cause of “brain fog” is not well understood. Some experts believe that HCV itself may affect the central nervous system, or that the virus may alter or stimulate the immune system in ways that impact the brain. In addition, “brain fog” may be related to fatigue, lack of sleep, stress, depression, or side effects of interferon. But in people without advanced cirrhosis, the liver is usually still able to process toxins and blood usually still flows well through the liver. Thus, “brain fog” cannot be assumed to be an early manifestation of hepatic encephalopathy—even though the signs of “brain fog” and some of the symptoms of grade 0 or grade 1 encephalopathy may be similar.
Treating Hepatic Encephalopathy
The U.S. Food and Drug Administration (FDA) approved XIFAXAN® (rifaximin) 550 mg tablets for the reduction in risk of overt HE recurrence in patients 18 years of age or older on March 24, 2010. Xifaxan550 will be available for physicians and patients in the U.S. on May 24, 2010. For more information on Xifaxan550, please visit http://www.xifaxan550.com/.
Salix Pharmaceuticals, Ltd. today announced plans for the Hepatic Encephalopathy Living Program (H.E.L.P.).
H.E.L.P. is a first-of-its-kind patient and health care provider support program for the management of hepatic encephalopathy (HE) and will launch on May 24, 2010. The program will provide patients with HE educational materials, co-pay assistance, treatment adherence support and a 24-hour toll-free hotline.
http://www.helpenroll.com/ or call 1-866-XIFAXAN (934-2926).
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Hepatic encephalopathy in people with chronic hepatitis can usually be treated, and symptoms are generally reversible once metabolic abnormalities are corrected. (This is less likely to be the case for those with encephalopathy due to fulminant liver failure, which is often fatal). Whenever possible, precipitating causes should be identified and dealt with as first step.The primary goal of treatment is to eliminate or neutralize toxins such as ammonia in the intestines.
The first line treatment is lactulose, a nondigestible sugar.
Lactulose alters the metabolism of intestinal bacteria, makes the gut environment more acidic, and acts as a laxative. It inhibits intestinal ammonia production and absorption and increases elimination in the stool. Studies have shown that lactulose (available as a syrup or an enema) is safe and effective. It causes loose stools or diarrhea as part of its mechanism of action. It can be used long-term to prevent hepatic encephalopathy symptoms in patients prone to frequent recurrences.Antibiotics may also be used to reduce the amount of toxins produced by intestinal bacteria; this is usually tried if lactulose is ineffective. Metronidazole (Flagyl), neomycin, or paromomycin may be used, but long-term administration of neomycin can cause ear and kidney damage. Sodium benzoate and ornithine aspartate can be used to bind ammonia and increase its elimination in the urine.
Other potential therapies—which have had mixed results in clinical trials—include flumazenil, levodopa, bromocriptine, levocarnitine, and zinc.In the past, strict diet modification was seen as a mainstay of liver disease management, but this is less true today. The body needs sufficient protein for tissue maintenance repair, and long-term low-protein diets are not usually recommended for people with cirrhosis because they can lead to malnutrition. However, limiting protein consumption for short periods can decrease blood ammonia levels and reduce encephalopathy symptoms.
Many experts recommend eating proteins from vegetable sources—or from dairy products, fish, or chicken—rather than from red meat. In severe cases, dietary supplements containing branched-chain amino acids may be used.Patients who have progressed to hepatic coma may require intubation, mechanical respiration, and cardiac life support. People with end-stage liver disease should be considered for a liver transplant.Hepatic encephalopathy can rapidly progress to become an acute emergency condition, but even mild encephalopathy can have a detrimental effect on the quality of life of people with chronic hepatitis. Alert your health-care provider promptly if you notice any changes in mental status, intellectual functioning, level of alertness, or motor function so that you can be evaluated and treated without delay.
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