Keywords

Patient Scenario 1

A 35-year-old female with past medical history of compensated alcoholic cirrhosis presented with altered mental status after alcohol binge drinking. On physical exam, her vital signs were stable. She was only oriented to self and had marked jaundice and asterixis. Her laboratory result showed leukocyte count of 15 × 109/L, creatinine of 5.7 mg/dL (with baseline of 1.0 mg/dL), aspartate aminotransferase of 288 U/L, alanine aminotransferase of 119 U/L, alkaline phosphatase of 383 U/L, total bilirubin of 28.6 mg/dL, direct bilirubin of 23.8 mg/dL, and international normalized ratio of 3.1. Urinalysis showed pyuria and urine culture showed Escherichia coli >100,000 cfu/mL. She was diagnosed with hepatic encephalopathy (HE), urinary tract infection, severe alcoholic hepatitis, and acute-on-chronic liver failure.

Discussion

This patient had hepatic encephalopathy in a setting of acute-on-chronic liver failure (ACLF) given that she had acute renal injury as an extrahepatic organ failure. Patients with HE in the context of ACLF had a heightened risk of mortality compared to isolated HE. Thus, early detection of extrahepatic organ failure was vital for risk stratification purposes and to determine the need for organ support. Intensive care unit admission should be considered as she was likely to require renal replacement therapy. In addition, she would require treatment for severe alcoholic hepatitis and urinary tract infection, the precipitating factors for hepatic encephalopathy.

Patient Scenario 2

A 66-year-old female with decompensated nonalcoholic steatohepatitis cirrhosis and chronic kidney disease presented with worsening altered mental status for 2 days. She had been compliant with the maintenance lactulose regimen that had been started after one prior episode of precipitated HE. Her vital sign demonstrated slight tachycardia with heart are of 114/min with normal blood pressure of 145/77 mmHg. Her oxygen saturation is 95% on room air. She was awake but confused and not able to answer any questions. Asterixis was noted. The white blood cell count was 8.5 × 109/L and the creatinine was at her baseline of 1.7 mg/dL. The microscopic urinalysis showed >50 white blood cells/high power field and the urine culture was positive for Escherichia coli.

Discussion

Because the patient did not have any other evidence of extrahepatic organ failure other than hepatic encephalopathy, she was diagnosed with isolated hepatic encephalopathy. Because she had recurrent episode of hepatic encephalopathy while on lactulose, rifaximin was added. In addition, the urinary tract infection which was the precipitating factor was treated.

Patient Scenario 3

A 65-year-old male with decompensated nonalcoholic steatohepatitis cirrhosis, model for end-stage liver disease (MELD) score of 13, was admitted with persistent hepatic encephalopathy. He had multiple previous admissions for episodic overt hepatic encephalopathy and no precipitating factors were identified. His examination was consistent with West Haven Criteria (WHC) Grade 3 HE. He did not respond to lactulose, rifaximin, and zinc therapy. Computed tomography of the abdomen with intravenous contrast demonstrated a large splenorenal shunt.

Discussion

The patient should be considered for splenorenal shunt embolization for persistent HE not responding to medical treatment and relatively low MELD score (MELD <15). Previous studies showed that approximately 45–70% of patients with refractory HE had large portosystemic shunts discovered on evaluation and that the embolization of the portosystemic shunt was a safe and effective treatment. The patient received the embolization of the splenorenal shunt and his hepatic encephalopathy significantly improved.

Introduction

Hepatic encephalopathy (HE) is a major neuropsychiatric abnormality seen in patients with decompensated cirrhosis or portosystemic shunting. The clinical presentation ranges from subtle brain function changes that require neuropsychometric testing for diagnosis to a hepatic coma state. The severity of HE can be graded into covert HE (West Haven criteria grade 0–1) and overt HE (West Haven criteria grade 2–4). Most patients with overt HE will require inpatient management and this will be the focus for this chapter.

Overt HE occurs in approximately 30–45% of patients with cirrhosis and 10–60% of patients with transjugular portosystemic shunt (TIPS) [1,2,3]. In the US Nationwide Inpatient Sample, the national estimate of annual incidence of overt HE admission is 110,000–115,000. The average length of inpatient stay was 8.5 days and the average total inpatient charges were $63,108 per case [4]. Moreover, overt HE is associated with increased risk of mortality in hospitalized patients with cirrhosis independently of the severity of cirrhosis (adjusting for the MELD score) [5] or extrahepatic organ failures [6].

Management of the hospitalized patient with overt HE focuses on correcting the underlying precipitating factors and providing pharmacologic treatment that reduces ammoniagenesis. Most patients will require maintenance medication to prevent recurrence of HE and to prevent hospital readmission. The prevention of HE will be discussed in Chap. 7.

Hepatic Encephalopathy in Acute-on-Chronic Liver Failure

For the past two decades, the concept of acute-on-chronic liver failure (ACLF) has been proposed on the basis that patients with chronic liver disease or cirrhosis who developed acute unexpected hepatic decompensation and extrahepatic organ failure have significant increased risk of short-term mortality [7]. Three different definitions have been proposed from three different regions of the world [8,9,10]. The most current definition by a working group on behalf of the Working Party of the World Gastroenterology Organization is as follows: “ACLF is a syndrome in patients with chronic liver disease with or without previously diagnosed cirrhosis which is characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the international normalized ratio) and one or more extrahepatic organ failures that is associated with increased mortality within a period of 28 days and up to 3 months from onset” [11].

The prevalence of ACLF is difficult to assess given the difference in the ACLF definition. In the European multicenter study, the prevalence among hospitalized cirrhotic patients with acute decompensation was 31% [8]. A study from US Nationwide Inpatient Sample reported ACLF prevalence of 5% among hospitalizations for cirrhosis in 2011 [12]. With the increase in ACLF recognition, there is an emerging concept that differentiates hepatic encephalopathy that occurs in the setting of decompensated cirrhosis from that arising in the context of ACLF.

Isolated Hepatic Encephalopathy

Isolated hepatic encephalopathy occurs in a setting of decompensated cirrhosis without evidence of extrahepatic organ dysfunction. Isolated hepatic encephalopathy seems to occur in older cirrhotic patients who are inactive drinkers. It is not clearly associated with hepatic dysfunction but rather develops in the setting of chronic diuretic use. There is no significant inflammatory reaction. The prognosis is good even in those requiring intensive care unit admission and mechanical ventilation for airway protection [13, 14].

Hepatic Encephalopathy Associated with Acute-on-Chronic Liver Failure

HE associated with ACLF occurs in the setting of extrahepatic organ failures. It seems to occur in young cirrhotic patients who are active drinkers [14]. This type of HE is associated with hepatic dysfunction and bacterial infections. In contrast with isolated hepatic encephalopathy, HE associated with ACLF has a grave prognosis. In addition to hyperammonemia that is observed in both types of HE, the significant inflammatory reaction found in ACLF may explain this prognostic gap [15].

Pathophysiology of Hepatic Encephalopathy in Acute-on-Chronic Liver Failure

Pathophysiology for HE is discussed in detail in Chaps. 2 and 3. In this chapter, we focus on the pathophysiology of HE in the setting of ACLF. Jalan et al. proposed the pathophysiology of ACLF using a four-part model of predisposing event, injury resulting from precipitating event, response to injury, and organ failure (Fig. 6.1) [7, 16]. Predisposition is the underlying chronic liver disease. Injury can be from multiple etiologies, e.g., bacterial infection, alcohol intake, viral hepatitis, reactivation of hepatitis B, gastrointestinal bleeding, drug-induced liver injury, ischemia, infection, or surgery. The inflammatory response is important as suggested by the presence of increased C-reactive protein and an increase in leukocyte count. In the setting of bacterial translocation, lipopolysaccharide and other pathogen-associated molecular patterns (PAMPs) trigger Kupffer cells to release proinflammatory cytokines, namely IL-1, IL-6, and tumor necrosis factor alpha, which induce inflammatory reaction by leukocyte recruitment and oxidative stress. In addition to bacterial translocation, sterile processes such as alcohol, ischemia, or surgery can elicit an inflammatory response by damaging hepatocytes and with subsequent release of damage-associated molecular patterns (DAMPs), Fig. 6.1 [17, 18]. Organ failure is the final step of the pathway. An increase in the number of organ failure is associated with increase in the mortality rate [8].

Fig. 6.1
figure 1

Pathophysiology of ACLF. Asrani et al. 7. PAMP pathogen-associated molecular pattern, SBP spontaneous bacterial peritonitis, TNF tumor necrosis factor, UTI urinary tract infection

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The pathophysiology of HE in ACLF is multifactorial and hyperammonemia and systemic inflammation are important factors [2]. Studies in animal models have shown that induction of hyperammonemia leads to brain edema and the reduction of ammonia level could reduce brain swelling [19]. In addition, reduction in ammonia level prevented brain edema and delayed the development of coma in response to LPS challenge in an animal model [20]. Clinically, HE associated with ACLF may lead to cerebral edema and increased intracranial pressure whereas isolated hepatic encephalopathy typically will not [21]. Cerebral edema has been observed in imaging studies [22] and confirmed by electron microscopic studies in animal models showing astrocyte swelling and collapsed microvessels [23].

Management of Hepatic Encephalopathy in the Hospitalized Patient

General Approach

Early risk stratification to differentiate isolated HE from HE associated with ACLF is necessary (Fig. 6.2). This is due to the significant difference in short-term mortality between these two groups [14]. Prognostic scores including the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score may be utilized to determine the severity of ACLF [8]. If HE associated with ACLF is detected, intensive care unit admission should be considered. Airway protection should be considered in all patients with grades 3–4 HE, particularly those with ACLF, or if there is evolving respiratory failure. Inotropes or vasopressors should be considered to maintain adequate cerebral perfusion.

Fig. 6.2
figure 2

Management of hospitalized patients with hepatic encephalopathy

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In addition to the treatment of HE that is present at hospital admission, there is also a potential benefit from preventing the progression of HE. In a study from 1,560 patients from the North American Consortium for Study of End-stage Liver Disease evaluating hospitalized patients with cirrhosis, the maximum HE grade and not the admission HE grade was found to be prognostic for mortality independently of the extrahepatic organ failures [6].

Direct Treatment at Precipitating Factors

The most common precipitating factors of HE are diuretic use, bacterial infection, and alcohol use [14]. Any identifiable precipitating event should be promptly treated and early antibiotics administration should be considered when infection is suspected.

Specific Treatment

Nonabsorbable Disaccharides

Nonabsorbed disaccharides (e.g., lactulose and lactitol) and nonabsorbable antibiotics (e.g., neomycin and rifaximin) represent the mainstay of specific treatment for HE. Lactulose (b-galactosidofructose) and lactitol (b-galactosidosorbitol) reduce ammonia absorption in the colon by acidification of the colon resulting in the conversion of ammonia to ammonium, shifting the colonic flora from urease- to nonurease-producing bacterial species, and by their cathartic effect. A large meta-analysis in 2004 showed that nonabsorbable disaccharides were superior to placebo. However, when only high-quality trials were included, nonabsorbable disaccharides were found to have no effect on HE [24]. The inconsistent finding in this study is most likely explained by the heterogeneity of HE in previous nonabsorbable disaccharide clinical trials. For example, an overt HE episode may occur in the setting of acute liver failure, acute-on-chronic liver failure, or may be precipitated by a reversible precipitating factor [25]. Although a pivotal trial to prove its effectiveness is lacking, nonabsorbable disaccharides continue to be recommended as the first-line therapy because of decades of clinical experience supporting its effectiveness [26].

Rifaximin

Rifaximin is a rifampicin derivative and is mostly unabsorbed by the intestine. Rifaximin is Food and Drug Administration (FDA) approved only for prevention of recurrent HE based on a large multicenter randomized trial [27]. Interestingly, it was not effective in preventing HE in a setting of a transjugular intrahepatic portosystemic shunt (TIPS) [28]. For treating episodic overt HE, the data suggests that rifaximin has equivalent efficacy compared to nonabsorbable disaccharides [29,30,31]. Although rifaximin is better tolerated in most studies compared to lactulose, the question of using rifaximin as monotherapy for overt HE remains unanswered given the small number of trials. The use of rifaximin in addition to lactulose for overt HE is supported by a randomized controlled trial (RCT) that found a higher proportion of HE reversal in rifaximin and lactulose group compared to lactulose and placebo group (76% vs. 50.8%, P < 0.004) in patients with overt HE [32]. This study also reported a significant decrease in mortality in the rifaximin and lactulose group compared to lactulose and placebo group (23.8% vs. 49.1%, P < 0.05). However, the generalizability of this finding is limited because of the higher-than-expected mortality rate observed in the control arm (49.1%) when compared to the reported inpatient mortality due to HE in the United States (15%) [4, 33].

Neomycin, Metronidazole, and Vancomycin

Neomycin is a poorly absorbed aminoglycoside. It is used to decrease gut bacteria-derived ammonia and it is approved by FDA for use in episodic overt HE but not chronic HE. Earlier RCTs did not find difference in its efficacy when compared to lactulose [34] or placebo [35]. Neomycin was widely used in the past. However, the evidence for neomycin in episodic overt HE is weak, and its use is complicated by the risk of ototoxicity and nephrotoxicity. There are small trials supporting the short-term use of metronidazole and vancomycin [36, 37]. However, the risk of neurotoxicity and vancomycin-resistant enterococci colonization limit its long-term use.

Zinc

Zinc is important in ammonia reduction pathways both for ammonia conversion to urea in liver and for ammonia conversion to glutamine in skeletal muscle. Zinc deficiency is very common in cirrhosis. Zinc supplement has been shown to increase the speed of urea formation from ammonia and amino acid [38]. Data to support zinc use are very limited and the results are mixed. Furthermore, previous RCTs (n = 15–90) included chronic HE in the study, thus limiting the generalizability in episodic HE setting [39,40,41]. The most recent RCT of 79 patients with overt HE showed that zinc supplement was effective in deceasing HE grade and blood ammonia levels [42]. This is the only recent study with evidence to support the use of zinc in HE. The optimal dose of zinc supplement remains unknown.

l-Ornithine l-Aspartate

l-Ornithine l-aspartate (LOLA) is not available in the United States, but it is frequently used for HE treatment outside the United States. The mechanism of LOLA is to increase ammonia reduction in both liver and skeletal muscle. In the liver, LOLA can increase urea formation by stimulating ornithine transcarbamolyase and carbamoyl phosphate synthetase. In skeletal muscle, LOLA can stimulate glutamine synthesis. Data to support the use of LOLA are mainly in the setting of chronic HE and the efficacy of LOLA in episodic overt HE is not validated [43, 44]. One study from Pakistan evaluated LOLA as adjunctive treatment versus placebo in patients with episodic overt HE and found higher improvement rate of HE grade 2 in LOLA compared to placebo group [45].

Branched-Chain Amino Acids

Branched-chain amino acids (BCAAs) consist of valine, leucine, and isoleucine. In skeletal muscle, BCAAs are the substrate for glutamate which is used to synthesize glutamine in ammonia detoxification. The decrease in BCAA level and the increase in aromatic acids have been observed in cirrhosis and hepatic encephalopathy [46]. Studies have evaluated the effects of BCAAs, either intravenously or orally. For cirrhotic patients, two RCTs found that BCAAs improved important composite end points of death/hospitalization metrics in one study [47] and hepatic failure, variceal bleeding, hepatocellular carcinoma, and mortality in a second study [48]. In the recent meta-analysis of 16 RCTs with 827 patients with hepatic encephalopathy [49], BCAAs had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63–0.92) but there was no difference in mortality (RR 0.88, 95% CI 0.69–1.11). Currently, the European Society for Parenteral and Enteral Nutrition (ESPEN) guideline provides a grade A recommendation for the use of BCAA-enriched enteral formula in patients with hepatic encephalopathy who require enteral nutrition [50]. For parenteral nutrition, ESPEN guideline provides a grade A recommendation for the use of BCAAs in hepatic encephalopathy grades 3 and 4 [51].

Percutaneous Embolization of Large Portosystemic Shunts

Patients with large portosystemic shunts usually present with persistent HE resulting in episodic hospital admission and coma. In some patients with HE, large portosystemic shunts are accessible to embolization. Multiple retrospective studies have reported the efficacy and safety of the embolization of large portosystemic shunts in refractory HE [52,53,54,55]. In a European multicenter study (n = 37), 59% and 49% were free of HE at 100 days and 2 years, respectively. The HE recurrence was less in those with MELD score of 11 or less [52]. In a US series (n = 20), 100% (20/20) achieved immediate improvement and durable benefit was achieved in 92% (11/12) at 6–12 months after the procedure [55]. The overall procedural complication rate was 10%. One patient had bacterial cholangitis and another patient required readmission from pain at the puncture site. Importantly, 35% (7/20) developed evidence of worsening portal hypertension at some point within 12-month follow-up time [55]. In a Korean case-control series (n = 17), the 2-year HE recurrence rate was lower in the embolization group (40% vs. 80%, P = 0.02) but there was no difference in the 2-year overall survival rates (65% vs. 53%, P = 0.98). In addition, they observed an improvement in overall survival in the embolization group (100% vs. 60%, P = 0.03) in the subgroup analysis of only patients without hepatocellular carcinoma and with MELD score < 15 [54].

Molecular Adsorbent Recirculating System

Albumin has been shown to be a multifunctional protein with antioxidant, immunomodulatory, and detoxification functions [56]. Molecular adsorbent recirculating system (MARS) was introduced in 1999 and is based on the concept of albumin dialysis. MARS was designed to remove protein- and albumin-bound toxins, such as bilirubin, bile acids, nitrous oxide, and endogenous benzodiazepines. In addition, MARS also removes non-protein-bound ammonia that accumulates in liver failure [57]. Although there was no survival benefit observed in previous trials, MARS did show a beneficial effect on HE treatment. In a study designed specifically to evaluate the effect of MARS on HE, 70 patients with grade 3–4 HE were enrolled. The MARS-treated patients were found to have a higher proportion of patients with a 2-grade improvement in HE when compared to standard treatment alone. The MARS-treated patients were also found to have more rapid improvement [58]. The RELIEF trial enrolled 189 patients with ACLF and showed higher proportion of patients with HE grade 3 or 4 improvement to HE grade 0 or 1 in MARS-treated patients (15 of 24; 62.5%) compared with standard therapy (13 of 34; 38.2%), which trended toward significance (P = 0.07) [59]. In a small study, MARS had a statistically significant effect on improvement of HE in nine patients with alcoholic hepatitis and HE [60]. The FDA initially approved the use of MARS for grade 3–4 HE related to decompensation of chronic liver disease but has since retracted its approval. In summary, MARS is a reasonable option for patients with severe HE refractory to standard medical therapy.

Liver Transplantation

Liver transplantation (LT) is the most definitive treatment option for HE. Therefore, cirrhotic patients with HE and MELD ≥15 should be evaluated for liver transplantation. It is important to distinguish other conditions such as neurodegenerative diseases like Alzheimer’s, and Wernicke’s encephalopathy, which would not improve after liver transplant. Although HE should improve after LT, pretransplant episodes of HE are associated with impair of posttransplant neurological outcome [61]. Data are limited for liver transplant outcomes in patients with HE in the setting of ACLF. Although posttransplant survival rates for ACLF have been reported to be 80–90%, long-term outcome is scarce [10]. Patients with ACLF usually have high MELD scores but they may have LT contraindication such as active infection, and hemodynamic instability with the need for inotropes.

With the current organ allocation system using the MELDNa score, HE does not result in a higher prioritization for LT. However, there are cases with severe HE who would benefit from LT, particularly in the context of ACLF. A new scoring system, chronic liver failure consortium ACLF score (CLIF-C ACLFs), has been developed and validated in cirrhotic patients with ACLF. This score will need further evaluation to determine whether it can accurately discriminate or rank individuals according to their mortality risk, before it could be utilized for organ allocation in ACLF setting [62].