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Introduction
Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed.In this review we focused on the effectivness of rifaximin for hepatic encephalopathy with consideration of different randomised control trials.
Hepatic encephalopathy, Rifaximin, Hyperammonia
Hepatic encephalopathy (HE) represents a diverse spectrum of complex neuropsychiatric disturbance resulting from liver disease and its concomitant metabolic and immunological derangements. [1] Hepatic encephalopathy (HE) presents in 30-60% of patients with cirrhosis of the liver. It is a clinical expression of a spectrum of potentially reversible neuropsychiatric abnormalities secondary to the accumulation of neurotoxic substances in brain tissue that is proportional to the synthetic function and functional reserve of the liver [2] It is characterized by deficits in cognitive, psychiatric, and motor function and can range in severity from minimal (or covert) hepatic encephalopathy (MHE) to overt hepatic encephalopathy (OHE), coma, and death. Patients with MHE demonstrate neuropsychological alterations including disrupted sleep–wake cycle, personality changes, impairment of attention, cognitive and memory dysfunction, and changes in motor coordination. These can progress through to higher grades of OHE, including lethargy, stupor, coma, and death; these are more pronounced in patients with acute liver failure.[1] The most well understood pathophysiological mechanism of HE is the neurotoxicity of ammonia in the brain, either due to increased production or impaired excretion. The majority of ammonia production occurs in two primary areas: the intestines (both small and large, contributing about 50%) and the kidneys (around 40%). Within the gastrointestinal system, ammonia is formed through the breakdown of dietary proteins by urease-producing bacteria, as well as through the metabolism of glutamine by enterocyte glutaminase. In the kidneys, proximal tubular cells generate ammonia from glutamine while producing bicarbonate as a by-product. Various factors can influence the production of ammonia in these areas, including gastrointestinal bleeding, conditions of low blood volume, excessive diuresis, low potassium levels, acidosis, and high protein intake.[3]
The liver plays a crucial role in ammonia detoxification through the urea cycle (also known as the Krebs-cycle), which transforms ammonia into urea, a water-soluble compound. This urea is then excreted through the intestines and urine. When liver function is compromised due to cellular damage or shunting, its ability to detoxify ammonia decreases, leading to elevated ammonia levels in the bloodstream. Additionally, the kidneys may further hinder ammonia excretion due to imbalances in acid-base levels and potassium, increased protein consumption, and dysregulation of glucocorticoid hormones. Skeletal muscle also aids in ammonia detoxification via the enzyme glutamine synthase, which converts ammonia into glutamine. Thus, sarcopenia—a frequent complication of cirrhosis—can exacerbate issues related to hepatic encephalopathy.Changes in gut flora are a key factor in the development of hepatic encephalopathy (HE). It is believed that a reduction in bile acid production enables urease-producing bacteria to thrive, replacing beneficial bacteria like lachnospiraceae . Research has consistently highlighted the microbiota’s crucial role in HE progression. In addition to ammonia, other substances— especially altered neurotransmitters—could also contribute to the onset of HE. These substances may include glutamine, histamine, serotonin, γ-aminobutyric acid, and manganese. More research is needed to uncover other aspects of HE pathophysiology to facilitate quicker diagnosis and treatment.[3]
Hyperammonemia is a metabolic condition characterized by the raised levels of ammonia, a nitrogen-containing compound. Normal levels of ammonia in the body vary according to age. Hyperammonemia can result from various congenital and acquired conditions in which it may be the principal toxin. Hyperammonemia may also occur as a part of other disorders that involve various other metabolic abnormalities. Normally, ammonia is produced in the colon and small intestine from where it is transported to the liver to be converted to urea via the urea cycle. Urea, a water soluble compound, can then be excreted via the kidneys. Ammonia levels rise if the liver is unable to metabolize this toxic compound as a result of an enzymatic defect or hepatocellular damage. The levels may also rise if portal blood is diverted to the systemic circulation, bypassing the liver, or there is increased production of ammonia due to an infection with certain microorganisms [4]
According to national guidelines, HE is classified using four main axes.The first criterion is based on the underlying cause of HE. Type A is HE seen in acute liver failure, Type B in the portal systemic bypass setting with no intrinsic hepatocellular disease, and Type C is in the setting of cirrhosis with portal hypertension or systemic shunting.(4)
There is no standardised serologic testing or imaging modality to accurately diagnose HE and assess its severity. Ammonia is classically associated with HE; however, increased blood ammonia level alone does not help with the diagnosis or prognosis of HE. Elevation of ammonia in combination with the clinical picture of HE can be more useful, as isolated increased ammonia level can be seen in other medical conditions [5]
The first-line pharmacologic therapy for HE is laxative. The initial goal of therapy is to prevent ammonia absorption through non-absorbable disaccharides (i.e., lactulose).[6] They are potent laxatives and additionally help alter the intestinal microbiome to non-urease-producing bacteria that reduce ammonia production [7]. Lactulose also lowers the pH of the colon, causing conversion of ammonia to the ammonium ion, which is not readily absorbable in the colon.Disaccharide enemas and polyethylene glycol have also been proven to be useful for removing excess ammonia from the colon.From all that therapy, we decided to focus on the treatment of the antibiotics that is Rifaximin
Pharmacological characteristics of Rifaximin:Rifaximin is a semisynthetic, water-insoluble, rifamycin-based nonsystemic antibiotic with very low gastrointestinal absorption and good antibacterial activity.[8] intestinal absorption and good antibacterial activity.[8] Compared with rifampicin, it contains an extra pyrido imidazole ring to reduce systemic absorption that is less than 1% after oral administration [8,9] (Fig. 2). Nevertheless, it is important to note that rifaximin plasma concentrations are not negligible in patients with cirrhosis, particularly in those with moderate-to severe liver function impairment (Child B or C patients).[10] There are some published reports on potential muscle toxicity in cirrhosis in patients receiving rifaximin in combination with simvastatin 40 mg/day.[11] However, the possibility of these systemic muscle effects of rifaximin seems remote because in studies with large numbers of patients with cirrhosis, no muscle or other systemic adverse events have been reported.The slight increase in systemic exposure to rifaximin in subjects with cirrhosis should be interpreted in the context of its low systemic availability as well as the rifaximin safety data in cirrhosis. Therefore, no dosage adjustment in patients with advanced cirrhosis is recommended. Both experimental and clinical data show that rifaximin has a broad-spectrum antibacterial action covering gram-positive and gram-negative aerobic and anaerobic bacteria.[8] Rifaximin elicits its antimicrobial properties by binding the betaDNA-dependent RNA polymerase and thus inhibting subunit of the bacterial RNA synthesis. It has the advantage of low microbial resistance and few systemic adverse events and is safe in all patient populations.[8] Being virtually nonabsorbed, bioavailability of rifaximin within the gastrointestinal tract is high with intraluminal and fecal drug concentrations largely exceeding the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The gastrointestinal tract represents, therefore, the primary therapeutic target of rifaximin. [8,9] Rifaximin has been shown to modify the gut microbiome. However, changes in overall gut microbiome composition have shown to be relatively sparse, and the effects on microbiome have been described to be mediated also by rifaximin-induced changes in bile acid composition and modulation of microbiome function.
Open-label experiences and evaluation of a placeboassigned group that was subsequently given rifaximin showed continued reduction in HE-related episodes, even outside the clinical trial setting.
Based on its pharmacological characteristics and the putative effects on pathogenetic mechanisms of cirrhosis, rifaximin is considered by many hepatologists to be the logical alternative to quinolones or other systemic antibiotics for the prophylaxis of spontaneous bacterial peritonitis (SBP) and potentially of non SBP bacterial infections, with the belief that rifaximin is active on a broader range of intestinal gram-positive and gram-negative bacteria, is safer, and carries a low risk of inducing resistance to antibiotics.
Unfortunately, after more than a decade of clinical research, a conclusive indication on the use of rifaximin in prevention of bacterial infections cannot currently be given. Almost all the published data are related to primary or secondary prophylaxis for SBP. In general, retrospective studies have shown that the use of rifaximin is associated with lower incidence of SBP and other complications of the disease
Conversely, prospective observational studies have yielded less consistent results. Only a few RCTs have been performed so far, in Egypt and South Arabia, comparing the efficacy of rifaximin versus norfloxacin; in these studies, an advantage was seen in favor of rifaximin given for primary or secondary SBP ; in the former study, rifaximin was also given alternated to norfloxacin and compared with norfloxacin alone. However, the strength of these positive results is undermined by some methodological drawbacks. To overcome the limitations inherent to each single study, several systematic reviews and meta-analysis assessing both the observational cohort studies and the RCTs have been performed. Again, results suggest that only low-quality evidence supports the superiority of rifaximin over norfloxacin or other systemic antibiotics for either primary or secondary SBP prophylaxis.) In all these studies, the high heterogeneity in terms of patient inclusion criteria, type and modalities of administration of the comparative prophylactic therapies, primary and secondary endpoints, and the moderate-to-high risk of methodological biases related to randomization, blinding, attrition, and intention-to-treat analysis preclude the possibility to reach solid conclusions [12].
HE remains one of the major challenges and morbidities facing patients with decompensated liver cirrhosis. Even in its subclinical presentation, it exerts a profound influence on patient quality of life and functional capability and confers a damning prognosis. Recurrent encephalopathy is in itself an extended criterion for consideration of liver transplantation. Increasing understanding of the interplay between the liver, the intestinal microbiome, and the innate immune system allows for the development of exciting new technologies and treatments to include in the clinician’s armory for tackling this neurophysiological manifestation of decompensated liver disease (Fig. 3). A low threshold of suspicion and early specialist review, complex neuropsychological evaluation, and identification and treatment of precipitants are required in the approach to a patient with liver cirrhosis and altered mentation.
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