Hepatic encephalopathy therapy: An overview

Table 1 RCTs on the prevention of episodes of overt hepatic encephalopathy

Ref.	Type and NO. of patients included	Aim of the study	Tested treatment (s)	Control treatment	Results
Riggio et al[38] 2005	Patients submitted to TIPS (75)	Prevention of post TIPS HE	Lactitol (60 g/d) rifaximin (1200 mg/d)	No treatment (25)	No difference between treatment and control groups
Sharma et al[39] 2009	Patients who recovered from HE (140)	Prevention of recurrence of HE (secondary prophylaxis)	Lactulose (30-60 mL in 2 or 3 divided doses)	No treatment (70)	Lactulose effective
Kanematsu et al[42] 1988	Patients submitted to surgery (56)	Prevention of HE precipitated by surgery	BCAA enriched solution, (29)	Conventional AA solution (27)	No difference between treatment and control groups
Rolachon et al[24] 1994	Patients bleeding from varices	Prevention of HE precipitated by bleeding	Gut cleansing using mannitol by naso-gastric tube	No treatment	Gut cleansing effective
Bass et al[53] 2009	History of HE	Prevention of recurrence of HE (secondary prophylaxis)	Rifaximin 550 mg twice daily for 6 mo	Placebo	Rifaximin effective

TIPS: Transjugular intrahepatic portosystemic shunt; HE: Hepatic encephalopathy; BCAA: Branched-chain amino acid.

Table 2 RCTs on the treatment of MHE

Ref.	Type of study	Type of HE/patients (n)	Tested treatment	Control treatment	Results
Prasad et al[46] 2007	RCT	MHE (61)	Lactulose (30-60 mL of lactulose in 2 or 3 divided doses)	No treatment	Lactulose improved the quality of life
Bajaj et al[41] 2008	Prospective randomized trial	MHE (25)	Probiotic yoghurt	No treatment	Probiotic improved the psychometric performance
Liu et al[73] 2004	Double blind, randomized study	MHE (55)	Bioactive, fermentable fibers and lactic acid bacteria Bioactive, fermentable fibers	Placebo	Synbiotic treatment improved the psychometric performance and the Child-Turcotte-Pugh class
Malaguarnera et al[74] 2009	Randomized study	MHE (125)	Bifidobacterium + fructo-oligosaccharides	Lactulose	Both treatments improve blood ammonia and psychometric performance

MHE: Minimal hepatic encephalopathy.

Table 3 Treatment strategies in patients with precipitant-induced episodic HE

General supportive care
	Prevention of falls or body harm in disorientated patients
	Care of bladder and bowel function
	Care of i.v. lines
	Monitor fluid balance
	Monitor glycaemia and electrolytes
	Monitor arterial blood gases
	Correct acid/base disturbances
	Monitor blood pressure
	Avoid aspiration pneumonia
	Prevent causes of sepsis
Support nutritional needs	An energy intake of 35-40 kcal /kg BW/d and a protein intake of 1.2-1.5 g/kg BW/d are recommended. Energy should be provided by glucose and fat in a ratio of 65-50: 35%-50% of non protein calories according to the ESPEN guidelines for nutrition in liver disease (31) In patients with severe hepatic encephalopathy (Grade III-IV), solutions with an increase content of BCAAs and reduced amount of aromatic amino acid can ameliorate neurological symptoms ensuring adequate protein intake
Treatment of the precipitating event
GI bleeding	Stop bleeding with vasoactive drugs, endoscopic therapy or angiographic shunt (TIPS) Correct anaemia with blood transfusion Nasogastric tube to facilitate upper GI cleansing
Infection (pulmonary, urinary tract, spontaneous bacterial peritonitis)	Appropriate antibiotic terapie
Exogenous sedatives	Discontinue benzodiazepines
Electrolyte abnormalities	Discontinue diuretics Correct hypo or hyperkalemia
Constipation	Cathartic Bowel enema
Deterioration of renal function	Discontinue diuretics Correct dehydration Discontinue nephrotoxic antibiotics

Table 4 Some of the RCTs available on the treatment of hepatic encephalopathy

Ref.	Type of study	Type of HE/patients (n)	Tested treatment	Control treatment	Results
Uribe et al[23] 1987	Double-blind, controlled trial	Episodic overt HE (20)	Lactitol and lactose enemas	Nonacidifying enemas	Acidifying agents like lactose and lactitol are effective and superior to tap-water enemas for the treatment of HE
Hassanein et al[31] 2007	Prospective, randomized, controlled, multicenter trial	Severe episodic overt HE (70)	Molecular adsorbent recirculating system (MARS) and standard medical therapy	Standard medical therapy	MARS is associated with an earlier and more frequent improvement of HE
Kircheis et al[57] 1997	Randomized, double-blind, placebo-controlled, multicenter trial	MHE (53) and mild overt HE (grade I-II, 53)	L-ornithine-L-aspartate, 20 g/d i.v.	Placebo	Therapy improves psychometric performance and is safe and effective in HE treatment
Stauch et al[58] 1998	Randomized, double-blind, placebo-controlled clinical trial	MHE (23) and mild overt HE (43)	L-ornithine-L-aspartate, 9 g/d orally	Placebo	Therapy improves psychometric performance, blood ammonia levels and is safe and effective in HE treatment
Ahmad et al[59] 2008	RCT	Overt HE (80)	L-ornithine-L-aspartate, 20 g/d i.v.	Placebo	Treatment improves blood ammonia and mental state
Sushma et al[62] 1992	Prospective randomized double-blind study	Overt HE (74)	Sodium Benzoate, 5 g	Lactulose	Improvement in portal-systemic encephalopathy parameters occurred in both treatment groups and was similar
Reding et al[66] 1984	Double-blind randomised trial	Chronic HE (22)	Zinc acetate 600 mg/d	Placebo	Treatment improves psychometric performance
Riggio et al[67] 1991	Double-blind, crossover trial	Chronic HE (15)	Zinc sulfate 600 mg/d and lactitol	Lactitol	Zinc was significantly raised after oral administration, but no modification in the parameters included in Conn's index were observed
Loguercio et al[72] 1995	Double blind parallel trial	HE (40)	SF-68	Lactulose	SF-68 improves blood ammonia and psychometric performance
Gentile[75] 2005	Randomized, double-blind, crossover study	HE (107)	Acarbose 300 mg/d	Placebo	Acarbose improves blood ammonia levels and HE clinical parameters

Table 5 Possible future approaches to HE treatment

Objectives	Approaches currently used	Proposed approaches under evaluation
To reduce the production of Gut-derived toxins	Disaccharides Low-absorbable antibiotics	Probiotics Fermentable fibers, acarbose Spherical adsorptive carbon (AST 120)
To favor nitrogen metabolism	Liver transplantation Reduction of TIPS diameter Closure of a spontaneous portal systemic shunt Ornithine Aspartate Zinc Sodium benzoate	Artificial liver support Sodium benzoate + phenylacetate (Ammonul) L-ornithine phenylacetate HPN-100 (Phenylbutyrate + phenylacetic acid)
To correct the alterations in neurotransmission	BCAA Flumazenil