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Open Access Review
Therapeutic Strategies and Current Management for Hepatic Encephalopathy in Liver Cirrhosis

Kazuyuki Suzuki 1, *, Akinobu Kato 2, Yasuhiro Takikawa 1

1. Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, Japan

2. Department of Gastroenterology, Morioka Municipal Hospital, Morioka, Iwate, Japan

Correspondence: Kazuyuki Suzuki

Academic Editor: Tatsuo Kanda

Special Issue: Pathology and Management of Cirrhosis

Received: February 04, 2019 | Accepted: July 10, 2019 | Published: July 16, 2019

OBM Hepatology and Gastroenterology 2019, Volume 3, Issue 3, doi:10.21926/obm.hg.1903027

Recommended citation: Suzuki K, Kato A, Takikawa Y. Therapeutic Strategies and Current Management for Hepatic Encephalopathy in Liver Cirrhosis. OBM Hepatology and Gastroenterology 2019;3(3):18; doi:10.21926/obm.hg.1903027.

© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with a wide spectrum of symptoms and one of the serious complications seen in patients with acute and chronic liver disease or spontaneous portal-systemic shunting. HE is usually classified into three types according to the underlying cause (A, B, and C). Some recent discussions suggest a fourth type (D) to exclusively include HE patients with acute-on-chronic liver failure. HE has also been classified into coma grades I to IV according to the West Haven criteria, while the International Society for Hepatic Encephalopathy and Nitrogen Metabolism has proposed two distinct categories: covert HE (includes minimal HE, which is identified solely through psychometric or neurological tests and coma grade I) and overt HE (coma grade II-IV). Although modern therapeutic approaches based on clinical evidence have gradually improved the outcomes of cirrhotic patients with HE, recurrent or resistant HE is still common and the prognosis in patients with severe liver dysfunction is still poor. In this article, we discuss the therapeutic strategies and current management, except for liver transplantation and interventional procedures for portal-systemic shunting, in cirrhotic patients with HE.

Keywords

Hepatic encephalopathy; liver cirrhosis; portal-systemic shunting; disaccharides; rifaximin; branched-chain amino acids; zinc; carnitine; ammonia-lowering drugs

1. Introduction

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome and one of the serious complications often observed in patients with acute and chronic liver failure or spontaneous portal-systemic shunting (PSS) [1]. HE is classified into three types according to the underlying cause: type A results from acute liver failure; type B results from porta-systemic shunting without liver dysfunction; and type C results from liver cirrhosis (LC) [2,3]. Further, recent discussions have also proposed the fourth type (type D) to separately include HE patients with acute-on-chronic liver failure (ACLF), because they are different in terms of their clinical, pathophysiological, and prognostic features from those with types A–C [4,5]. HE shows a wide spectrum of clinical symptoms that include personality change, intellectual impairment, changes in neuromuscular activity (in particular, asterixis), and disturbed consciousness ranging from minor deficits in orientation and coordination to deep coma (grades I-IV according to the West Haven criteria) [1,2,3]. HE, according to its time course, is also subdivided into episodic, recurrent, and persistent HE [2]. Recently, the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) recommended that HE needs to be classified into two more distinct categories: covert HE and overt HE [6,7]. Covert HE involves minimal HE (MHE) and coma grade I (Figure 1). Although MHE is identified solely through psychometric or neurological tests, a global standard method for the diagnosis of MHE has not been established [7,8,9]. The therapeutic outcome and final prognosis of HE are mainly affected by the severity of liver damage even when appropriate medical treatments (except liver transplantation) have been performed [10,11,12].

Although the pathogenesis of HE has not been fully clarified, many neurotoxic substances, such as ammonia, short-chain fatty acids, amines, mercaptan, indoles, phenols, and benzodiazepine-like compounds produced mainly in the gut, have been seen to be closely associated with the onset and recurrence of HE [13,14,15]. Of these neurotoxic substances, ammonia is the most important factor participating in the pathogenesis of HE. Hyperammonemia finally induces the swelling of astrocytes, which is the only compartment for the detoxification of ammonia released by the synthesis of glutamine (Gln) in the brain, resulting in a disturbance of neurotransmission [16,17,18]. Many studies, using 1H-magnetic resonance spectroscopy, have supported astrocyte swelling and Gln accumulation in the brain in cirrhotic patients with or without HE [18,19,20]. Furthermore, some recent studies have also shown that gut dysbiosis is closely associated with the pathogenesis of HE in LC [21,22,23,24]. Therefore, fecal microbial transplantation (FMT) has been in focus as an option of treatment in LC patients with HE [21,22,23,24,21,22,23,24]. However, FMT has still not been confirmed and carries many problems including its indication and method of implication.

Figure 1 Definition and classification of hepatic encephalopathy.

HE is usually divided into three types (Type A-C), according to the underlying cause: type A results from acute liver failure; type B results from porta-systemic shunting without liver dysfunction; and type C results from liver cirrhosis. Some researchers have proposed, type D resulting from acute-on-chronic liver failure.
WHC, West Haven criteria; MHE, minimal hepatic encephalopathy; ISHEN, International Society for Hepatic Encephalopathy and Nitrogen Metabolism.

In this issue, we mainly discuss the therapeutic strategies and current management practices of HE in LC patients (so-called type C HE), except liver transplantation and interventional procedures such as transjugular intrahepatic portosystemic shunt (TIPS) or embolization for PSS.

2. Evaluation Associated with the Pathogenesis of HE in LC

A systemic evaluation, including the severity of liver damage, the existence of PSS, participating factors, and other complications such as spontaneous bacterial peritonitis (SBP), must be carried out before the treatment of LC patients with HE (Figure 2). In particular, both the evaluation of the severity of liver damage and clinical characteristics are very important in LC. In fact, LC is classified into two types based on the severity of liver damage: hepatocellular injury-dominant type and shunt-dominant type. The former (including acute-on-chronic type based on LC) usually shows hyperbilirubinemia and low prothrombin time activity, while the latter shows only mild hepatocellular damage. These disease types affect the prognosis of LC. Hyperammonemia is commonly observed in both types. The factors precipitating HE in LC include dietary indiscretion (usually overdose of dietary protein), gastrointestinal bleeding (rupture of gastroesophageal varices and bleeding from portal hypertensive gastropathy), constipation, infection, psychoactive medication (excessive administration of sedative/analgesic drugs), electrolyte disorder due to diuretic overdose, and dehydration [1,2]. The prevalence of these precipitating factors differs between the episodic type and the recurrent type in LC patients with HE [2]. In addition, it is important to note that intra-abdominal bleeding is caused by the rupture of extrahepatic progressive hepatocellular carcinoma in LC patients with advanced HCC. Certain respiratory and systemic circulatory disturbances (e.g., hypoxemia, hypotension, and congestion) are also associated with exacerbations and the prognosis of HE [12]. In recent time, the cases of HE due to gastrointestinal bleeding have dramatically decreased, as treatment modalities such as pharmaceutical and interventional therapies for gastroesophageal varices and portal hypertensive gastropathy have advanced. On the other hand, the cases of HE without obvious precipitating factors still occur. A TIPS is useful in the management of the complications of portal hypertension, in particular, gastroesophageal varices, although its insertion precipitates HE [27,28]. A recent study by Routhu et al. suggested that several factors (in particular, age, pre-TIPS portal venous pressure, serum creatinine, presence of diabetes mellitus, and etiology of portal hypertension) are significantly associated with the development of overt HE after TIPS [29].

Figure 2 Systemic evaluation of cirrhotic patients with hepatic encephalopathy before treatment.

3. Management

A flow chart of the available pharmacological modalities to treat LC patients with HE is shown in Figure 3. The management of HE in LC patients is classified into two categories (nutritional management and drugs). The goal of the initial management of HE is to improve disturbed consciousness and reduce blood ammonia concentration. First, the coma grade of HE is determined and the possibility of oral administration of nutrients and drugs is explored. The first therapeutic step is the use of non-absorbable disaccharides to improve the hyperammonemic state. Ammonia is metabolized in the liver, digestive organs (stomach, small and large intestines), kidney, muscle, lung, and brain. Since the causes of hyperammonemia in each patient with HE are complex and diverse, it is very important to understand the ammonia metabolism in various organs and the interactions between them.

Figure 3 The flow chart of the proposed management for cirrhotic patients with hepatic encephalopathy.

* Infusion therapy of BCAA-enriched amino acid solution has not yet been adopted worldwide;
+ including ammonia-lowering drugs and fecal microbiota transplantation

3.1 Nutritional Management

Nutritional management is fundamental in LC patients, regardless of HE, because the liver is the central organ in nutritional metabolism. In general, LC patients have malnutrition, which is characterized by protein-energy malnutrition (PEM) and is associated with LC prognosis [31,32,33,34,35]. Furthermore, sarcopenia or skeletal muscle atrophy is often observed in LC patients [36]. While muscles play an important role in ammonia detoxification by increasing glutamine synthesis, hyperammonemia may induce muscle dysfunction and contribute to muscle mass loss [37,38]. Therefore, sarcopenia contributes to survival, health-related quality of life, outcomes after liver transplantation, and severe complications including HE in LC patients [39,40,41,42,43].

In order to formulate nutritional recommendations for LC patients with HE, the practice consensus was proposed by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) [44,45]. More recently, the European Association for the Study of the Liver (EASL) proposed a clinical practice guideline on the nutrition in chronic liver disease [46], and described the approaches and treatments for malnutrition (or undernutrition), sarcopenia, obesity, HE, and bone diseases (osteoporosis) in LC patients in detail. In contrast, the guideline on nutritional management of patients with LC of the Japanese Nutritional Study Group for Liver Cirrhosis suggests a restriction on dietary iron intake when LC patients show frequent hyperferritinemia because the excess deposition of iron in the liver causes oxidative stress and promotes hepatocarcinogenesis [47].

In general, since in LC patients with HE and coma over grade III, oral intake is impossible, nutrition is provided by a nasogastric tube or parenterally. However, HE patients with gastrointestinal bleeding (mainly rupture of gastroesophageal varices) and gastrointestinal motility dysfunction should be maintained by intravenous nutritional supplementation. In intravenous supplementation, a solution of glucose and high branched-chain amino acid (BCAA), with low aromatic amino acid (AAA) concentrations is recommended [48,49]. However, in cases with severe liver dysfunction with hyperbilirubinemia and low prothrombin time activity (i.e., hepatocellular injury-dominant type), the administration of amino acid solutions is mostly contraindicated, because the excess nitrogen load exacerbates hyperammonemia and worsens coma grading [49].

By the middle of the 20th century, it was believed that the daily dosage of dietary protein should be strictly limited in LC patients with HE, as the overdosage of daily protein accelerated the hyperammonemic state as observed in dogs with the Eck fistula [50]. Additionally, a long-term protein-restricted diet results in progressive protein catabolism and exacerbates PEM in LC patients [51]. However, some other studies have shown that the restriction of dietary protein may not be necessary over the short term [52,53,54]. In addition, recent studies have recommended that the administration of enteral nutrients involving BCAA-enriched formulas is effective in improving the nitrogen balance in LC patients [55,56,57,58,59]. Further, Maharshi et al. reported in a randomized controlled trial that nutritional intervention (30–35 kcal/kg/day, 1.0–1.5 g vegetable protein/kg/day) for six months is effective in the treatment of MHE and health-related quality of life [60]. In an open randomized clinical trial carried on Mexican patients, it was observed that a high-fiber (30 g/day) high-protein (1.2 g/kg) diet, supplemented with BCAA (8.63 g/day involving sachets of 110 grams), over six months, was safe without elevation of blood ammonia and glucose levels and helped in increasing muscle mass [61]. Furthermore, Campollo et al. suggested that stable LC patients can tolerate standard mixed meals (protein intake of 1.2–1.5 g/kg body weight/day) but further study is necessary for decompensated LC patients [62]. Although these results suggest that the type of protein ingested may be important in countries where the use of BCAA-enriched formula is practically feasible, it is better to mildly restrict dietary protein and to add a BCAA-enriched enteral supplement in LC patients with HE and a large PSS.

On the other hand, the nutritional management in HE patients with diabetes mellitus (DM) and/or obesity has not been well established. However, total calorie intake should be carefully limited, even though hypoglycemic drugs and/or insulin are often administered as needed. The recent guidelines for the management of LC patients with DM recommend that a late evening snack (LES) may also ameliorate the hyperglycemic state [46,47]. Furthermore, it has been reported that acarbose, an α-glucosidase inhibitor, is effective as a therapeutic agent for low-grade HE in LC patients with type 2 DM [63]. Our previous examination (unpublished data) showed that LES with α-glucosidase inhibitors is effective in correcting the energy metabolic abnormalities using indirect calorimetry in LC patients. The total nutritional management involving the BCAA formula is also useful in patients with MHE diagnosed by neuropsychological tests [64].

3.2 Drugs

3.2.1 Non-Absorbable Disaccharides

Lactulose (β-galactosido-fructose) and lactitol (β-galactosido-sorbitol) are synthetic disaccharides and non-absorbable in the small intestine. These drugs are metabolized by the bacteria in the colon to acetic and lactic acids. This acidification in the colon not only creates a hostile environment for the survival of intestinal bacteria with urease activity involved in the production of ammonia in the gut but also facilitates the conversion of ammonia to non-absorbable ammonium, and, then, by an osmotic laxative effect, it flushes the ammonium ions out [65,66,67]. Furthermore, it is important to focus on the relationship between the gut microbiome composition and the pathogenesis of HE in LC patients [21,22,23,24,21,22,23,24]. However, this relationship has not been clearly confirmed following lactulose administration [21,22,23,24,21,22,23,24]. At present, these two drugs are widely used for the initial treatment of covert and overt HE both [1,2,3]. The effect of the two drugs in improving coma grade and blood ammonia concentration is almost equal. However, since the rate of adverse effects (nausea, vomiting, abdominal pain, flatulence, diarrhea, etc.) is lower with lactitol than that with lactulose, the former is better tolerated, though it is not available in the United States [71]. Both drugs are generally administered by the oral route (three to four times a day), and the dosage is appropriately adjusted according to the stool characteristics and daily frequency after administration. In an emergency condition, an enema using a mixture of lactulose (100 mL) and physiological saline (700 mL) is recommended (usually repeated every 4–6 h) [72,73]. There have been conducted some randomized controlled trials comparing polyethylene glycol (PEG) and lactulose in LC patients with HE [74,75]. The results of the trials indicated that an enema using both PEG and lactulose is safe and more effective than lactulose alone in the treatment of HE.

3.2.2 Antibiotics

Non-absorbable antibiotics are usually recommended when the treatment using synthetic disaccharides fails to improve hyperammonemia. Although neomycin, kanamycin, polymyxin B, vancomycin, and metronidazole have been used previously [76,77,78], rifaximin is the first-line antibiotic for the treatment of HE with hyperammonemia worldwide [79,80,81,82,83,84,85]. Furthermore, rifaximin shows few adverse effects during long-term use [85]. At present, the indication for rifaximin is HE (covert HE and overt HE) or a hyperammonemic state in chronic liver diseases according to the guidelines of the American Association for the Study of Liver Diseases and EASL [2]. We have recently reported that the efficacy of rifaximin is good and it is well tolerated in Japanese patients with HE and hyperammonemia [86]. In another study, the therapeutic effect of rifaximin on MHE and its effectiveness were reported [85]. Furthermore, rifaximin has been used in LC patients with SBP [87,88,89,90,91]. SBP is considered one of the severe complications in LC patients and is also a participating factor in HE and hepatorenal syndrome. The aforementioned reports suggest that rifaximin is highly promising for the treatment of LC patients with several complications.

3.2.3 BCAA-Enriched Formulas

A BCAA-enriched solution was developed for the purpose of improving intracerebral neurotransmission by correcting the amino acid imbalance in the blood and brain [13]. BCAA-enriched formulas, including an infusion solution, enteral nutritional supplement, and BCAA granules, are used depending on the clinical stage (coma or recovery stage) and the presence or absence of PEM [49,56,57,58,59,56,57,58,59]. Although the infusion therapy is generally used during the overt coma stage in Japan [49], its use could not be adopted worldwide, because it does not improve the prognosis of patients with HE [2].

Enteral nutrition is usually possible in patients within grade II coma and without abnormalities (bleeding or dysfunction of motility) of the gastrointestinal tract. A BCAA-enriched enteral nutritional supplement and BCAA granules were originally developed to improve the status of HE and are recommended in Japan for PEM [57,59]. A BCAA-enriched enteral nutritional supplement is also occasionally used as a late evening snack (LES) to improve serum albumin levels and the nonprotein respiratory quotient in patients with LC [56,57,58,59]. BCAA granules (at a compounding ratio of approximately 1.2:2:1) were developed to correct the malnutrition status of LC patients with hypoalbuminemia (serum albumin concentration below 3.5 g/dL) in Japan [59]. Regarding the usefulness of long-term administration of BCAA granules to LC patients with malnutrition, the event-free rate (progression of ascites, edema, hepatic encephalopathy, jaundice, rupture of esophagogastric varices, incidence of liver cancer, death due to other causes, etc., during the course of treatment) was significantly lower in a BCAA granule administered group than that in a diet therapy group. Furthermore, it has been shown that male LC patients with both hepatitis C viral infection and a BMI greater than or equal to 25 kg/m2 have a lower incidence of HCC [93]. Furthermore, some recent studies have indicated that BCAA-enriched formulas prevent carcinogenesis and poor outcomes in patients with LC [94]. Thus, many reports suggest that BCAA supplementation is the fundamental treatment for LC patients with PEM or hypoalbuminemia; however, it is not available in the United States [95].

3.2.4 Other Ammonia-Lowering Drugs

L-ornithine L-aspartate (LOLA): LOLA is a mixture of two amino acids, which metabolizes ammonia in the form of urea and/or glutamine in the liver and muscles [96]. The treatment by LOLA (in oral and intravenous forms) for covert HE and HE has been recently developed in European countries, although it is not available in the United States and Japan. In clinical trials, intravenous administration of LOLA showed a significant effect by reducing HE grade, decreasing venous blood ammonia concentration, and improving psychomotor function in patients with MHE and OHE compared to placebo [97,98,99,100]. A large scale study by Sidhu et al. reported that five days of intravenous LOLA (30 g daily), as an add-on therapy with lactulose (30–120 mL through a nasogastric tube or orally and/or lactulose enema) and ceftriaxone (2 g twice daily), can significantly improve the grade of HE over days 1–4, but not on day 5 compared to placebo [98]. It also decreased venous blood ammonia concentration, time until recovery, and length of hospital stay, in the same study. In contrast, Alvares-da-Silva et al. reported no significant differences between oral LOLA administration (for 60 days) and placebo in the mental state and neuropsychological tests in MHE patients [99], but the therapy was useful in preventing further episodes of OHE. In summary, the administration of LOLA has shown improvement in the mental state and a decrease in the blood ammonia concentration in LC patients with OHE or CHE [100,101]. However, further studies considering the degree of hepatocellular damage and the stage of HE are necessary.

Zinc: Zinc is an essential trace element that is associated with many metabolic pathways in the liver [102,103]. Thus, zinc deficiency has frequently been seen in advanced LC patients with decreased dietary intake, decreased absorption from digestive tract, higher urinary excretion, activation of certain zinc transporters, and induction of hepatic metallothionein [104,105,106,107]. Zinc is also required for detoxification of ammonia via the urea cycle in the liver and its serum level shows a significant inverse relationship with blood ammonia concentrations in LC patients [108]. Since zinc is closely related to the pathogenesis of HE, several studies have examined the effects of zinc supplementation in patients with HE and hyperammonemia [109,110,111,112]. Our research group has recently performed a prolonged, randomized, placebo-controlled, double-blind trial and found that zinc supplementation for three months is effective and safe in treating hyperammonemia in patients with LC [113]. Although a large-scale controlled study examining the dosage of zinc, duration of administration, and basal condition of LC is needed to recommend zinc supplementation as a treatment option for HE patients with hyperammonemia.

Carnitine (CA): CA plays an important role in fat metabolism and energy production in the mitochondria and is also closely associated with the detoxification of ammonia via the urea cycle [114,115]. It is considered that there is a high prevalence of a secondary CA deficiency state in LC [116,117]. However, the deficiency of CA caused by the administration of some drugs, e.g., valproate, induces HE with hyperammonemia, and this deficiency can overcome by supplementation with CA [118,119,120]. At present, the administration of L-carnitine (L-CA) and/or acetyl-L-CA (ALC) is also suggested as an optional therapy for LC patients with covert and overt HE [118,119,120,118,119,120]. As a mechanism of the effect of L-CA against hyperammonemia, a previous experimental study suggested that L-CA administration improves ammonia metabolism through energy metabolism in the brain [123]. However, the precise role of L-CA in regulating ammonia metabolism in astrocytes still remains unclear. Recently, our preliminary experimental study indicated that L-CA protects against acute ammonia-induced cytotoxicity in human astrocytes via ameliorating the intracellular amino acid disturbance [124]. Further studies are needed to clarify the mechanism through which L-CA/ALC improves energy metabolism in astrocytes loaded with ammonia.

Sodium benzoate: Sodium benzoate has occasionally been used to promote the excretion of ammonia into the urine, but it is mainly used for congenital urea cycle disorders [125].

Benzodiazepine receptor antagonist: Flumazenil has also been reported to show a short-term beneficial effect in HE but exerts no direct effect on hyperammonemia [126,127].

Acarbose: Acarbose, a hypoglycemic agent acting through the inhibition of glucose absorption in the intestine, is usually used in patients with DM. Gentile et al. demonstrated that acarbose administration (100 mg thrice daily) improved the grade of coma and blood ammonia concentration in mild HE patients [63]. Acarbose may be helpful in treating HE patients with DM.

Probiotics: Probiotics are a mixture of beneficial bacteria. Since the recent studies suggest that the changes in the gut microbiome or dysbiosis in LC patients are associated with the pathogenesis of HE [68,69,70], probiotics are expected to be used as a long-term treatment in patients with HE. However, the supremacy of probiotics over lactulose or lactitol in HE is still uncertain [128,129,130]. High-quality randomized trials are needed to further clarify the efficacy of probiotics.

4. Conclusions

There are multiple factors associated with the risk and prognosis of LC in patients with HE. Furthermore, the causes of hyperammonemia in a patient with HE are complex and diverse. In clinical practices, early detection and appropriately addressing the risk factors are necessary to improve the outcome and reduce mortality in LC patients with HE.

Author Contributions

Dr. Suzuki Kazuyuki planed and wrote this article. Dr. Kato Akinobu and Dr. Takikawa Yasuhiro actively contributed and checked this article.

Competing Interests

All authors have declared that no competing interests exist.

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