Hepatic Encephalopathy Medical Presentation

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HEPATIC ENCEPHALOPATHY
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Content Definition Epidemiology Clinical Features Pathogenesis Common Precipitants of Hepatic Encephalopathy Diagnostic Tests Management Medical Therapy for Hepatic Encephalopathy Case study References
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Hepatic Encephalopathy It’s a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of brain disease. Hepatic encephalopathy is observed in patients with cirrhosis and also described in patients without cirrhosis with either spontaneous or surgically created portosystemic shunts. 3
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A nomenclature has been proposed for categorizing hepatic encephalopathy: Type A: hepatic encephalopathy describes encephalopathy associated with A cute liver failure. Type B: hepatic encephalopathy describes encephalopathy associated with portal-systemic Bypass and no intrinsic hepatocellular disease. Type C: hepatic encephalopathy describes encephalopathy associated with Cirrhosis and portal hypertension or portal-systemic shunts. Type C hepatic encephalopathy is, in turn, subcategorized as episodic, persistent, or minimal. 4
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Epidemiology: The exact incidence of hepatic encephalopathy in the general population is unknown. It affects males and females in equal numbers and can occur in individuals of any age who have acute or chronic liver disease. Approximately 24-53 % of individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present) develop hepatic encephalopathy. Approximately 70 % of individuals with cirrhosis may develop symptoms of hepatic encephalopathy. Because some mild cases of hepatic encephalopathy may go undiagnosed, it is difficult to determine the true frequency in the general population. 5
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West Haven criteria for hepatic encephalopathy: 6
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Pathogenesis A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with cirrhosis. Some investigators contend that hepatic encephalopathy is a disorder of astrocyte function. Astrocytes account for about one third of the cortical volume. They play a key role in: Regulation of the blood-brain barrier. Maintaining electrolyte homeostasis . Providing nutrients and neurotransmitter precursors to neurons. Detoxification of a number of chemicals, including ammonia. 7
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Ammonia hypothesis 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: 1) The decrease in the mass of functioning hepatocytes, resulting in fewer opportunities for ammonia to be detoxified by the above processes. 2) Portosystemic shunting may divert ammonia-containing blood away from the liver to the systemic circulation. Ammonia has multiple neurotoxic effects: 1)Alter the transit of amino acids, water, and electrolytes across astrocytes and neurons. 2)Impair amino acid metabolism and energy utilization in the brain. 8
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GABA Hypothesis GABA is a neuroinhibitory substance produced in the gastrointestinal tract. Of all brain nerve endings, 24-45% may be GABAergic. For over 20 years, it was postulated that hepatic encephalopathy was the result of increased GABAergic tone in the brain. However, experimental work is changing perceptions regarding the activity of the GABA receptor complex in cirrhosis. Neurotoxins, like ammonia and manganese, increase the production of the peripheral-type benzodiazepine receptor (PTBR) in astrocytes. PTBR, in turn, stimulates the conversion of cholesterol to pregnenolone to neurosteroids. Neurosteroids are then released from the astrocytes. They are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission. 9
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10 Pathogenesis
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Common Precipitants of Hepatic Encephalopathy 11
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Diagnosis Hepatic encephalopathy is a diagnosis of exclusion of other causes of altered mental status with exploring precipitating factors for hepatic encephalopathy. Diagnostic tests include: Laboratory Testing . Imaging. Neuropsychometric Tests. 12
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Laboratory Testing arterial and venous ammonia levels: There are many non-hepatic causes of hyperammonemia, such as gastrointestinal bleeding, renal failure, hypovolemia, extensive muscle use, urea cycle disorder, parenteral nutrition, urosepsis, and with use of certain drugs (e.g. valproic acid). Although patients with hepatic encephalopathy have elevated serum ammonia levels, the severity of hepatic encephalopathy does not correlate with serum ammonia levels beyond a certain point. Moreover, serial ammonia levels are not routinely utilized to follow patients, as the clinical presentation and clinical response to treatment is most important. Other laboratory tests : to assess for precipitating causes of hepatic encephalopathy, such as tests of liver and renal function, electrolytes, glucose, cultures, and drug screening. 13
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Imaging Brain computed tomographic (CT) imaging : low sensitivity for detecting early cerebral edema but may help to exclude other causes of altered mentation, such as an intracerebral hemorrhage. Brain magnetic resonance imaging (MRI): can be used to diagnose cerebral edema and other brain abnormalities associated with hepatic encephalopathy. Other types of imaging can also be used to assess for hepatic encephalopathy precipitating factors, such as infection (e.g. chest radiograph) or bowel obstruction or ileus (e.g. abdominal imaging). 14
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Neuropsychometric Tests neuropsychometric tests include both ‘paper and pencil’ tests and computerized tests that can be used to identify impairments in visuo-spatial functioning, attention, processing speed and response inhibition. These tests are helpful in identifying minimal hepatic encephalopathy. The Psychometric Hepatic Encephalopathy Score (PHES) is the current ‘gold standard’ pencil-and-paper test battery for the psychometric evaluation of patients with HE. 15
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Neuropsychometric Tests The PHES includes: The line tracing test (LTT) Serial dotting test (SDT) Digit symbol test (DST) number connection test A and B 16
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Management of Hepatic Encephalopathy the management of acute hepatic encephalopathy should focus on : providing supportive care, identifying and treating any precipitating causes, reducing nitrogenous load in the gut, and assessing the need for long term therapy and liver transplant evaluation. Common precipitating factors for HE include: Increased nitrogen load (e.g. gastrointestinal bleed, infection, excess dietary protein). Decreased toxin clearance (e.g. hypovolemia, renal failure, constipation, portosystemic shunt, medication noncompliance, acute on chronic liver failure), Altered neurotransmission (e.g. sedating medication, alcohol, hypoxia, hypoglycemia). 17
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Medical Therapy for Hepatic Encephalopathy Rapid response to first-line medical therapy supports the diagnosis of hepatic encephalopathy. 18
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Non absorbable Disaccharides “lactulose” first-line treatment for hepatic encephalopathy. Lactulose is metabolized by bacteria in the colon to acetic and lactic acid which: reduces colonic pH. decreases survival of urease producing bacteria in the gut. facilitates conversion of ammonia (NH3) to ammonium (NH4+) “↓absorption” The cathartic effect also increases fecal nitrogen waste. 19
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Non absorbable Disaccharides “lactulose” For acute overt hepatic encephalopathy, the usual starting oral dose of lactulose is 10 to 30 g (15 to 45 mL) every 1 to 2 hours until a bowel movement occurs. Then adjust to 10 to 30 g (15 to 45 mL) 2 to 4 times daily, titrated to induce 2 to 3 soft bowel movements daily. For comatose patients, the medication can be administered through a nasogastric tube or rectally as an enema (300 mL in 1 L of water every 6 to 8 hours) until the patient is awake enough to start oral therapy. Side effects can include an excessively sweet taste, abdominal cramping, flatulence, and diarrhea. Severe cases of diarrhea can lead to hypovolemia and electrolyte imbalances. 20
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Antibiotics Rifaximin is a minimally absorbed (less than 0.4%) oral antibiotic with broad spectrum activity against gram-positive and gram-negative aerobic and anaerobic bacteria. Rifaximin (550 mg twice daily) can be used to treat hepatic encephalopathy. rifaximin with lactulose maintained remission from hepatic encephalopathy better than lactulose alone. In clinical practice, lactulose is typically used initially and rifaximin added if needed. 21
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Nutrition Dietary protein restriction is not advised for the management of hepatic encephalopathy since loss of skeletal muscle, which metabolizes ammonia, can lead to worsening hepatic encephalopathy. patients with cirrhosis are recommended to consume a high-protein diet of at least 1.0 g/kg to 1.5 g/kg daily. Non-absorbable vegetable fiber can help promote colonic acidification. Zinc is a cofactor for urea cycle enzymes and is commonly deficient in cirrhotic patients. 22
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CASE STUDY 23
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Subjective: Chief complain: coma History of patient: H.I. 49 years old male suffer from cirrhosis of unknown cause, abdominal pain, fever, edema, ascites (mild), urinary urgency and painful urination, change in mental status and cough. Past medical history: DM. Pelvic abdominal ultrasound at 2015 reveal: spleenomegaly, chronic cystitis,average size cirrhotic liver and marked ascites. Viral hepatitis –ve , liver biopsy –ve. No bilhariziasis. 24
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Objective “Day 1” Physical examination Mild ascites. Mild LL edema. Temp. 37.9 °c. BP 80/40. Pulse 83. No diarrhea. No melena. No constipation. Chest crepitation. Lab results 25
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Objective “Day 2” Physical examination Temp :37 °C Pulse : 72 b/min. BP : 130/80 mmHg. Lab results 26
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Objective “Day 2” Cont. Lab results: 27
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Objective “Day 3” Physical examination No ascites. Mild LL edema. No melena, No constipation . no diarrhea. No flapping tremors. Vital signs: BP: 120/80. Pulse: 76 b/min Temp.:37 °C Lab results Radiology investigation: Chest and heart PA view: -normal cardiac size -no mediastirnal mass or adenopathy -clear lung -clear heart 28
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Objective “Day 4” Physical examination Temp: 37 °C. BP: 140/70mmHg. Pulse: 86 b/min. Lab results 29
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Assesment Hepatic Encephalopathy grade four (emergency case): Precipitating factors: Clinical symptoms: Coma 30
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Assesment Cirrhosis class c: According to child-Pugh score for cirrhosis mortality : 15 points Child Class C Life Expectancy : 1-3 years Abdominal surgery peri-operative mortality: 82% Other investigations Pelvic abdominal ultrasound : Average sized cirrhotic liver AST>ALT 31
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Assesment 3) Moderate to marked ascites Pelvic abdominal ultrasound 4) Spontaneous bacterial pretonitis Indication for diagnostic paracentisis: 32
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Assesment Diagnostic paracentisis(10 ml of ascetic fluid): Distinguishing SBP from secondary bacterial pretonitis: 33
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Assesment Hypersplenism: Hepatocellular jaundice kidney dysfunction and chronic cystitis and electrolytes imbalance 34
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Assesment Normocytic normochromic anemia and thrombocytopenia and polymorph nuclear leukocytosis 35
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plan
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1- pharmaceutical care plan : Treatment of HE according to AASLD/EASL guidelines (2014) Actual treatment plan of the patient Comments and interventions
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Description of patient’s hepatic encephalopathy : According to AASLD/ EASL Guideline for H.E Type C Grade 4 ‘’overt HE” Episodic by : Infections “ SBP” Electrolyte disturbance hypokalemia (serum K = 3) hyponatremia ( serum Na =127 ) 1: the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesAASLD/EASL, Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline , Journal of Hepatology 2014 vol. xxx j xxx–xxx Precipitated
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2:Leise et al., Management of Hepatic Encephalopathy in the Hospital , Mayo Clin Proc. Author manuscript; available in PMC 2014 August 11. NIH-PA
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2:Leise et al., Management of Hepatic Encephalopathy in the Hospital , Mayo Clin Proc. Author manuscript; available in PMC 2014 August 11. NIH-PA Portal vein Urea cycle Non absorbable disaccharides ..lactulose or lactitol Antibiotics as Rifaximin … most effective , mainly used Neomycin , metronidazole …. Not widely used First approach : Treating precipitating factors as infection , GIT bleeding Diet …plant based protein diet , no protein restriction , BCAA Urea cycle alternative substrate as L-Ornithine L-Aspartate LOLA
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Patient’s treatment : 1- treatment of precipitating factors According to EASL guideline : Cefotaxime, a third-generation cephalosporin, is the first line antibiotic for empiric treatment of patients with SBP because it covers most causative organisms its high ascetic fluid concentrations during therapy Effective dose : 4 gm. / day Correct choice and dose Should be administered with IV albumin **the European Association for the Study of the Liver, EASL clinical practice guidelines on the management ofascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis,Journal of Hepatology 2010 vol. 53 j 397–417 Correct choice and dose N- acetyl cysteine can be started along with acetaminophen ta avoid any risk Acetaminophen is the best choice : Is safe at reduced dose for short term . This assumption is supported by a double-blind, 2-period crossover study of 20 patients with chronic stable liver disease (8 with cirrhosis), who tolerated acetaminophen at a dosage of 4 g/d for 13 days without adverse effects. In patients with cirrhosis, NSAIDS should be avoided to avert renal failure
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**Liverpool Hospital, potassium chloride drug guideline in ICU, LH_ICU2016_Pharmacology_Potassium_Chloride, https://www.aci.health.nsw.gov.au/__data/assets/pdf_file/0017/306404/liverpoolPotassium_Chloride.pdf19/11/2017 Patient’s treatment : 1- treatment of precipitating factors Patient’s K = 3 Meq /L Sub dose …. Not effective for correcting hypokalemia Correct use High dose Ringer acetate solution …. Limited source for K replacement 500 ml ringer acetate = 4-5 Meq/L potassium ion 1 ampoule of KCL (5ml) = 10 Mmol / 5 ml = 10 Meq/ 5 ml Dose 1 : 1 ampoule (10 Mmole/5 ml ) in 100 ml ringer solution Should be administered slowly with maximum administration rate = 10 Mmole/ 1hr = 1.5 ml/min Dose 2 : 2 ampoule ( 20 Mmole / 10 ml ) in 100 m ringer solution Maximum concentration for peripheral infusion is 10 mmol/100mL
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Patient’s treatment : 2- Treatment of grade IV hepatic encephalopathy 4:Ganesh Pantham etal, Practical Issues in the Management of Overt Hepatic Encephalopathy, Gastroenterology & Hepatology Volume 13, Issue 11 November 2017 Over prescribed ..stopped Sub dose Correct dose : 300 ml laxolac in 700 ml warm water / 1-2 hrs. Enema should be retained for 30 to 60 Minutes Stopped in case of diarrhea or hypotension Rifaximin is the most widely used antibiotic , best add on therapy for HE . Rifaximin along with lactulose should be administered to all unconscious patients with grade 3 or 4 HE Dose : 550 mg orally twice daily = 1100 mg / day Prescribed dose : 400 mg /8hr = 1200 mg / day Appropriate choice and dose
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Patient’s treatment : 2- Treatment of grade IV hepatic encephalopathy 4:Ganesh Pantham etal, Practical Issues in the Management of Overt Hepatic Encephalopathy, Gastroenterology & Hepatology Volume 13, Issue 11 November 2017 Over prescribed ..stopped Sub dose Appropriate choice and dose Over prescribing used if no response to standard therapy IV Over prescribing used if no response to standard therapy Over prescribing Used if no response to standard therapy as oral formulation IV
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Patient’s treatment : 2- Treatment of grade IV hepatic encephalopathy Over prescribed ..stopped Sub dose Appropriate choice and dose Over prescribing used if no response to standard therapy Over prescribing used if no response to standard therapy Over prescribing Used if no response to standard therapy as oral formulation
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Patient’s treatment : 2- Treatment of grade IV hepatic encephalopathy Enema / 8 hr Appropriate choice and dose Oral LOLA ineffective for OHE should be stopped Shift patient to oral BCAA Hepa-merz oral instead of IVI Increase dose and continued even after discharge as prophylactic treatment Should be stopped As patient regained his consciousness thus : Enema should be stopped . Use oral lactulose with dose : 25 ml / 12 hr. until at least 2-3 soft bowel movement / day continued after discharge as prophylactic therapy
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Patient’s treatment : 3- supportive treatment of liver disease ( cryptogenic cirrhosis score c) INR = 2.6 on admission INR = 2.1 on discharge correct route parenteral better than oral Correct choice to correct elevated INR but no evidence to support its use Vit.K IVI [ 1 amp. 10 mg in NS once daily] …more effective Nurse recommendation Vitamin . K should be protect from light all the time Vitamin K is involved in post-translational modification of coagulation factors within the liver Low levels of vitamin K are often found in patients with liver disease who are malnourished resulting in decreased production of pro-coagulation factors II, VII, IX, and X and anticoagulation factors, protein C and protein S Even with the high prevalence of vitamin K deficiency in patients with liver disease, evidence about the overall benefit of vitamin K repletion on the coagulation profile of these patients is scant Fresh Frozen Plasma : contains all coagulation factors that are essential to clot formation (that is, factors II, V, VII, VIII, IX, X and XI) Repletion of coagulation factors with FFP bypasses the need for vitamin K carboxylation in the liver for coagulation factor formation As elevated INR is commonly found in patients with liver disease, an inordinate amount of FFP is often used in patients with cirrhosis for prophylaxis without evidence of utility. **Shah, N. L., Northup, P. G. & Caldwell, S. H. A clinical survey of bleeding, thrombosis and blood product use in decompensated cirrhosis patients. Ann. Hepatol. 11, 686–690 (2012).0 Evidence has shown that the INR is not an accurate marker of bleeding risk in patients with cirrhosis and has wide inter-laboratory variation Studies have shown the importance of using global coagulation measures on whole-blood samples rather than plasma alone, which is used in INR calculations **Trotter, J. F. et al. Changes in international normalized ratio (INR) and model for endstage liver disease (MELD) based on selection of clinical laboratory. Am. J. Transplant. 7, 1624–1628 (2007). **Lisman, T. et al. Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver Int. 28, 1344–1351 (2008). Thromboelastography **Neeral L. Shah etal, Procoagulant therapeutics in liver disease: a critique and clinical rationale, Nature Reviews Gastroenterology and Hepatology 11, 675–682 (2014) doi:10.1038/nrgastro.2014.121,
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**Manonmani Alvin Jose, Anjana Abraham etal, Effect of silymarin in diabetes mellitus patients with liver diseases,J Pharmacol Pharmacother. 2011 Oct-Dec; 2(4): 287–289. **Claus Hellerbrand, Jörn M. Schattenberg etal, The potential of silymarin for the treatment of hepatic disorders, Clinical PhytoscienceInternational Journal of Phytomedicine and Phytotherapy20162:7 Patient’s treatment : 3- supportive treatment of liver disease ( cryptogenic cirrhosis score c) Correct choice, suitable dose Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients Previous reports of both pre-clinical and clinical studies revealed that silymarin has got some anti-diabetic potential Protect … HCC Lower RBG Increase albumin Lower ALT,AST Lower bilirubin
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Patient’s treatment : 3- supportive treatment of liver disease ( cryptogenic cirrhosis score c) Correct choice, suitable dose Good choice but ineffective dose For day 1,2 then shift to 1350 mg/day Correct choice, effective dose Ursodeoxycholic acid (UDCA) : is a non-toxic, hydrophilic bile acid The major human bile acids are hydrophobic, and when in excess contribute to direct biliary toxicity through their detergent effects on lipid membranes UDCA in doses of 13–15 mg/kg/day increase the concentration to 40–60%, making UDCA the predominant bile acid Increasing bile pool hydrophilicity leading to improve cholestasis and minimize toxicity Although UDCA is used for non-cholestatic liver diseases, where liver biochemistry is frequently abnormal, the practice guidelines do not endorse its use. Recommended adult dose : 13-15mg/kg/day [ 850-100mg/day ] administered in two to four divided doses with food Patient’s lab data on admission Patient’s lab data on discharge **Jillian Reardon etal, Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review,J Clin Transl Hepatol. 2016 Sep 28; 4(3): 192–205.
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2- preventive care plan after discharge : Patient/ his family counseling [ patient education ] Secondary prophylaxis to prevent recurrence
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the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesAASLD/EASL, Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline ,Journal of Hepatology 2014 vol. xxx j xxx–xxx 1- Patient and family counseling [ patient education ] Education of patient and relatives should include: Ibw = 66kg Energy intake = 2310 - 2640 kcal/day Ibw = 66kg Protein intake = 79.2 – 99 g/day Plant based protein diet
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2- Secondary prophylaxis of patient’s OHE Patients who recover from grade 3 or 4 overt HE should be kept on maintenance treatment with lactulose and rifaximin Patient’s precipitating factors should have been resolved and kept under well-control before patients discharge [ infection , liver function, electrolyte disturbance , uncontrolled DM,…] FDA-approved for secondary prevention of overt HE the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesAASLD/EASL, Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline ,Journal of Hepatology 2014 vol. xxx j xxx–xxx 4:Ganesh Pantham etal, Practical Issues in the Management of Overt Hepatic Encephalopathy, Gastroenterology & Hepatology Volume 13, Issue 11 November 2017
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Discontinuation of the prophylactic therapy : There is uniform policy to continue treatment indefinitely after it has successfully reversed a bout of OHE. The concept may be that once the thresholds for OHE is reached, then patients are at high risk for recurrent episodes that is worsen as liver function deteriorates According to guideline’s recommendations, prophylactic therapy can be discontinued under certain circumstances the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesAASLD/EASL, Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline ,Journal of Hepatology 2014 vol. xxx j xxx–xxx the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesAASLD/EASL, Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline ,Journal of Hepatology 2014 vol. xxx j xxx–xxx
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Thank you
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References: Butterworth RF. Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities. J Steroid Biochem Mol Biol. 2016 Jun. 160:94-7. [Medline]. Luo M, Guo JY, Cao WK. Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis. World J Gastroenterol. 2015 Nov 7. 21(41):11815-24. [Medline]. Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: diagnosis and management. Clin Gastroenterol Hepatol. 2015 Nov. 13(12):2048-61. [Medline]. Shawcross DL, Dunk AA, Jalan R, et al. How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist. Eur J Gastroenterol Hepatol. 2016 Feb. 28(2):146-52. [Medline]. Riggio O, Efrati C, Catalano C, et al. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology. 2005 Nov. 42(5):1158-65. [Medline]. 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. 2002 Mar. 35(3):716-21. [Medline]. Bismuth M, Funakoshi N, Cadranel JF, Blanc P. Hepatic encephalopathy: From pathophysiology to therapeutic management. Eur J Gastroenterol Hepatol. 2011;23:8–22. [PubMed] Butterworth RF. Editorial: Rifaximin and minimal hepatic encephalopathy. Am J Gastroenterol. 2011;106:317–8. [PubMed Blei AT, Cordoba J, Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. Am J Gastroenterol. 2001 Jul. 96(7):1968-76. [Medline]. Kappus MR, Bajaj JS. Covert hepatic encephalopathy: not as minimal as you might think. Clin Gastroenterol Hepatol. 2012 Nov. 10(11):1208-19. [Medline]. 58
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References: Munoz SJ. Driving with minimal hepatic encephalopathy: real world consequences?. Am J Gastroenterol. 2007 Sep. 102(9):1910-1. [Medline]. Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Navigation skill impairment: Another dimension of the driving difficulties in minimal hepatic encephalopathy. Hepatology. 2008 Feb. 47(2):596-604. [Medline]. Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology. 2009 Oct. 50(4):1175-83. [Medline]. [Full Text]. Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design of clinical trials in hepatic encephalopathy--an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. 2011 Apr. 33(7):739-47. [Medline]. Brusilow SW. Hyperammonemic encephalopathy. Medicine (Baltimore). 2002 May. 81(3):240-9. [Medline]. Chatauret N, Butterworth RF. Effects of liver failure on inter-organ trafficking of ammonia: implications for the treatment of hepatic encephalopathy. J Gastroenterol Hepatol. 2004. 19:S219-223. Stahl J. Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance. Ann Intern Med. 1963 Jan. 58:1-24. [Medline]. Schafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet. 1982 Jan 2. 1(8262):18-20. [Medline]. Butterworth RF. Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies. J Hepatol. 2003 Aug. 39(2):278-85. [Medline] Ahboucha S, Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at GABA from the molecular standpoint. Metab Brain Dis. 2004 Dec. 19(3-4):331-43. [Medline]. Butterworth RF. The astrocytic ("peripheral-type") benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy. Neurochem Int. 2000 Apr. 36(4-5):411-6. [Medline]. 59
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References: 60 Ahboucha S, Pomier-Layrargues G, Mamer O, et al. Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma. Neurochem Int. 2006 Sep. 49(4):372-8. [Medline]. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107:1043-50 Bajaj BS. Review article: the modern management of hepatic encephalopathy. Aliment Pharmacol Ther. 2010;31:537-47. [PubMed Abstract] – Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. 2001;96:1968-76. [PubMed Abstract] – Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977;72:573-83. [PubMed Abstract] – Hassanein T, Blei AT, Perry W, et al. Performance of the hepatic encephalopathy scoring algorithm in a clinical trial of patients with cirrhosis and severe hepatic encephalopathy. Am J Gastroenterol. 2009;104:1392-400. [PubMed Abstract] – Poordad FF. Review articles: the burden of hepatic encephalopathy. Aliment Pharmacol Ther. 2007; 25 Suppl 1:3-9. [PubMed Abstract] – Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2010;7:515-25. [PubMed Abstract] – Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108:1458 [PubMed Abstract] -
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References: the European Association for the Study of the Liver and the American Association for the Study of Liver DiseasesAASLD/EASL, Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline , Journal of Hepatology 2014 vol. xxx j xxx–xxx 2:Leise et al., Management of Hepatic Encephalopathy in the Hospital , Mayo Clin Proc. Author manuscript; available in PMC 2014 August 11. NIH-PA 3: the European Association for the Study of the Liver, EASL clinical practice guidelines on the management ofascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis,Journal of Hepatology 2010 vol. 53 j 397–417 4:Ganesh Pantham etal, Practical Issues in the Management of Overt Hepatic Encephalopathy, Gastroenterology & Hepatology Volume 13, Issue 11 November 2017 5: Liverpool Hospital, potassium chloride drug guideline in ICU, LH_ICU2016_Pharmacology_Potassium_Chloride, https://www.aci.health.nsw.gov.au/__data/assets/pdf_file/0017/306404/liverpoolPotassium_Chloride.pdf19/11/2017 6:Neeral L. Shah etal, Procoagulant therapeutics in liver disease: a critique and clinical rationale, Nature Reviews Gastroenterology and Hepatology 11, 675–682 (2014) doi:10.1038/nrgastro.2014.121, 7:Manonmani Alvin Jose, Anjana Abraham etal, Effect of silymarin in diabetes mellitus patients with liver diseases,J Pharmacol Pharmacother. 2011 Oct-Dec; 2(4): 287–289. 8:Claus Hellerbrand, Jörn M. Schattenberg etal, The potential of silymarin for the treatment of hepatic disorders, Clinical PhytoscienceInternational Journal of Phytomedicine and Phytotherapy20162:7. 61