Rifaximin treatment in hepatic encephalopathy

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  • Bass et al did a study by enrolling 299 pt from
  • Bass et al. (March 25 issue)1 conducted a randomized, double-blind, placebo-controlled trial comparing 6-month rifaximin therapy with placebo in patients with chronic liver disease who were in remission from recurrent hepatic encephalopathy. They found that rifaximin not only maintained remission more effectively than placebo but also significantly reduced the risk of hospitalization for hepatic encephalopathy. Nevertheless, several issues deserve discussion. First, since infection or gastrointestinal bleeding is known to precipitate an episode of hepatic encephalopathy,2 the authors should provide data on the frequency of breakthrough episodes without precipitating factors to reduce the confounding effects. Second, patients with cirrhosis usually have complications associated with infections caused by enteric bacteria. Because of the antimicrobial effect of rifaximin against enteric bacteria, patients who received this drug appeared to have fewer episodes of bacteremia, sepsis, or bacterial peritonitis than did those receiving placebo (3 of 140 patients in the rifaximin group vs. 8 of 159 patients in the placebo group). However, whether the frequency of recurrence of spontaneous bacterial peritonitis could be reduced or prevented by the prophylactic use of rifaximin deserves further investigation.3Bass et al. have omitted some important details from their report. Excluded from the study were patients with hepatic encephalopathy who had variceal bleeding. No information was given about the spontaneous shunts, arterial ammonia, gut flora, presence of abnormal results on psychometric testing or testing of critical flicker frequency (a psychophysical measure of temporal sensitivity), prophylaxis for spontaneous bacterial peritonitis and variceal hemorrhage, or infections that require therapy with oral antibiotics during follow-up.In a subgroup of patients who were not receiving lactulose and who had increased scores (>18) on the Model for End-Stage Liver Disease (MELD) scale, rifaximin was not effective in preventing hepatic encephalopathy. In our study,1 the majority of patients had Child–Pugh class B or C disease, and lactulose was effective in preventing hepatic encephalopathy, as compared with no lactulose, with 19.6% of patients who received lactulose having an episode of hepatic encephalopathy, as compared with 46.8% of those not receiving lactulose (P=0.001). During the study by Bass et al., more than 90% of patients were receiving lactulose and tolerated it well. In spite of the lack of evidence, a majority of hepatologists still recommend the use of lactulose.2Since in the study by Bass et al. there was no true placebo group (i.e., one receiving neither lactulose nor rifaximin), the effectiveness of rifaximin alone cannot be determined. Thus, the results must be modified, since a combination of rifaximin and lactulose is more effective than lactulose alone for secondary prophylaxis of hepatic encephalopathyThe clinical criteria that Bass et al. used for the selection of patients at high risk for hepatic encephalopathy were not sufficient, and the treatment of hepatic encephalopathy in patients with the rare condition of acute liver failure and in those with the much more common chronic liver disease should be considered separately. Furthermore, the hazard ratio can be misleading for clinicians if such ratios are interpreted properly as an average effect across the entire study period and population. Such hazard ratios should not be used as a measure of relative benefit.1Wang and Kao note the importance of infection and gastrointestinal bleeding in precipitating episodic hepatic encephalopathy and the potentially confounding effects of these events. In our study, a spontaneous event (i.e., one of unknown cause) was the most frequently recorded precipitating factor (in 53 of 104 patients). Infection and gastrointestinal hemorrhage were precipitating factors in 14 and 2 patients, respectively. We agree that further investigation of broader prophylactic use of rifaximin is warranted.Sharma and Sharma inquire about details that were not provided in our article in part because of word limitations. We did not prospectively seek the presence of spontaneous portosystemic shunts, and patients who had gastrointestinal hemorrhage or had undergone placement of a transjugular intrahepatic portosystemic shunt within 3 months before screening were excluded, as were patients who were receiving daily prophylactic antibiotics. Gut flora were not characterized, since this was of unclear significance for our study. The primary end point, the time to breakthrough hepatic encephalopathy, was evaluated on the basis of the Conn score and asterixis grade, with no dependence on psychometric testing. However, we used the Hepatic Encephalopathy Scoring Algorithm1 as a confirmatory assessment tool at scheduled visits. Both blood ammonia and critical flicker frequency were measured at baseline and during selected visits; both variables showed significant improvement in rifaximin-treated patients.2,3 The use of beta-blocking agents for prophylaxis of variceal bleeding was common and similar in the two study groups. Only 6.3% of the placebo-treated patients and 3.5% of the rifaximin-treated patients took other antibiotics for more than 30 days during the study.With respect to patients who had a MELD score of more than 18 or were not taking lactulose (less than 9% in each group), the hazard ratio favored rifaximin in both cases but with large 95% confidence intervals because of the small numbers of patients in these subgroups. Patients in the study were required to have had at least two episodes of overt hepatic encephalopathy within the previous 6 months at study entry, and a total of 104 such episodes occurred during the 6-month study. Since the discontinuation of lactulose in patients at high risk for hepatic encephalopathy was considered unethical, we did not include an additional placebo group receiving neither drug. Equal percentages of patients in both groups were taking lactulose, and the results clearly show that rifaximin was more effective than placebo in maintaining remission of hepatic encephalopathy and was significantly associated with a reduction in the risk of hospitalization.We can reassure Xue and colleagues that patients with acute liver failure were not included in our study. The hazard ratio is commonly used in time-to-event analyses and was appropriate for the end points in this study.
  • Since in the study by Bass et al. there was no true placebo group (i.e., one receiving neither lactulose nor rifaximin), the effectiveness of rifaximin alone cannot be determined. Thus, the results must be modified, since a combination of rifaximin and lactulose is more effective than lactulose alone for secondary prophylaxis of hepatic encephalopathy.hepatic encephalopathy in patients with the rare condition of acute liver failure COULD NOT BE ACCESSED.And as in cases of chronic liver failure with history of overt he usually have the precipitating factors like gi hemorrhage ,electrolyte imbalance and renal impairment so study lacks the eeficacy of rifampicin in that group of pts.The primary end point, the time to breakthrough hepatic encephalopathy, was evaluated on the basis of the Conn score and asterixis grade, with no dependence on psychometric testing. Blood ammonia level of the enrolled participant were not mentioned.Ammonia is a normal constituent of all body fluids. At physiologic pH, it exists mainly as ammonium ion. Reference serum levels are less than 35 µmol/L. Excess ammonia is excreted as urea, which is synthesized in the liver through the urea cycle. Sources of ammonia include bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine-nucleotide cycle and amino acid transamination in skeletal muscle, and other metabolic processes in the kidneys and liver.
  • The Mini-Mental State Examination (6) is a summed score evaluating various dimensions of cognition (memory, calculation, orientation in space and time, language, and word recognition). It is used as an index of global cognitive performance and ranges from 0 to 30.The Digit Symbol Substitution Test (13) explores attention and psychomotor speed. Given a code table displaying the correspondence between pairs of digits (from 1 to 9) and symbols, the subjects have to fill in blank squares with the symbol that is paired to the digit displayed above the square. The subjects have to fill in as many squares as possible in 90 seconds. In PAQUID, the score ranges from 0 to 76 even if the theoretical maximum is 90.Block design test:A non-verbal performance test of intelligence, useful with the language and hearing impaired. Block design is a subtest on many intelligence tests that measures visuospatial and motor skills. The testee is required to take blocks that have all white sides, all red sides, and red and white sides and arrange them according to a pattern. They are timed on this task and compared to a normative sample.
  • Note: The sensitivity and specificity were 87% and 94%, respectively. NCT result was influenced by age and educational background and the sensitivity was low for the scanning of SHEZhong B, Chen M, Wang J, Yuan Y, Hu P.The value of number connection test in the diagnosis of subclinical hepatic encephalopathy.Zhonghua Nei Ke Za Zhi. 2001 Jan;40(1):13-5
  • Hepatic encephalopathy is a neuropsychiatric syndrome for which symptoms, manifested on a continuum, are deterioration in mental status, with psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration, disorientation, and — in severe forms — coma.
  • The clinical diagnosis of overt hepatic encephalopathy is based on two concurrent types of symptoms: impaired mental status, as defined by the Conn score (also called West Haven criteria) (on a scale from 0 to 4, with higher scores indicating more severe impairment),9 and impaired neuromotor function.1,10 The Conn score is recommended by the Working Party on Hepatic Encephalopathy8 for assessment of overt hepatic encephalopathy in clinical trials. Signs of neuromotor impairment include hyperreflexia, rigidity, myoclonus, and asterixis (a coarse, myoclonic, “flapping” muscle tremor), which is measured with the use of an asterixis severity scale.10-12
  • Signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. And in 24-53% of patients who undergo portosystemic shunt surgery. Approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma.
  • Diagnosis and management Approach in case of he should focus on the following points:Assess the severity of liver damageExclude the nonhepatic cause of encephalopathy.Recognize and correct the precipitating factors.Treat the hyperammonemia :hallmark of most cases of HEConsider :Patients with severe encephalopathy (ie, grade 3 or 4) who are at risk for aspiration should undergo prophylactic ET intubation. They are optimally managed in the intensive care unit.
  • He is a diagnosis of exclusion.A number of differentials are needed to consider and work up should follow proper history ,examination and investigations to rule out the other causes.
  • Renal failure: Renal failure leads to decreased clearance of urea, ammonia, and other nitrogenous compounds.Gastrointestinal bleeding: blood cells are hemolyzed in the intestines, releasing protein.The presence of blood in the gastrointestinal tract results in increased ammonia and nitrogen absorption from the gut. Bleeding may predispose to kidney hypoperfusion and impaired renal function. Infection: Infection may predispose to impaired renal function and to increased tissue catabolism, both of which increase blood ammonia levels.Constipation: Constipation increases intestinal production and absorption of ammonia.Medications: Drugs that act upon the central nervous system, such as opiates, benzodiazepines, antidepressants, and antipsychotic agents, may worsen hepatic encephalopathy.Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion of NH4 + to NH3.diuretic-induced hypovolemia is the most common reason for patients with previously well-controlled hepatic encephalopathy to present to the emergency room with worsening mental function.Dietary protein overload: This is an infrequent cause of hepatic encephalopathyand portacaval shunts leads to increase delivery of ammonia to cns
  • In the late 19th century, it was recognized that the feeding of a high-protein to dogs that had undergone portosystemic shunt surgery could produce symptoms of abnormal coordination and stupor in the treated animals.In the 20th century, low-protein diets were routinely recommended for patients with cirrhosis, in hopes of decreasing intestinal ammonia production and of preventing exacerbations of hepatic encephalopathy. An obvious consequence was the worsening of preexisting protein-energy malnutrition. Protein restriction may be appropriate in some patients immediately following a severe flare of symptoms (ie, episodic hepatic encephalopathy). However, protein restriction is rarely justified in patients with cirrhosis and persistent hepatic encephalopathy. Indeed, malnutrition is a more serious clinical problem than hepatic encephalopathy for many of these patients.In the author's experience, it is the infrequent patient who is intolerant of a diet high in protein. Most patients with mild chronic hepatic encephalopathy tolerate more than 60-80 g of protein per day. Furthermore, one study administered a protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms.[23 ]Another study randomized patients with severe episodic encephalopathy to either a low-protein diet or a high-protein diet, administered via nasogastric tube.[24 ]All patients received the same regimen of neomycin per nasogastric tube. Mental function improved at the same rate in both treatment groups. Importantly, patients receiving the low-protein diet had evidence for increased protein breakdown during the duration of the study.Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein, especially proteins derived from red meats. This may be because of increased content of dietary fiber, a natural cathartic, and less ammoniagenic. Vegetable protein have decreased levels of aromatic amino acids. Aromatic amino acids, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen hepatic encephalopathy.In Acute severe cases protein diet can be given in low amounts 20-30 g/d and Protein intake is increased by 10 gm/day every 3rd day until normal intake (60-80 gm/d)Calories intake is maintained at 2000 cal /day or above either oral or IV.Vitamins :Daily intake of multivitamins especially containing more branched chain amino acids(pork, wheat , red meats, dairy products, beans and brown rice. ), trace element , minerals , zinc is recommended ,
  • Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s. Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. They are degraded by intestinal bacteria to lactic acid and other organic acids.The conversion of Lactulose to lactic acid results in acidification of the gut lumen. This favors conversion of NH4 + to NH3 and the passage of NH3 from tissues into the lumen. 2. Traps luminal ammonia and decrease its absorption.3. Gut acidification inhibits ammoniagenic coliform bacteria, leading to decrease ammonia production. 4. These osmotic laxatives also works as a cathartic, reducing colonic bacterial load.Patients should take sufficient lactulose as to have 2-4 loose stools per day.Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated.Great care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed.
  • Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s. Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. They are degraded by intestinal bacteria to lactic acid and other organic acids.The conversion of Lactulose to lactic acid results in acidification of the gut lumen. This favors conversion of NH4 + to NH3 and the passage of NH3 from tissues into the lumen. 2. Traps luminal ammonia and decrease its absorption.3. Gut acidification inhibits ammoniagenic coliform bacteria, leading to decrease ammonia production. These osmotic laxatives also works as a cathartic, reducing colonic bacterial load.Patients should take sufficient lactulose as to have 2-4 loose stools per day.Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated.Great care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed.
  • AntibioticsNeomycin and other antibiotics, such as metronidazole,and oral quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria. Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as 4000 mg/d may be administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and nephrotoxicity because of some systemic absorption.
  • Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that the drug will not pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics. It is used to treat diarrhea caused by E. coliRifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic. Rifaximin acts by inhibiting RNA synthesis in susceptible bacteria by binding to the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme. It is also used to treat diarrhea caused by E. coli and in irritable bowel syndrome.Half life : Approximately 6 hoursAffected microorganisms: Enteric bacteriaIn March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al.
  • A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with liver disease. The most well known postulations in development of Hepatic encephalopathy is the result of accumulated neurotoxic substances in the brain. Why accumulation of neurotoxins in brain in severe liver disease ……….Putative neurotoxins include short-chain fatty acids; mercaptans; false neurotransmitters, such as tyramine, octopamine, and beta-phenylethanolamines; manganese; ammonia; and gamma-aminobutyric acid (GABA).A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with liver disease. Some literatures contend that hepatic encephalopathy is a disorder of astrocyte function. Astrocytes play a key role in the regulation of the blood-brain barrier. They are involved in maintaining electrolyte homeostasis and in providing nutrients and neurotransmitter precursors to neurons. They also play a role in the detoxification of a number of chemicals, including ammonia.[4 ]neurotoxic substances,like ammonia and manganese, may gain entry into the brain in the setting of liver failure. And then contribute to morphologic changes in astrocytes. There may occur astrocyte swelling that can be so marked as to produce brain edema. This may lead to increased intracranial pressure and, potentially, brain herniation.
  • ProductionAmmonia is released from several tissues (kidney, muscle), but its highest levels can be found in the portal vein.Portal ammonia is derived from both the urease activity of colonic bacteria and the deamination of glutamine in the small bowel, by the activity of glutaminase.[7 ]and is a key substrate for the synthesis of urea and glutamine in the liver. Normally, ammonia is detoxified in the liver by conversion to urea by the Krebs-Henseleit cycle. Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends upon the activity of glutamine synthetase. Two factors contribute to the hyperammonemia that is seen in cirrhosis. First, there is a decreased mass of functioning hepatocytes, resulting in fewer opportunities for ammonia to be detoxified by the above processes. Secondly, portosystemic shunting may divert ammonia-containing blood away from the liver to the systemic circulation.Normal skeletal muscle cells do not possess the enzymatic machinery of the urea cycle but do contain glutamine synthetase. Glutamine synthetase activity in muscle actually increases in the setting of cirrhosis and portosystemic shunting. Thus, skeletal muscle is an important site for ammonia metabolism in cirrhosis. However, the muscle wasting that is observed in patients with advanced cirrhosis may potentiate hyperammonemia.And other thing is around 50 percent of nh3 is pooled in skeletal muscle,so in cases of muscle wasting there is release of ammonia in the blood leading to hyperammoniaThe kidneys express glutaminase and, to some extent, play a role in ammonia production. However, the kidneys also express glutamine synthetase and play a key role in ammonia metabolism and excretion.[7 ]Brain astrocytes also possess glutamine synthetase. Thus, the brain remains vulnerable to the effects of hyperammonemia.
  • Ammonia has multiple neurotoxic effects. Additional support for the ammonia hypothesis comes from the clinical observation that treatments that decrease blood ammonia levels can improve hepatic encephalopathy symptoms.[8 ]One argument against the ammonia hypothesis is the observation that approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence for encephalopathy. Also, ammonia does not induce the classic electroencephalographic (EEG) changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis.
  • Ammonia has multiple neurotoxic effects. Additional support for the ammonia hypothesis comes from the clinical observation that treatments that decrease blood ammonia levels can improve hepatic encephalopathy symptoms.[8 ]One argument against the ammonia hypothesis is the observation that approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence for encephalopathy. Also, ammonia does not induce the classic electroencephalographic (EEG) changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis.
  • Glutamate is an excitatory neurotransmitter
  • And not only nh3 Other gut-derived toxins have been proposed. Benzodiazepinelike substances (9) have been postulated to arise from a specific bacterial population in the colon (10). Other products of colonic bacterial metabolism (11), such as neurotoxic short- and medium-chain fatty acids, phenols, and mercaptans, are also produced.mercaptans are also supposed to have direct neurotoxic effects.Manganese may deposit in basal ganglia and induce extrapyramidal symptomatology (12). All of these compounds may interact with ammonia and result in additional neurochemical changes. For example, ammonia activates peripheral-type benzodiazepine receptors with subsequent stimulationof the GABA-ergic system, an effect also induced directly by ammonia (13).
  • The Working Group on Hepatic Encephalopathy recommended updating the nomenclature of HE according to clinical presentation and aetiology.[1] These definitions were formulated with the aim to simplify the diagnosis of HE clinically and also to include the HE associated with congenital shunts, urea-cycle disorders and acute liver failure into the entire spectrum of HE. The group recommended dividing HE into three broad categories: A (acute liver failure), B (porto-systemic bypass without intrinsic liver disease) and C (cirrhosis). Type C hepatic encephalopathy is, in turn, subcategorized as episodic, persistent, or minimal.graphical representation of the time course of HE type C or in cirrhosis is shown in the figure. It is clinically divided into episodic or persistent HE depending on their chronicity and clinical behaviour, as shown in Figure 1: Episodic HE remains clinically undetectable in between HE episodes, persistent HE patients never become free of HE and patients with MHE remain below the clinical detection level.[5]Acute liver failure is defined as coagulopathy due to acute liver dysfunction of more than 10 days, but less than 30 days total duration by clinical criteria.
  • This figure shows the graphical representation of the time course of HE type C or in cirrhosis. It is clinically divided into episodic or persistent HE depending on their chronicity and clinical behaviour:In cirrhosis, recurrent episodes of an altered mental state may occur in the absence of precipitating factors (recurrent encephalopathy) or neurological deficits may not completely reverse (persistent encephalopathy).And in minimal or subclinical he , neurological disturbance is not clearly evident on clinical examination: mild cognitive abnormalities only recognizable with psychometric or neurophysiologic tests (minimal or subclinical encephalopathy).
  • There are several systems that have been used to diagnose the severity of HE clinically. . The most widely used are the West-Haven criteria.Only low-stage HE, i.e. pre-coma stages 1 and 2 in the West-Haven criteria, and MHE are the components of HE that require a detailed neuropsychological evaluation. Altered mental status is assessed by using west haven critera .and level of conciousness can be assessed using glascow coma scale.In precoma stage ,there can be alteration in behaviour, disorientation, asterixis ,micrographia ,and constructional apraxia. While these features are absent in coma stages.In pre coma there can be ataxic gait ,increased tone of muscles ,plantar responses are flexor.While in coma stages pt is flaccid ,absent reflexes with plantar extensor response.
  • ALF is defined as deteriorating liver function with feature of hepatic encephalopathy occuring within 12 wks of onset of precipitating illness in the absence of evidence of preexisting liver disease.Most common causes of alf are acute viral illness, hepatotoxic drugs like acetaaminophen ,and cryptogenic.
  • In acute liver failure= Spontaneously appearing, Severe fatal hepatic dysfunction + abrupt mental deterioration + coma/death In chronic liver disease= Insidious onset with long hx of ld and stigmata of chronic liver disease usually with f/o liver failure.
  • Investigation in case of hepatic encephalopathy is done toAccess severity of liver damage .To find the correctable metabolic derrangements To identify the precipitating factorsTo rule out non hepatic causes.Gcs :Useful for patients with Grade 3-4 HE,• Incorporates motor components
  • GI hemorrhage. Exploration requires stool analysis with FOBT and/or placement of a nasogastric tube.Infections. This factor requires culture of all appropriate body fluids, especially ascites when present. Spontaneous bacterial peritonitis and pneumonia may presentwith HE.Renal and electrolyte disturbances. These include renal failure, metabolic alkalosis, hypokalemia, dehydration,and diuretic effects.Use of psychoactive medication. This factor may require a urine screen for benzodiazepines, narcotics, and other sedatives.
  • Brain imaging• Useful for ruling out other causes of encephalopathy• Imaging findings in HE patientsCTCortical atrophy cerebral edemaMRIHyperintensity of basal ganglia (due to manganese deposits)Cerebral and cerebellar atrophyCerebral edema
  • In the late 19th century, it was recognized that the feeding of a high-protein to dogs that had undergone portosystemic shunt surgery could produce symptoms of abnormal coordination and stupor in the treated animals.In the 20th century, low-protein diets were routinely recommended for patients with cirrhosis, in hopes of decreasing intestinal ammonia production and of preventing exacerbations of hepatic encephalopathy. An obvious consequence was the worsening of preexisting protein-energy malnutrition. Protein restriction may be appropriate in some patients immediately following a severe flare of symptoms (ie, episodic hepatic encephalopathy). However, protein restriction is rarely justified in patients with cirrhosis and persistent hepatic encephalopathy. Indeed, malnutrition is a more serious clinical problem than hepatic encephalopathy for many of these patients.In the author's experience, it is the infrequent patient who is intolerant of a diet high in protein. Most patients with mild chronic hepatic encephalopathy tolerate more than 60-80 g of protein per day. Furthermore, one study administered a protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms.[23 ]Another study randomized patients with severe episodic encephalopathy to either a low-protein diet or a high-protein diet, administered via nasogastric tube.[24 ]All patients received the same regimen of neomycin per nasogastric tube. Mental function improved at the same rate in both treatment groups. Importantly, patients receiving the low-protein diet had evidence for increased protein breakdown during the duration of the study.Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein, especially proteins derived from red meats. This may be because of increased content of dietary fiber, a natural cathartic, and less ammoniagenic. Vegetable protein have decreased levels of aromatic amino acids. Aromatic amino acids, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen hepatic encephalopathy.In Acute severe cases protein diet can be given in low amounts 20-30 g/d and Protein intake is increased by 10 gm/day every 3rd day until normal intake (60-80 gm/d)Calories intake is maintained at 2000 cal /day or above either oral or IV.Vitamins :Daily intake of multivitamins especially containing more branched chain amino acids(pork, wheat , red meats, dairy products, beans and brown rice. ), trace element , minerals , zinc is recommended ,
  • Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s. Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. They are degraded by intestinal bacteria to lactic acid and other organic acids.The conversion of Lactulose to lactic acid results in acidification of the gut lumen. This favors conversion of NH4 + to NH3 and the passage of NH3 from tissues into the lumen. 2. Traps luminal ammonia and decrease its absorption.3. Gut acidification inhibits ammoniagenic coliform bacteria, leading to decrease ammonia production. These osmotic laxatives also works as a cathartic, reducing colonic bacterial load.Patients should take sufficient lactulose as to have 2-4 loose stools per day.Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated.Great care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed.
  • Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s. Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. They are degraded by intestinal bacteria to lactic acid and other organic acids.The conversion of Lactulose to lactic acid results in acidification of the gut lumen. This favors conversion of NH4 + to NH3 and the passage of NH3 from tissues into the lumen. 2. Traps luminal ammonia and decrease its absorption.3. Gut acidification inhibits ammoniagenic coliform bacteria, leading to decrease ammonia production. These osmotic laxatives also works as a cathartic, reducing colonic bacterial load.Patients should take sufficient lactulose as to have 2-4 loose stools per day.Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated.Great care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed.
  • AntibioticsNeomycin and other antibiotics, such as metronidazole,and oral quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria. Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as 4000 mg/d may be administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and nephrotoxicity because of some systemic absorption.
  • Rifaximin, a nonabsorbable derivative of rifampin, has been used in Europe for more than 20 years for a wide variety of gastrointestinal indications. Side effects”Peripheral edema and nausea are the side effects.Rifaximin, a nonabsorbable derivative of rifampin, has been used in Europe for more than 20 years for a wide variety of gastrointestinal indications. Since 2005 It has also been used in the treatment of hepatic encephalopathy.Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.[25,26,27 ]Similarly, rifaximin was as effective as neomycin and paramomycin. Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics.In March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al.[28 ]Bass et al evaluated rifaximin’s ability to reduce the risk of recurrent hepatic encephalopathy (HE).[28 ]In this double-blind, placebo-controlled, multinational, phase 3 clinical trial, 299 patients received either rifaximin 550 mg or placebo BID. Each group also received lactulose. Breakthrough episodes of HE occurred in 22% of patients treated with rifaximin and 46% of patients with placebo (P <0.001). HE-related hospitalization occurred in 14% of patients treated with rifaximin and 23% of patients treated with placebo (P = 0.01).Peripheral edema and nausea are described in some rifaximin-treated patients. There are also questions whether long-term treatment with rifaximin can induce microbial resistance. Thus far, microbial resistance has not been reported in patients using the medication. It remains unclear whether diarrhea caused by Clostridium difficile occurs at a higher rate in rifaximin-treated patients than untreated patients. In the study by Bass et al, 2 rifaximin-treated patients and no placebo-treated patients developed C difficile infection.[28 ]
  • Treatments to Increase Ammonia ClearanceL-ornithine L-aspartate (LOLA)LOLA is available in Europe in both intravenous formulations and oral formulations.. LOLA is a stable salt of the 2 constituent amino acids. L-ornithine stimulates the urea cycle, with resulting loss of ammonia. Both l-ornithine and l-aspartate are substrates for glutamate transaminase. Their administration results increased glutamate levels. Ammonia is subsequently used in the conversion of glutamate to glutamine by glutamine synthetase. LOLA was found to be effective in treating hepatic encephalopathy in a number of European trials.[29,30 ].It is contraindicated in renal failure.ZincZinc deficiency is common in cirrhosis. Even in patients who are not zinc deficient, zinc administration has the potential to improve hyperammonemia by increasing the activity of ornithine transcarbamylase, an enzyme in the urea cycle. The subsequent increase in ureagenesis results in the loss of ammonia ions.Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials. Hepatic encephalopathy improved in 2 studies[31 ]; there was no improvement in mental function in 2 other studies.[32 ]Sodium benzoate, sodium phenylbutyrate, sodium phenylacetateSodium benzoate interacts with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy.[33 ]Use of the medication is limited by the risk of salt overload and by its unpleasant taste. The medication, also used as a food preservative, is available through many specialty chemical manufacturers throughout the United States. The author has limited its use to patients with severe encephalopathy symptoms. However, in the author’s opinion, doses of sodium benzoate as low as 2.5 g orally three times per week significantly improved mental function in outpatients who had persistent encephalopathy symptoms despite cotherapy with lactulose and rifaximin.Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in turn, reacts with glutamine to form phenylacetylglutamine. This chemical is subsequently excreted in the urine, with loss of ammonia ions. Sodium phenylbutyrate (Buphenyl, Ucyclyd Pharma, Scottsdale, Ariz) and intravenous sodium phenylacetate in combination with sodium benzoate (Ammonul, Ucyclyd Pharma, Scottsdale, Ariz) are approved by the FDA for the treatment of hyperammonemia associated with urea cycle disorders.[34 ]Newer oral reformulations of these ammonia-lowering drugs that lack the high salt content of the older agents are currently in clinical trials.L-carnitineL-carnitine improved hepatic encephalopathy symptoms in several small studies of patients with cirrhosis.[35 ]Whether the medication works by improving blood ammonia levels or whether it works centrally perhaps by decreasing brain ammonia uptake remains unclear.[36 ]
  • ZincZinc deficiency is common in cirrhosis. zinc absorption is not greatly depressed but urinary zinc excretion is increased in patients with cirrhosis, which seems to be the basic cause of their zinc depletion.Therefore we are in favour of zinc Even in patients who are not zinc deficient, zinc administration has the potential to improve hyperammonemia by increasing the activity of ornithine transcarbamylase, an enzyme in the urea cycle. The subsequent increase in ureagenesis results in the loss of ammonia ions.Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials. Hepatic encephalopathy improved in 2 studies[31 ]; there was no improvement in mental function in 2 other studies.[32 ]Sodium benzoate, sodium phenylbutyrate, sodium phenylacetateSodium benzoate interacts with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy.[33 ] Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in turn, reacts with glutamine to form phenylacetylglutamine. This chemical is subsequently excreted in the urine, with loss of ammonia ions. L-carnitineL-carnitine improved hepatic encephalopathy symptoms in several small studies of patients with cirrhosis.[35 ]
  • Sodium benzoate, sodium phenylbutyrate, sodium phenylacetateSodium benzoate interacts with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy.[1 ] Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in turn, reacts with glutamine to form phenylacetylglutamine. This chemical is subsequently excreted in the urine, with loss of ammonia ions. L-carnitineL-carnitine improved hepatic encephalopathy symptoms in several small studies of patients with cirrhosis.[2 ]The direct neurological therapies such as bromocriptine and flumazenil have fallen out of favour because of their potential for decreasing seizure threshold and efficacy concerns.
  • Sleep disturbances are more common in patients with minimal hepatic encephalopathy. Whether or not this relates to hepatic encephalopathy is unclear. A trial compared the histamine H1 blocker hydroxyzine to placebo in patients with cirrhosis and minimal hepatic encephalopathy.[1]Sleep efficiency and the patients' subjective quality of sleep improved in patients receiving hydroxyzine (25 mg) at bedtime. However, there was no accompanying improvement in cognition, as measured by neurophysiologic tests. The authors urged caution when prescribing hydroxyzine, on account of the risk of worsening encephalopathy in some patients.
  • Most therapies for hepatic encephalopathy focus on treating episodes as they occur and are directed at reducing the nitrogenous load in the gut, an approach that is consistent with the hypothesis that this disorder results from the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.2,3,13 The current standard of care for patients with hepatic encephalopathy, treatment with nonabsorbable disaccharides lactitol or lactulose, decreases the absorption of ammonia through cathartic effects and by altering colonic pH.14In an open-label, single-site study, Sharma et al. reported that lactulose, as compared with placebo, was effective in the prevention of overt hepatic encephalopathy.15 In that study, 125 patients who had recovered from a recent episode of hepatic encephalopathy were randomly assigned, in a 1:1 ratio, to receive either lactulose or placebo for up to 20 months. During a median study period of 14 months, the proportion of patients with episodes was smaller in the lactulose group than in the placebo group (19.6% vs. 46.8%, P=0.001). However, side effects of lactulose therapy — including an excessively sweet taste and gastrointestinal side effects such as bloating, flatulence, and severe and unpredictable diarrhea possibly leading to dehydration — result in frequent noncompliance.16-18
  • In general, the oral antibiotics neomycin, paromomycin, vancomycin, and metronidazole have been effectively used, with or without lactulose, to reduce ammonia-producing enteric bacteria in patients with hepatic encephalopathy.14,16,17 However, some oral antibiotics are not recommended for long-term use because of nephrotoxicity, ototoxicity, and peripheral neuropathy19,20 and are specifically contraindicated in patients with liver disease.19,21,22
  • Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance. 23-25 In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute hepatic encephalopathy.26-39 
  • Rifaximin treatment in hepatic encephalopathy

    1. 1. RIFAXIMIN TREATMENT IN HEPATIC ENCEPHALOPATHY.1 A Journal Presentation Pratap Sagar Tiwari ,Resident ,Internal Medicine, NGMC Ref: 1. Bass N.M, Mullen K.D, Sanyal A, Poordad F, Guy Neff G, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81.
    2. 2. BACKGROUND • Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. • The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.
    3. 3. METHODS • In this randomized, double-blind, placebo-controlled trial, 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease were randomly assigned to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. • The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. • The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy
    4. 4. RESULTS • Rifaximin significantly reduced the risk of an episode of HE, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). • A breakthrough episode of HE occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. • A total of 13.6% of the patients in the rifaximin group had a hospitalization involving HE, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). • More than 90% of patients received concomitant lactulose therapy. • The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.
    5. 5. CONCLUSIONS • Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. • Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy.
    6. 6. DISCUSSION 1. Blood ammonia level ? 2. The primary end point, the time to breakthrough HE, was evaluated on the basis of the Conn score and asterixis grade, with no dependence on psychometric testing !!! 3. There was no true placebo group (i.e., one receiving neither lactulose nor rifaximin), the effectiveness of rifaximin alone cannot be determined. 4. HE in patients with the rare condition of acute liver failure COULD NOT BE ACCESSED. 5. As in cases of chronic liver failure with history of overt HE usually have the precipitating factors like gi hemorrhage ,electrolyte imbalance and renal impairment so study lacks the efficacy of rifaximin .
    7. 7. PSYCHOMOTRIC TESTS: • 1- Number connection test 2- Digital symbol test 3- Mini Mental State Examination 4- Block design test.
    8. 8. Number Connection test Note: The sensitivity and specificity were 87% and 94%, respectively. NCT result was influenced by age and educational background and the sensitivity was low for the scanning of Subclinical HE Zhong B, Chen M, Wang J, Yuan Y, Hu P.The value of number connection test in the diagnosis of subclinical hepatic encephalopathy. Zhonghua Nei Ke Za Zhi. 2001 Jan;40(1):13-5
    9. 9. DIGITAL SYMBOL SUBSTITUTION TEST
    10. 10. MINI MENTAL STATE EXAMINATION
    11. 11. INTRODUCTION :HEPATIC ENCEPHALOPATHY • Hepatic encephalopathy is a neuropsychiatric syndrome for which symptoms, manifested on a continuum, are deterioration in mental status, with psychomotor dysfunction, impaired memory, sensory abnormalities, poor concentration, disorientation, and — in severe forms — coma. 1 1. POORDAD FF. THE BURDEN OF HEPATIC ENCEPHALOPATHY. ALIMENT PHARMACOL THER 2007;25:SUPPL 1:3-9
    12. 12. CLINICAL DIAGNOSIS OF HE • The clinical diagnosis of hepatic encephalopathy is based on two concurrent types of symptoms: 1. impaired mental status 2. impaired neuromotor function 2 1 1. Conn HO, Lieberthal MM. The hepatic coma syndromes and lactulose. Baltimore: Williams & Wilkins, 1979. 2. Córdoba J, Blei AT. Hepatic encephalopathy. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's diseases of the liver. 10th ed. Vol. 1. Philadelphia: Lippincott Williams & Wilkins, 2007:569-99
    13. 13. PREVALENCE 1 • Signs of HE are observed in nearly 70% of patients with cirrhosis. • 24-53% of patients who undergo portosystemic shunt surgery. • Approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma. 1. Ferenci P. Hepatic encephalopathy. In: Haubrich WS, Schaffner F, Berk JE, eds. Bockus Gastroenterology. 5 th ed. Philadelphia, Pa: WB Saunders; 1995:1998-2003.
    14. 14. • Approximately 5.5 million persons in the United States have hepatic cirrhosis, a major cause of complications and death. 1,2 • In 2003, more than 40,000 patients were hospitalized with hepatic encephalopathy, a number that increased to over 50,000 in 2004. 3 1. Poordad FF. The burden of hepatic encephalopathy. Aliment Pharmacol Ther 2007;25:Suppl 1:3-9 2. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812. 3. Wright G, Jalan R. Management of hepatic encephalopathy in patients with cirrhosis. Best Pract Res Clin Gastroenterol 2007;21:95-110
    15. 15. • The prevention of episodes of hepatic encephalopathy is an important goal in the treatment of patients with liver disease, 1,2,3,4 especially since symptoms of overt encephalopathy are debilitating and decrease the ability for self-care, leading to improper nutrition and nonadherence to a therapeutic regimen, which in turn leads to severe symptoms, frequent hospitalizations, and a poor quality of life. 1. Poordad FF. The burden of hepatic encephalopathy. Aliment Pharmacol Ther 2007;25:Suppl 1:3-9 2. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812 3. Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 2007;52:737-741 4. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890-895
    16. 16. APPROACH Approach: 1. Assess the severity of liver damage 2. Exclude the nonhepatic cause of encephalopathy. 3. Recognize and correct the precipitating factors. 4. Treat the hyperammonemia :hallmark of most cases of HE Consider : 1. Patients with severe encephalopathy (ie, grade 3 or 4) who are at risk for aspiration should undergo prophylactic ET intubation.
    17. 17. Differential Diagnosis I-Intracranial lesions -Trauma (e.g., subdural hematoma), -Bleeding, Cerebral infarction -Tumors , Abscess 2-Infections -Meningitis ,Encephalitis, -Subarachnoid hemorrhage 3-Metabolic Encephalopathies -Anoxia, Uremia ,Ketoacidosis -Hypoglycemia, Electrolyte imbalance -Inborn error of urea cycle 4-Toxic encephalopathy -Alcohol: -Acute intoxication -Withdrawal syndrome - Wernicke's syndrome 5-Neuropsychatric disorders
    18. 18. PRECIPITATING FACTORS:1 • • • • • • • Renal failure Gastrointestinal bleeding Infection Constipation Medication: Opiates, benzodiazepines, Antipsychotic Diuretic therapy ,Paracentesis ,Dehydration, Electrolyte imbalance Dietary protein overload 1. Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. Jul 2001;96(7):1968-76
    19. 19. TREATING HYPERAMMONIA 1. Treatments to Decrease Intestinal Ammonia Production • Diets • Cathartics • Antibiotics 2. Treatments to Increase Ammonia Clearance • L-ornithine L-aspartate (LOLA) • Zinc • Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate • L-carnitine
    20. 20. DIET • Most patients with HE tolerate =60-80 g of protein /d. • Furthermore, one study administered protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms.1 • Another study randomized patients with severe episodic encephalopathy to low-protein diet Vs high-protein diet, administered via NG tube.2 All patients received the same regimen of neomycin per NG tube. Mental function improved at the same rate in both treatment groups. 1. Guy S, Tanzer-Torres G, Palese M, et al. Does nasoenteral nutritional support reduce mortality after liver transplant?. Hepatology. 1995;22:144A. 2. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. Jul 2004;41(1):38-43.
    21. 21. CATHARTICS • Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s. • Patients should take sufficient lactulose as to have 2-4 loose stools per day. • Initial dosing = 30 mL orally, daily or twice daily. The dose may be increased as tolerated. • A/E: ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. • High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by NG tube to patients hospitalized with severe HE. • Administered as enema to Comatose patients. The recommended dosing is 300 mL lactulose plus 700 mL water, q4hrly
    22. 22. EFFECTS OF LACTULOSE
    23. 23. ANTIBIOTICS Neomycin, Metronidazole ,Paramomycin, Quinolones • Initial neomycin dosing is 250 mg orally 2-4 times a day. 1 • A/E: ototoxicity and nephrotoxicity 1. David C Wolf,Hepatic Encephalopathy source: www.emedcine.com Updated: Mar 9, 2011
    24. 24. RIFAXIMIN VS LACTILOL VS RIFAXIMIN+LACTILOL 1 • Forty out-patients (29 males, 11 females, mean age: 59 years, range 40-70), with viral liver cirrhosis and chronic HE (1st-2nd degree) were studied. HE was assessed by considering: mental state, asterixis, number connection test (NCT), arterial blood ammonia levels. Patients were randomly assigned to the following treatments: rifaximin (gp R); lactitol (gp L); rifaximin plus lactitol (gp RL). All treatments were continued for 15 days for 3 cycles, intervalled by 15 days . RESULTS: • The 3 treatments reduced HE, but with different efficacy: patients of group R and RL significantly (p<0.05) documented a faster improvement in HE degree, a higher percentage of patients which normalized mental state and NCT, a faster improvement of asterixis and a longer persistence of normal ammonia levels than patients of group L. CONCLUSIONS: • Rifaximin in combination with lactitol represents an effective and safe treatment of chronic HE. 1. Loguercio C, Federico A, DeGirolamo V, Ferrieri A, DelVecchio C.Cyclic treatment of chronic hepatic encephalopathy with rifaximin.Minerva Gastroenterol Dietol. 2003 Mar;49(1):53-62.
    25. 25. RIFAXIMIN VERSUS NONABSORBABLE DISACCHARIDES IN THE MANAGEMENT OF HEPATIC ENCEPHALOPATHY: A META-ANALYSIS1 • Methods: a meta-analysis of comparative randomized trials of rifaximin and nonabsorbable disaccharides. • Results: 5 randomized controlled trials were included. There was no significant difference between rifaximin and nonabsorbable disaccharides on improvement in patients with hepatic encephalopathy [relative risk (RR) 1.08; 95% confidence interval (CI), 0.85-1.38; P=0.53]. RR was 0.98 (95% CI: 0.85-1.13; P=0.74) for acute hepatic encephalopathy in 157 patients and 0.87 (95% CI: 0.40-1.88; P=0.72) for chronic hepatic encephalopathy in 96 patients, respectively. There was no significant difference between rifaximin and nonabsorbable disaccharides on diarrhea (RR=0.90; 95% CI: 0.17-4.70; P=0.90). However, a significant difference in favor of rifaximin on abdominal pain (RR=0.28; 95% CI: 0.08-0.95; P=0.04) was identified. • Conclusion: Rifaximin is not superior to nonabsorbable disaccharides for acute or chronic hepatic encephalopathy in the long-term or short-term treatment except that it may be better tolerated. 1. Qiana J, Xue-Huaa j, Ming-Huac z, Liu-Mingd j, Yong-Pingc c, Wang, Lib W et al.Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis.European Journal of Gastroenterology & Hepatology:November 2008 - Volume 20 - Issue 11 - pp 1064-1070
    26. 26. • The current study differs from previous randomized studies in that it involved a larger group of patients and a longer study period. In previous randomized studies, rifaximin was administered for 21 days or less1,2,3 or intermittently, for 14 or 15 days per month for 3 or 6 months. 1. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy.Curr Med Res Opin 1993;13:109-118 2. Festi D, Mazzella G, Orsini M, et al. Rifaximin in the treatment of chronic hepatic encephalopathy: results of a multicenter study of efficacy and safety. Curr Ther Res Clin Exp 1993;54:598-609 3. Puxeddu A, Quartini M, Massimetti A, Ferrieri A. Rifaximin in the treatment of chronic hepatic encephalopathy. Curr Med Res Opin 1995;13:274-281
    27. 27. • This study shows the superiority of rifaximin therapy over treatment with lactulose alone. More than 90% of patients received concomitant lactulose during the study period. • The safety profile of rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease. • The occurrence of nephrotoxicity and ototoxicity with the use of aminoglycosides (e.g., neomycin and paromomycin) and of nausea and peripheral neuropathy with prolonged use of metronidazole restricts their use in patients with hepatic encephalopathy. 1,2,3 • Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current medical diagnosis & treatment. 38th ed. Stamford, CT: Appleton & Lange, 1999:1453-5. 1. Hampel H, Bynum GD, Zamora E, El-Serag HB. Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroenterol 2001;96:2206-2210 2. Gerard L, Garey KW, DuPont HL. Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections. Expert Rev Anti Infect Ther 2005;3:201-211
    28. 28. • Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.1,2,3 1. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. May 1 2004;328(7447):1046. 2. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. Jan 2003;38(1):51-8. 3. Miglio F, Valpiani D, Rossellini SR, et al. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin. 1997;13(10):593-601.
    29. 29. RIFAXIMIN • Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic. • Rifaximin acts by inhibiting RNA synthesis in susceptible bacteria by binding to the betasubunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme. • It is also used to treat diarrhea caused by E. coli and in irritable bowel syndrome. • Half life : Approximately 6 hours • Affected microorganisms: Enteric bacteria • In March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy.
    30. 30. Thankyou Sources: Bass N.M, Mullen K.D, Sanyal A, Poordad F, Guy Neff G, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81. • • • • • THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 7, 2001 www.emedicine.com hepatic encephalopathy by David C Wolf, MD, FACP, FACG, AGAF, Medical Director of Liver Transplantation ,updated march 9 ,2011 Harrison’s 17 th edition Davidson’s Principle & practice of Internal Medicine 21 st ed The Modern Management of Hepatic Encephalopathy by J. S. Bajaj Posted: 04/15/2010; Alimentary Pharmacology & Therapeutics. 2010;31(5):537-547. © 2010 Blackwell Publishing
    31. 31. PATHOGENESIS • Accumulation of neurotoxins in brain • Impaired Astrocytes function . [1 ] • Synergistic neurotoxins • Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis 1. Brusilow SW. Hyperammonemic encephalopathy. Medicine (Baltimore). May 2002;81(3):240-9
    32. 32. NEUROTOXINS: AMMONIA HYPOTHESIS Production • Ammonia is released from several tissues (kidney, muscle), but its highest levels can be found in the portal vein. • Portal ammonia is derived from both the urease activity of colonic bacteria and the deamination of glutamine in the small bowel. Degradation: -Liver: (synthesis of urea, glutamine) -Skeletal muscle: alternative target for NH3 detoxification Glutamine glutamate + Ammonia
    33. 33. AMMONIA HYPOTHESIS …CONTINUE • In acute and chronic liver disease, increased arterial levels of ammonia are commonly seen. • In FHF, elevated arterial levels (>200 mg/dl) have been associated with an increased risk of cerebral herniation .1 • The blood-brain barrier permeability to ammonia is increased in patients with HE .2 1. Clemmesen JO, Larsen FS, Kondrup J, et al. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999;29:648 –53. 2. Lockwood AH, Yap EW, Wong WH. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab 1991;11:337–41.
    34. 34. AMMONIA HYPOTHESIS …CONTINUE • Furthermore, the alterations in neurotransmission induced by ammonia also occur after the metabolism of this toxin into astrocytes.1,resulting in a series of neurochemical events caused by the functioning alteration of this cell .2 • Additional support for the ammonia hypothesis comes from the clinical observation that treatments that decrease blood ammonia levels can improve hepatic encephalopathy symptoms.3 1. Norenberg MD. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996;16:245–53. 2. Haussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: A clinical manifestation of astrocyte swelling and low grade cerebral edema? J Hepatol 2000;32:1035– 8. 3. Stahl J. Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance. Ann Intern Med. Jan 1963;58:1-24
    35. 35. • Glutamine is neuronally inactive, it modifies astrocyte signaling and action of glutamate. • In hepatic encephalopathy: 1- cerebral glutamine are increased 2- cerebral glutamate decreased • Increased glutamine in astrocytes → osmotic stress → cellular swelling and cellular change, termed Alzheimer type 2 astrocytosis
    36. 36. Sources and potential role of ammonia Intestinal protein /bacteria Reduced hepatic removal Reduced muscle mass NH3 Alter BBB Astrocyte damage glutamine Direct effects Excitatory pathways
    37. 37. ADDITIVE MECHANISMS • Benzodiazepinelike substances [1] have been postulated to arise from a specific bacterial population in the colon .[2] • Other products of colonic bacterial metabolism [3], such as neurotoxic short- and medium-chain fatty acids, phenols, and mercaptans, are also produced. • Manganese may deposit in basal ganglia and induce extrapyramidal symptomatology .[4] 1. Mullen KD, Jones EA. Natural benzodiazepines and hepatic encephalopathy. Semin Liver Dis 1996;16:255– 64. 2. Yurdaydin C, Walsh TJ, Engler HD, et al. Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res 1995;679:42– 8. 3. Zieve L, Doizaki WM, Zieve J. Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma. J Lab Clin Med 1974;83:16 –28. 4. Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology 1999;117:640–4.
    38. 38. AMINO ACID IMBALANCE HYPOTHESIS • Abnormal balance between Branched chain Amino Acids (BCAA) and Aromatic Amino Acids (AAA) . • In Cirrhosis : ↓ BCAA and ↑ AAA BCAA = Isoleucine ,Leucine ,valine => metabolised in muscle & brain AAA =Phenylalanine,Tyrosine, Tryptophan => metabolised in liver Two consequences : 1. ↑ protein catabolism =lean mass 2. ↑ Synthesis of false NT and ↓ Synthesis of normal NT Normally Leucine (BCAA) promote protein synthesis & inhibit protein catabolism
    39. 39. SUMMARY HE may represent the synergistic effects of a number of toxins on an unusually susceptible nervous system
    40. 40. CLINICAL SUBTYPES
    41. 41. CLASSIFICATION[1] Types Description A Encephalopathy associated with acute liver failure B Encephalopathy with porto-systemic bypass and no intrinsic hepatocellular disease C Encephalopathy associated with cirrhosis or portal hypertension ⁄ porto-systemic shunts Subcategory Episodic Persistent Minimal 1. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. Mar 2002;35(3):716-21
    42. 42. CLINICAL DETECTION RELATIONSHIP OF HE SUBTYPES
    43. 43. CLINICAL MANIFESTATIONS • Patients with hepatic encephalopathy can presents with a variety of clinical features ranging from subclinical or minimal confusion to life-threatining coma with cerebral edema (often in fulminant hepatic faliure)
    44. 44. WEST-HAVEN CRITERIA FOR HE:1 Stage Consciousness Intellect and behaviour Neurological findings 0 Normal Normal Normal examination; if impaired psychomotor testing, then MHE 1 Mild lack of awareness Shortened attention span; impaired addition or subtraction Mild asterixis or tremor 2 lethargic Disoriented; inappropriate behaviour Obvious asterixis; slurred speech 3 Somnolent but arousable Gross disorientation; bizarre behaviour Muscular rigidity and clonus; Hyper-reflexia 4 Coma Coma Decerebrate posturing 1. Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. Jul 2001;96(7):1968-76
    45. 45. CLINICAL FEATURES:(IN SETTING OF ACUTE LIVER FAILURE ) Abrupt onset of Symptoms: fever, vomiting ,headache On Examination; • Icteric • Marked Fetor hepaticus • Hepatomegaly / splenomegaly: uncommon • F/o ↑ ICP :Systolic HTN, bradycardia, Hyperventilation, seizures, Pupillary dilatation and CN VI palsy(mass effect ). • Neuropsychiatric picture is more aggressive
    46. 46. CLINICAL FEATURES:(IN SETTING OF CHRONIC LIVER DISEASE ) • Insidious onset • Long Hx of liver disease . • Stigmata of Chronic liver disease • Features of Portal hypertension
    47. 47. INVESTIGATIONS AND MANAGEMENT
    48. 48. INVESTIGATIONS • Clinical Tests (Psychometric tests) and assess level of conciousness with Glascow Coma Scale • • Liver Function tests with PT/INR Blood Ammonia level : ↑ (n:19-60 ugm/dl) Raised but does not correlate with degree of encephalopathy.
    49. 49. INVESTIGATIONS TO IDENTIFY THE PRECIPITATING FACTORS • • • • • • • • FOBT Ascites fluid examination and Culture CXR CBC Urine R/M Examination Serum Urea, Creatinine ,Electrolytes ,ABG Consider : Urine screen for benzodiazepine, narcotics Blood Glucose
    50. 50. • CT Brain /MRI • EEG • Lumbar Puncture (for patients with unexplained fever and signs of meningeal irritation)
    51. 51. TREATING HYPERAMMONIA 1. Treatments to Decrease Intestinal Ammonia Production • Diets • Cathartics • Antibiotics 2. Treatments to Increase Ammonia Clearance • L-ornithine L-aspartate (LOLA) • Zinc • Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate • L-carnitine
    52. 52. DIET • Most patients with HE tolerate =60-80 g of protein /d. • Furthermore, one study administered protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms.[1 ] • Another study randomized patients with severe episodic encephalopathy to low-protein diet Vs high-protein diet, administered via NG tube.[2 ]All patients received the same regimen of neomycin per NG tube. Mental function improved at the same rate in both treatment groups. 1. Guy S, Tanzer-Torres G, Palese M, et al. Does nasoenteral nutritional support reduce mortality after liver transplant?. Hepatology. 1995;22:144A. 2. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. Jul 2004;41(1):38-43.
    53. 53. CATHARTICS • Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s. • Patients should take sufficient lactulose as to have 2-4 loose stools per day. • Initial dosing = 30 mL orally, daily or twice daily. The dose may be increased as tolerated. • A/E: ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. • High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by NG tube to patients hospitalized with severe HE. • Administered as enema to Comatose patients. The recommended dosing is 300 mL lactulose plus 700 mL water, q4hrly
    54. 54. EFFECTS OF LACTULOSE
    55. 55. ANTIBIOTICS 1. Neomycin, Metronidazole ,Paramomycin, Quinolones • Initial neomycin dosing is 250 mg orally 2-4 times a day. 1 • A/E: ototoxicity and nephrotoxicity 1. David C Wolf,Hepatic Encephalopathy source: www.emedcine.com Updated: Mar 9, 2011
    56. 56. 2. RIFAXIMIN • Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms.1,2,3 • Similarly, rifaximin was as effective as neomycin and paramomycin. Rifaximin was better tolerated than both the cathartics and the other antibiotics. 1. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. May 1 2004;328(7447):1046. 2. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. Jan 2003;38(1):51-8. 3. Miglio F, Valpiani D, Rossellini SR, et al. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin. 1997;13(10):593-601. In March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al.[4 ]
    57. 57. Thankyou Sources: Bass N.M, Mullen K.D, Sanyal A, Poordad F, Guy Neff G, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81. • • • • • THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 7, 2001 www.emedicine.com hepatic encephalopathy by David C Wolf, MD, FACP, FACG, AGAF, Medical Director of Liver Transplantation ,updated march 9 ,2011 Harrison’s 17 th edition Davidson’s Principle & practice of Internal Medicine 21 st ed The Modern Management of Hepatic Encephalopathy by J. S. Bajaj Posted: 04/15/2010; Alimentary Pharmacology & Therapeutics. 2010;31(5):537-547. © 2010 Blackwell Publishing
    58. 58. TREATING HYPERAMMONIA 1. Treatments to Decrease Intestinal Ammonia Production • Diets • Cathartics • Antibiotics 2. Treatments to Increase Ammonia Clearance • L-ornithine L-aspartate (LOLA) • Zinc • Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate • L-carnitine
    59. 59. L-ORNITHINE L-ASPARTATE (LOLA) • L-ornithine stimulates the urea cycle, with resulting consumption of ammonia and production of urea which is mostly excreted by kidneys. • LOLA was found to be effective in treating hepatic encephalopathy in a number of European trials.[1,2 ] 1. Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology. Jun 1997;25(6):1351-60. 2 .Delcker AM, Jalan R, Comes G. L-ornithine-l-aspartate vs. placebo in the treatment of hepatic encephalopathy: a meta-analysis of randomised placebo-controlled trials using individual data. Hepatology. 2000;32:310A
    60. 60. ZINC SULFATE AND ZINC ACETATE • Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials. • Hepatic encephalopathy improved in 2 studies[1 ]; there was no improvement in mental function in 2 other studies.[2 ] 1. Marchesini G, Fabbri A, Bianchi G, et al. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology. May 1996;23(5):1084-92. 2. Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long term treatment. Eur J Med. Aug-Sep 1993;2(7):414-6
    61. 61. Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate • Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy.[1] L-carnitine • L-carnitine improved hepatic encephalopathy symptoms in several small studies of patients with cirrhosis.[2 ] 1. Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology. Jul 1992;16(1):138-44. 2. Malaguarnera M, Pistone G, Elvira R, et al. Effects of L-carnitine in patients with hepatic encephalopathy. World J Gastroenterol. Dec 7 2005;11(45):7197-202
    62. 62. Treatments to Improve Sleep Disturbance • A trial compared the histamine H1 blocker hydroxyzine to placebo in patients with cirrhosis and minimal hepatic encephalopathy.[1] • Sleep efficiency and the patients' subjective quality of sleep improved in patients receiving hydroxyzine (25 mg) at bedtime. • However, there was no accompanying improvement in cognition, as measured by neurophysiologic tests. • 1. Spahr L, Coeytaux A, Giostra E, et al. Histamine H1 blocker hydroxyzine improves sleep in patients with cirrhosis and minimal hepatic encephalopathy: a randomized controlled pilot trial. Am J Gastroenterol. Apr 2007;102(4):744-53.
    63. 63. SOME COMMON REASONS FOR HE RESISTANT TO TREATMENT • Excess purgation leading to dehydration / free water loss • Failure to identify and treat sepsis • Ileus, especially in association with azotemia (may need dialysis) • Undiagnosed concomitant CNS problem • Profound zinc deficiency
    64. 64. IN THE END.. • In the Mx of persistent HE due to surgically created shunting , radiological interventions, such as ballooning, is required to occlude the TIPS shunt.[1] Other causes of persistence may be an undiscovered source of sepsis, i.e. abscesses, or an inability to tolerate medications prescribed for OHE. Liver Transplant • The ultimate management goal for OHE is the replacement of the diseased liver. Stewart et al. showed that OHE worsens prognosis over and above MELD score and results in worsened survival.[2] Therefore, liver transplant work-up is crucial for the management of OHE after correction of the acute insult and prevention of recurrences. 1. Fanelli F, Salvatori FM, Rabuffi P, et al. Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft. AJR Am J Roentgenol 2009; 193: 1696–702. 2. Stewart CA, Malinchoc M, Kim WR, Kamath PS. Hepatic encephalopathy as a predictor of survival in patients with endstage liver disease. Liver Transpl 2007; 13: 1366–71.
    65. 65. SUMMARY 1. HE is a neuropsychiatric syndrome caused by Severe liver disesase. 2. Features include change in intellect,personality,emotions, consciousness with or without neurological signs. 3. As encephalopathy progresses ,confusion is followed by coma. 4. In confusional state, rule out Dellerium tremens, Wernickes encephalopathy. And in Coma, rule out Subdural hematoma which can be due to fall injury in alcoholics. 5. Grade the HE as it is useful in assessing response to therapy. 6. Look for precipitating factors and manage it. 7. Carry out investigations to ruleout other causes of encephalopathy. 8. Treat the Hyperammonia as mentioned earlier.
    66. 66. PROTEIN CONTENT • One skinless chicken breast (130g): 41g protein. • One beef burger or pork sausage: 8g protein. • Half a can of tuna: 19g protein. • One portion of cheese (50g): 12g protein. • One medium egg: 6g protein. • 150ml glass of milk: 5g protein. • One tablespoon of boiled red lentils (40g): 3g protein. • One portion of tofu (125g): 15g protein. • One slice medium wholemeal bread: 4g protein. • One slice medium white bread: 3g protein.
    67. 67. Flumazenil • Mechanism of action: Endogenous and exogenous benzodiazepine • receptor antagonist Dopaminergic agents – L-Dopa, bromocriptine • Limited role in HE
    68. 68. • Most therapies for HE are directed at reducing the nitrogenous load in the gut, an approach that is consistent with the hypothesis that this disorder results from the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and PSS. 1 • The current standard of care for patients with HE, treatment with nonabsorbable disaccharides lactitol or lactulose, decreases the absorption of ammonia through cathartic effects and by altering colonic pH. 2 • In an study, Sharma et al. reported that lactulose, as compared with placebo, was effective in the prevention of overt HE. 3 1. Munoz SJ. Hepatic encephalopathy. Med Clin North Am 2008;92:795-812. 2. Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 2001;96:1968-1976. 3. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open label randomized controlled trial of lactulose versus placebo.Gastroenterology 2009;137:885-891.
    69. 69. • In general, the oral antibiotics neomycin, paromomycin, vancomycin, and metronidazole have been effectively used, with or without lactulose, to reduce ammonia-producing enteric bacteria in patients with hepatic encephalopathy.1 • However, some oral antibiotics are not recommended for long-term use because of nephrotoxicity, ototoxicity, and peripheral neuropathy2 and are specifically contraindicated in patients with liver disease. 3 1. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004;328:1046-1046. 2. Durante-Mangoni E, Grammatikos A, Utili R, Falagas ME. Do we still need the aminoglycosides? Int J Antimicrob Agents 2009;33:201-205. 3. Leitman PS. Liver disease, aminoglycoside antibiotics and renal dysfunction. Hepatology1988;8:966-968
    70. 70. RIFAXIMIN • Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum activity against gm+ & gm- aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance. 1 • In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute HE. 2 1. Debbia EA, Maioli E, Roveta S, Marchese A. Effects of rifaximin on bacterial virulence mechanisms at supra- and subinhibitory concentrations. J Chemother 2008;20:186-194 2. Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J 2005;46:399-407
    71. 71. DISCUSSION

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