Description of the condition

Cirrhosis is a chronic disorder of the liver associated with a variety of conditions such as excessive alcohol intake, infection with hepatitis B and hepatitis C, and obesity. In susceptible people, the damage caused to the liver results in the development of fibrosis (scar tissue) which replaces normal liver tissue, intermixed with areas of regeneration (nodules) which form as the liver attempts to repair itself.

Hepatic encephalopathy is the term used to describe the spectrum of neuropsychiatric complication which can arise in people with cirrhosis (Ferenci 2002; Dhiman 2010; Vilstrup 2014) and defined, most recently, as brain dysfunction caused by liver insufficiency or portal systemic shunting of blood, or both (Vilstrup 2014).

The spectrum of changes in brain functioning associated with hepatic encephalopathy ranges from the clinically 'indiscernible' to the clinically 'obvious'. The term 'minimal' hepatic encephalopathy is used to describe people with cirrhosis who are 'clinically normal' but in whom psychometric testing shows impairment of attention, decision making, and memory functions, while electrical recordings show slowing of their brain waves. There is no standard approach to the diagnosis of minimal hepatic encephalopathy; various psychometric and neurophysiological tools may be used, depending on local expertise. The term 'overt' hepatic encephalopathy is used to describe people with cirrhosis who show clinical evidence of neuropsychiatric abnormalities including alterations in intellect, behaviour, motor function, and consciousness (Weissenborn 1998; Ferenci 2002). The clinical changes may arise over a period of hours or days in people who have previously been stable. This so‐called 'episodic' hepatic encephalopathy may be precipitated by a number of diverse events such as gastrointestinal bleeding, infection, or constipation, although in 50% of instances no obvious cause can be identified. The diagnosis of overt hepatic encephalopathy is a clinical one, and scales such as the West Haven Criteria and Glasgow Coma Scale may be used to determine severity. Between episodes of hepatic encephalopathy, people may return to normal, although some degree of impairment may remain (Bajaj 2010). Less frequently, people present with persistent neuropsychiatric abnormalities that remain stable over time; many have extensive spontaneous portal‐systemic shunting of blood which develops as a complication of their cirrhosis or else a surgically created or transjugular intrahepatic portosystemic shunt undertaken to treat this problem.

The exact reason why people with cirrhosis develop hepatic encephalopathy is unknown, but the accumulation of toxic material, such as ammonia, which is produced in the gastrointestinal tract is thought to play a key role. These toxins are normally detoxified in the liver but this process fails when liver function deteriorates and when blood is shunted around the liver following the development of portal‐systemic shunting. The unprocessed toxins then enter the systemic circulation and impinge on the brain.

The prevalence of overt hepatic encephalopathy varies in relation to the stage of the underlying liver disease (Bajaj 2011). Thus, at the time of diagnosis with cirrhosis, the prevalence is of the order of 10% to 14% (Saunders 1981; Jepsen 2010), while in people with more longstanding cirrhosis, it is nearer 20% (D'Amico 1986; de Jongh 1992; Zipprich 2012). Overall, it is likely that 40% of people with cirrhosis will develop overt hepatic encephalopathy at some point during their disease evolution (Amodio 2001). The prevalence of minimal hepatic encephalopathy varies from 22% to 75% depending on the diagnostic paradigms used (Montagnese 2004); approximately 50% in people with previous overt hepatic encephalopathy retain features compatible with a diagnosis of minimal hepatic encephalopathy (Sharma 2010; Lauridsen 2011).

The presence of hepatic encephalopathy, whether minimal or overt, has a considerable impact on the execution of complex tasks, such as driving (Schomerus 1981; Bajaj 2009); health‐related quality of life (Groeneweg 1998; Montagnese 2009); patient safety (Román 2011); neurocognitive function post liver transplantation (Sotil 2009); and, ultimately, survival (D'Amico 2006; Stewart 2007; Wong 2015). It also places a considerable burden on healthcare resources (Rakoski 2012).

Description of the intervention

The non‐absorbable antibiotic rifaximin is recommended for the prevention of hepatic encephalopathy (EASL/AASLD guideline 2014a; EASL/AASLD guideline 2014b). Clinicians and researchers have previously evaluated other antibiotics, including aminoglycosides and metronidazole. Aminoglycosides (such as neomycin and paromomycin) are bactericidal antibiotics, which inhibit bacterial protein synthesis (Borovinskaya 2007). Metronidazole is also a bactericidal antibiotic, which inhibits bacterial DNA synthesis (Löfmark 2010). Aminoglycosides are particularly active against gram‐negative aerobes (Magnet 2005), while metronidazole is active against both gram‐positive and gram‐negative anaerobes (Löfmark 2010). The interventions may be administered enterally (orally or via an enteral tube) in the form of tablets or a solution. Rectal and intravenous administration is also possible. Aminoglycosides are normally poorly absorbed from the gastrointestinal tract. However, absorption may be increased in cirrhosis as the permeability of the gut increases, leading to drug‐induced ototoxicity or nephrotoxicity (Patidar 2014). Metronidazole is normally well absorbed from the gastrointestinal tract and can cause neurotoxicity in people with cirrhosis, who may have impaired clearance of the drug. As rifaximin is a relatively expensive antibiotic (Huang 2007), aminoglycosides and metronidazole could potentially be more cost‐effective interventions for the prevention and treatment of hepatic encephalopathy.

How the intervention might work

Although the exact pathogenesis of hepatic encephalopathy is unknown, hyperammonaemia is known to play a key role (Butterworth 2004). In people with cirrhosis, the liver is unable to clear the high levels of gut‐derived ammonia. As a result, organs such as the brain rely on glutamine synthesis as an alternative detoxification pathway. In the brain, ammonia is handled mainly by astrocytes, resulting in increased glutamine synthesis. Increased glutamine synthesis triggers a series of cellular events that results in astrocyte swelling, low‐grade oedema, and eventually brain dysfunction (Häussinger 2000; Albrecht 2006; Rai 2015). Other proposed effects of ammonia in the brain include blood‐brain barrier dysfunction, altered inhibitory and excitatory neurotransmission, and altered cerebral energy metabolism (Butterworth 2000). The main sources of ammonia include nitrogenous products in the diet, bacterial metabolism of urea and proteins in the colon, and deamination of glutamine in the small intestine. Antibiotics lower ammonia levels by eliminating urease‐producing gut bacteria and correcting for small intestinal bacterial overgrowth, which is frequently observed in people with cirrhosis (Yang 1998; Bauer 2001; Gunnarsdottir 2003; Pande 2009). The aminoglycoside neomycin is also a known glutaminase inhibitor (Hawkins 1994). In addition to their ammonia‐lowering effects, antibiotics may protect against hepatic encephalopathy by reducing the production of other bacteria‐derived neurotoxins, such as phenols and mercaptans, and by reducing gut bacteria translocation into the bloodstream (Jalan 2010). Reducing gut bacteria translocation into the bloodstream may reduce endotoxaemia and systemic inflammation, which are implicated in the development of hepatic encephalopathy (Patidar 2014).

Why it is important to do this review

From 1957 to 1966, the aminoglycoside neomycin was the recommended treatment for people with hepatic encephalopathy (Patidar 2014). After 1966, clinicians primarily used non‐absorbable disaccharides based on randomised clinical trials and clinical experience (Elkington 1969; Germain 1973; Heredia 1987; Heredia 1988; Grandi 1991; Horsmans 1997). A recent systematic review found that non‐absorbable disaccharides are associated with beneficial effects on mortality and morbidity (Gluud 2016a; Gluud 2016b). At present, we have limited data on the effectiveness of aminoglycosides and other antibiotics such as metronidazole and vancomycin, possibly because clinicians introduced and subsequently abandoned the intervention before it could be assessed using current norms in evidence‐based medicine (Patidar 2014). Moreover, concerns about organ toxicity and antibiotic resistance, particularly vancomycin resistance, have yet to be properly addressed (Leise 2014). However, antibiotics are still commonly used, in several countries, to treat hepatic encephalopathy, and the European Association for the Study of the Liver (EASL)/American Association for the Study of Liver Diseases (AASLD) guidelines report favourably on both neomycin and metronidazole (EASL/AASLD guideline 2014a; EASL/AASLD guideline 2014b).

Three trials found that neomycin may be as effective as lactulose in improving signs of hepatic encephalopathy (Conn 1977; Atterbury 1978; Orlandi 1980), and one study found that metronidazole may be as effective as neomycin (Morgan 1982). Two subsequent trials found that the aminoglycoside paromomycin may be as effective as the more widely used antibiotic rifaximin (Testa 1985; Parini 1992). In light of current practice guidelines and the available evidence, a thorough assessment of the use and safety of antibiotics in hepatic encephalopathy is warranted. One systematic review published in 2004 found no difference between antibiotics and non‐absorbable disaccharides (Als‐Nielsen 2004). However, the review did not include randomised clinical trials comparing antibiotics versus placebo or no interventions. In addition, methodological issues and lack of statistical power weakened the conclusions. This review will evaluate the beneficial and harmful effects of aminoglycosides and metronidazole using the evidence available.