Secondary Prophylaxis of Hepatic Encephalopathy: An Open-Label Randomized Controlled Trial of Lactulose Versus Placebo

Sharma, Barjesh Chander; Sharma, Praveen; Agrawal, Amit; Sarin, Shiv Kumar

doi:10.1053/j.gastro.2009.05.056

Cited by 279 publications

(203 citation statements)

References 45 publications

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“…So it is the addition of rifaximin to a standard lactulose regimen that adds advantage in terms of decreasing risk of both breakthrough HE episodes as well as hospitalizations when compared with lactulose alone. 47 Recently our group also showed that lactulose and probiotics are equally effective for secondary prophylaxis of HE in patients with cirrhosis and probiotics could be an alternative to patients who are intolerant to lactulose 50 (Table 3).…”

Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

“…47 The emergence of HE after transjugular intrahepatic portosystemic shunt (TIPS) is of major concern for patients undergoing this procedure. Riggio and colleagues 48 randomized seventy-five consecutive patients to receive lactitol 60 mL/day, rifaximin 1200 mg/day or no treatment.…”

Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

“…47,49 Sharma et al 47 showed in 125 cirrhotic patients who had recovered from at least one previous episode of HE that significantly more patients in the placebo group (30 of 64 patients [46.8%]) than in the lactulose group (12 of 61 patients [19.6%]) developed HE (P = 0.001). Bass and colleagues 49 enrolled 299 cirrhotic patients with a history of at least two episodes of overt HE to receive either rifaximin (550 mg twice daily; n = 140) or placebo (n = 159) for a period of 6 months.…”

Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

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Management of Overt Hepatic Encephalopathy

Sharma

2015

Journal of Clinical and Experimental Hepatology

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Hepatic encephalopathy (HE) is an important complication of cirrhosis with significant morbidity and mortality. Management of HE primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as non-absorbable disaccharides, antimicrobial agents like rifaximin and L-ornithine L-aspartate. The non-absorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and in primary and secondary prophylaxis of HE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Rifaximin is effective in treatment of HE and recent systemic reviews found it comparable to disaccharides and is effective in secondary prophylaxis of HE. H epatic encephalopathy (HE) is a complex neuropsychiatric syndrome, which may complicate acute, chronic liver failure or patients with portal-systemic shunting. It is characterized by changes in mental state including a wide range of neuropsychiatric symptoms ranging from minor signs of altered brain function to deep coma. 1,2 It is one of the commonest indications for admission in intensive care unit in patients with advanced cirrhosis. There were over 40 000 patients hospitalized in the United States alone for a primary diagnosis of HE, resulting in total charges of approximately $932 million. Data in other countries are lacking, hence it causes a huge burden financially to the patient and society. 3 The West Haven Criteria are most often used to grade HE, with scores ranging from I-IV (IV being coma). However, it is a challenge to diagnose patients with minimal hepatic encephalopathy (MHE) or grade 1 HE; so it might be practical to combine these entities and name them covert HE for clinical use and overt HE to patients with grade II to IV. 1,4,5 One of the major tenets of the pathophysiology of HE is hyperammonemia that results from an increased nitrogenous load from the gastrointestinal tract and reduced urea synthesis both due to portal-systemic shunting and decreased urea hepatic synthesis. Brain and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia is produced both by bacterial degradation of amines, aminoacids, purines, and urea as well as enterocytic glutaminase activity that converts glutamine to glutamate and ammonia. 6,7 Astrocytes play an important role in the pathogenesis of HE with consequences for neuronal function. Astrocytes have the ability to eliminate ammonia by the synthesis of glutamine through amidation of glutamate by the enzyme glutamine synthetase Hyperammonemia leads to the accumulation of glutamine within astrocytes, which exerts an osmotic stress that causes astrocytes to take in water and swell. 8,9 This article reviewed the clinical impact, pathogenesis, and management of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2013 were acquired through a MEDLINE search of different combi...

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Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

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Management of Overt Hepatic Encephalopathy

Sharma

2015

Journal of Clinical and Experimental Hepatology

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“…Comment: RCTs showed nonabsorbable disaccharides such as lactulose improve the parameters of hepatic encephalopathy (psychometric test scores and venous ammonia levels) [198,199]. Nonabsorbable disaccharides seemed to reduce the risk of no improvement in patients with hepatic encephalopathy but they showed no significant effect on mortality compared with placebo or no intervention [200].…”

Section: Cq: Is Albumin Infusion Effective For Treatment Of Cirrhoticmentioning

confidence: 99%

Evidence-based clinical practice guidelines for liver cirrhosis 2015

et al. 2016

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The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V 2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.

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“…These drugs pass through the small intestine without being absorbed or hydrolyzed and thus reduce the intestinal burden of ammonia by interacting with colonic bacteria to acidify the intestinal tract. This acidification increases the number of protein-synthesizing bacteria and reduces the number of protein-degrading bacteria (16,17). These treatments, however, also have unpleasant side effects that include diarrhea and flatulence (18).…”

Section: Introductionmentioning

confidence: 99%

pH-sensitive microemulsion-based gels for removal of colonic ammonia: A novel preventative oral preparation for hepatic encephalopathy in rats

Zhang

Duan

Tian

et al. 2015

Molecular Medicine Reports

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Abstract.Microemulsions with limited stability in mimetic gastrointestinal environments have previously demonstrated potential for the effective removal of ammonia from artificial colonic fluid. Specialized pH-sensitive microemulsion-based gels for the removal of colonic ammonia (MBG-RCA), however, possess relative stability in the gastrointestinal (GI) tract of normal rats, indicating potential use in in vivo applications. An investigation of the effects of oral MBG-RCA was conducted in order to evaluate the reduction of intestinal ammonia and the prevention of hepatic encephalopathy (HE) in rat models. Eighty rats were allocated into eight 4-day treatment groups: The HE model (intraperitoneal injection of thioacetamide) group; the high-, medium-and low-dose MBG-RCA therapeutic groups (15, 10 and 5 ml/kg MBG-RCA, respectively); and the normal, blank, lactulose and acetic acid control groups, each of which received daily treatment administration. Oral MBG-RCA effects were identified using behavioral monitoring observed by an infrared night vision supervisory control system, electroencephalograms, blood ammonia levels, intestinal ammonia levels, liver functionality and pathological observation. High-and medium-dose oral administrations of MBG-RCA significantly decreased the blood and intestinal ammonia levels (P<0.05), improved liver functionality and reduced the clinical manifestations of HE in rats. MBG-RCA demonstrated high clearance of rat colonic ammonia while maintaining sufficient stability in the GI tract, indicating the potential for the development of new clinically relevant oral preparations for the prevention of HE. Additionally, such preparations are advantageous in that ammonia is eliminated without the production of potentially harmful metabolic byproducts. IntroductionElimination of excess ammonia is the primary method of prevention and treatment of hepatic encephalopathy (HE), a progressive condition in which neurological function is impaired as the liver fails to remove toxic metabolites, particularly ammonia, from the bloodstream. The majority of intestinal ammonia is produced in the colon; however, no clinically viable oral treatment exists for the elimination of this excess ammonia, resulting in continuous low clearance levels due to poor ammonia elimination in the body.HE is a syndrome caused by serious hepatic diseases as a result of metabolic disturbance and dysfunction of the central nervous system. Its clinical manifestation includes deposition changes, ethological abnormalities and mental retardation. In severe cases, it may develop into a coma or even be life-threatening. A number of researchers have divided HE into three categories: Type A is associated with acute liver failure; type B is caused by severe portosystemic shunting without liver disease; and type C is associated with chronic liver disease and hepatic cirrhosis (1). Acute liver failure models are well recognized as a representative model of type A HE. These models may be used to examine the pathological response of HE to v...

show abstract

Secondary Prophylaxis of Hepatic Encephalopathy: An Open-Label Randomized Controlled Trial of Lactulose Versus Placebo

Cited by 279 publications

References 45 publications

Management of Overt Hepatic Encephalopathy

Management of Overt Hepatic Encephalopathy

Evidence-based clinical practice guidelines for liver cirrhosis 2015

pH-sensitive microemulsion-based gels for removal of colonic ammonia: A novel preventative oral preparation for hepatic encephalopathy in rats

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