Hepatic Encephalopathy Challenges, Burden, and Diagnostic and Therapeutic Approach
Beshoy Yanny, MDa,*, Adam Winters, MDa, Sandra Boutrosb, Sammy Saab, MD, MPHa,b,c
KEYWORDS
Hepatic encephalopathy Liver cirrhosis Portal hypertension Refractory hepatic encephalopathy
KEY POINTS
Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patientswith cirrhosis.
The impact of HE on the health care system is similarly profound.
The number of hospital admissions for HE has increased in the last 10-year period.
Patients with HE are also at high risk of hospital readmission.
HE is a huge burden to the patients, care givers, and the health care system.
INTRODUCTION
Hepatic encephalopathy (HE) is one of the most common and debilitating complications of liver disease. It is a reversible neurologic condition caused by the failure of the liver to detoxify blood in the portal circulation, either because of an insufficiency of the liver or shunting between the portal and systemic vasculature. Along with variceal hemorrhage, ascites, and jaundice, HE is a manifestation of hepatic decompensation in cirrhotic patients. In addition to its broad impact on the health of cirrhotic patients, HE presents a significant, increasing burden to the health care system, highlighting the need for better strategies designed to improve the diagnosis of subclinical disease and subsequent treatment.
Symptoms of HE are wide-ranging, although often subtle, and typically reflect the severity of underlying disease. The most recent joint guidelines from the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) suggest a universal definition of HE: “a brain dysfunction caused by liver insufficiency and/or [portosystemic shunting]; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma.”1 Given the spectrum of clinical manifestations, these guidelines have introduced the terms covert HE (CHE) and overt HE (OHE) to encompass the continuum of disease. OHE represents disease that is readily obvious to providers and family members, comprising symptoms such as confusion and behavioral changes, whereas CHE is subtle and typically requires office-based screening to reliably detect.
EPIDEMIOLOGY AND BURDEN OF DISEASE
HE is a common disorder of cirrhosis and has wide-ranging effects on patients, their caregivers, and the health care system. Because of its often overlapping clinical presentation, the reported epidemiology of HE varies greatly. In 2 studies of patients with alcohol-related disease, the prevalence of OHE at the diagnosis of cirrhosis was between 6% and 13%.2,3 In decompensated cirrhosis, OHE is estimated to occur in 16% to 21% of patients at the time of diagnosis.4,5 CHE has been detected in 20% to 53% of cirrhotic patients using various office-based diagnostic tests.6–10 With regard to patients undergoing transjugular intrahepatic portosystemic shunting, 1-year incidence of OHE is between 27% and 53%.11,12 Overall, patients’ risk of recurrence of OHE increases with each subsequent episode.13
HE is an important contributor to mortality in cirrhotic patients. In a study of 111 cirrhotic patients, survival rates at 1 and 3 years for patients who developed HE were 42% and 23%, respectively, in patients who developed grade 3 and 4 HE14 Patients on the waitlist for liver transplant with more advanced HE (grades 3 and 4) have significantly higher mortalities (66% greater risk of death) than those without HE or with more mild disease.15 In a study of more than 10,000 patients waitlisted for liver transplant, patients with severe HE (defined as West Haven criteria [WHC] grade 3 to 4) and a Model for End-stage Liver Disease score (MELD) greater than or equal to 30 had a 58% higher 90-day waitlist mortality than those with a MELD greater than or equal to 30 without severe HE.16 Further, they found that patients with a MELD of 30 to 34 and severe HE (defined as WHC grade 3 to 4) had a similar 90day mortality (71.1%) to patients with MELD greater than or equal to 35 without severe HE, implicating HE as an important, independent driver of mortality in patients awaiting liver transplant.
The effects of HE encompass not only the patients’ physical health but permeates into the psychological, financial, and personal facets of their lives.17 For example, the presence of prior HE has been shown to drastically lower rates of employment (87.5% vs 19%).17 Further, HE imposes a greater burden on caregivers compared with cirrhotic patients without a history of HE. Caregivers of patients with a prior diagnosis of HE have significantly higher scores on both the Perceived Caregiver Burden scale and Zarit Burden Interview test than those without.17 Caregiver scores correlated with the degree of cognitive impairment experienced by the patients.
Despite the importance of the role of the caregiver on the diagnosis and routine care of patients with HE, they may have poor insight into the disease. In a real-world questionnaire-based study of patients with previously diagnosed HE and their caretakers, only 48% of caretakers were aware of a prior diagnosis of HE and, more concerningly, only 6% were aware that their relative was on treatment.18
The impact of HE on the health care system is similarly profound. The number of hospital admissions for HE increased in the 10-year period between 2004 and 2014: 95,232 to 156,205.19 Costs per admission for HE are also increasing. Between the years 2005 and 2009, total inpatient charges increased from $46,663 to $63,108 per case.20 Total charges during that same period increased from $4.677 billion to more than $7 billion. Average length of stay also increased. Patients with HE are also at high risk of hospital readmission; 38.4% were readmitted within 30 days, and an additional 13.6% reentered the hospital within 31 to 90 days of their last stay.20 In a study of 1 health care system in Minnesota, HE was the most common reason for readmission of cirrhotic patients to their community centers.21 In a population-based study of cirrhotic patients with inpatient admissions in 6 states, HE was the complication of liver disease most strongly associated with 30-day and 90-day readmission rates.22 Another study designed to evaluate readmission rates in cirrhotic patients found HE to be the most common cause of preventable readmissions.23
PATHOPHYSIOLOGY
The pathophysiology precipitating HE is complex and incompletely understood. The interplay of increased concentrations of ammonia, alterations in amino acid metabolism, and inflammation are central to the current understanding of the disease.24 Hyperammonemia in particular forms the primary target of many current therapies.
Most ammonia synthesis occurs in the intestine, with some contribution from muscle and kidney.25 Amino acids, notably glutamine, from dietary proteins are metabolized to ammonia in the colon. Ammonia-rich blood is directed through the portal circulation, where it is metabolized by the liver and predominantly cleared by the kidneys.24,26 When the liver experiences injury, hepatic metabolism of ammonia is impaired and the portal hypertension resulting from chronic liver disease causes a shunting of ammonia into the systemic circulation.27 At high concentrations, ammonia crosses the blood-brain barrier, where it is taken up by astrocytes, the primary driver of neurologic injury in HE.24 Ammonia is metabolized with glutamate to form glutamine precipitating the formation of reactive oxygen species, which cause inflammation. Second, high concentrations of glutamine cause an osmotic gradient leading to astrocyte swelling and cerebral edema and, thus, neuronal dysfunction.
Other pathogenic mechanisms contributing to HE have been described. In both acute liver failure (ALF) and cirrhosis, alterations are seen in the permeability of the blood-brain barrier, allowing more entry of, in part, glutamate, causing additional formation of toxic glutamine (discussed earlier).25 Alterations in the production and use of neurotransmitters, specifically g-aminobutyric acid and serotonin, are also thought to play a role in phenomena such as alterations in the sleep-wake cycle.28
CLASSIFICATION AND GRADING
HE is characterized by the cause of underlying disease, severity of each episode, time course of each episode, and whether there is a precipitating cause.1,29 There are 3 defined types of HE that are based on the cause of disease. Type A encephalopathy occurs in the setting of ALF. Type B refers to encephalopathy in the setting of portalsystemic shunting without organic liver disease. Type C is HE in the presence of cirrhosis.
HE can then be subdivided based on severity using the WHC16 (Table 1). The WHC divides each episode into 4 separate grades. Grade 1 is characterized by a trivial lack of awareness, euphoria or anxiety, shortened attention span, impairment in simple arithmetic, and an altered sleep rhythm. Grade 2 defines episodes featuring lethargy or apathy, disorientation to time, obvious personality changes, inappropriate behavior, dyspraxia, and asterixis. Patients with grade 3 are somnolent or semistuporous, confused, and grossly disoriented, but they are responsive to stimuli. Grade 4 is reserved for comatose patients who do not respond to any stimuli, including pain. A fifth category, minimal HE (MHE), is only detected by psychomotor or neurophysiologic testing without overt clinical symptoms. Together with grade 1, MHE is considered CHE, whereas grades 2 to 4 are consistent with OHE.
HE can further be subdivided based on time course: episodic HE, recurrent HE (episodes occurring within 6 months of each other), or persistent HE (ongoing behavioral alterations that are exacerbated by bouts of OHE). In addition, each HE episode can be nonprecipitated or precipitated (ie, in the setting of concomitant infection or gastrointestinal bleeding).
DIAGNOSIS
The presentation of HE is often nonspecific and shares clinical features with many other disorders. Careful history and physical examination are essential to diagnosis. Care should be taken to assess for the presence of alternative causes as well as other disorders potentiating encephalopathy, such as uremia, hyponatremia, diabetes mellitus, and sepsis.30–42 Owing to the spectrum of presentations that comprises the continuum of HE, diagnostic testing differs depending on the severity of symptoms.
DIAGNOSIS OF COVERT HEPATIC ENCEPHALOPATHY
CHE (ie, patients with MHE or WHC grade 1 encephalopathy) can be difficult to diagnose given the relative lack of clinically appreciable symptoms. Detecting MHE remains important because of the psychiatric and financial consequences it may incur. For example, patients with cirrhosis and MHE are at higher risk of falls than cirrhotic patients without MHE, leading to increased health care use, including hospitalization.43 In addition, it serves as an important intervention point for providers to counsel patients and family members or caretakers about HE.30 One commonly used tool for diagnosing MHE is the Psychometric Hepatic Encephalopathy Score (PHES). It comprises the sum of 5 subtests designed to detect cognitive impairment: number connection tests A and B, a digit symbol test, serial dotting test, and a line tracing test.44 Other modalities have been studied for use in CHE, notable the Stroop test, which has been shown to have excellent sensitivity (80%) compared with the PHES.45 The Stroop test is important in that it is available as a free downloadable smartphone application (EncephalApp Stroop Test), which has shown similarly good sensitivity in detecting MHE.45,46 This kind of readily available, inexpensive screening test is an important tool in the diagnostic armamentarium, allowing patients and providers to detect HE in the early stages.
DIAGNOSIS OF OVERT HEPATIC ENCEPHALOPATHY
The diagnosis of OHE is clinical and is made based on 3 grades of the WHC (2–4), as discussed earlier.30 A high index of suspicion for precipitating events, such as infection, kidney injury, or infection, is an essential component of diagnosis and subsequent treatment. Other causes of encephalopathy should be ruled out, such as stroke or electrolyte abnormalities. Clinical presentation varies, although the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) defines the onset of disorientation or asterixis as the characteristics defining OHE.1,47–55 Asterixis is not specific to HE, because it may occur in other metabolic abnormalities, such as uremia and hypercarbia.56,57
THE ROLE OF AMMONIA
Although high levels of serum ammonia contribute to the pathophysiology of HE, there is little diagnostic or prognostic value in measuring ammonia in patients with chronic liver disease.1 However, patients who show signs of OHE and have normal ammonia concentrations should prompt consideration of alternative diagnoses.
In contrast, in patients with ALF there is evidence that plasma ammonia level does correlate with the severity of HE.58,59 Increased arterial ammonia levels in ALF are also an independent risk factor for increased intracranial pressure and brain herniation.31,35,55,59–68 Further, significantly increased ammonia levels on admission may be predictive of mortality in patients presenting with ALF.69 Increased blood ammonia level alone does not add any diagnostic, staging, or prognostic value for HE in patients with CLD. A normal value calls for diagnostic reevaluation (grade II-3, A, 1).31 Ammonia level greater than 200 mmol/L is predictive of poor outcome in ALF.2 Ammonia levels may be altered by inappropriate collection. Appropriate ammonia measurement requires an arterial blood sample that is immediately sent to the laboratory on ice and processed.31,60 Venous ammonia levels may not correlate well with HE.
REFRACTORY HEPATIC ENCEPHALOPATHY
Refractory HE is often used to describe individuals with severe HE that is not responsive to the widely used and recommended medication regimens.31,59,60 Studies defining refractory HE are scarce and there is no uniform agreement on treatment duration before diagnosing a patient with refractory HE. Studies have previously coined the diagnosis of refractory HE after 24 to 48 hours of failed lactulose with and without the use of rifaximin therapy in the absence of other precipitating factors.13,31,32,60,69,70 A proposed diagnostic and therapeutic approach in patients with HE includes identifying any precipitating events in patients with grade 3 to 4 HE, including infection, gastrointestinal bleeding, medications, dehydrations, electrolyte abnormalities, and hypoglycemia, and reversing any precipitating events in addition to lactulose therapy. If there is no improvement in 24 hours, ensure that the patient has an adequate stool output and reevaluate the diagnosis to verify that the patient does have HE.31,59,60 Strongly consider head imaging with computed tomography or MRI. If work-up is negative and HE is confirmed, add rifaximin if the patient is not already taking rifaximin or neomycin. Rifaximin is preferred to the side effect profile of neomycin (discussed later). If there is no improvement, the diagnosis of refractory HE can be made. If the patient has a MELD of less than 12 to 15, evaluate for a large portosystemic shunt such as a splenorenal shunt; if present, discuss embolization with interventional radiology and embolize if feasible. If there is no improvement, other rescue therapies can be used, including zinc, L-ornithine L-aspartate (LOLA), branched-chain amino acids (BCAAs), and sodium benzoate, and also consider molecular adsorbent recirculating system (MARS) if available. All patients who recover should be on maintenance therapy with lactulose and rifaximin unless otherwise contraindicated.31,59,60 If the MELD score is high enough based on the United Network for Organ Sharing (UNOS) region, refer for evaluation for for liver transplant and list. On rare occasions, a MELD exception may be obtained with approval of the transplant committee and UNOS. Fig. 1 outlines the diagnostic approach and management of refractory HE.
TREATMENT
Overt Hepatic Encephalopathy
Most patients require maintenance medications for OHE as secondary prophylaxis on hospital discharge after an episode of HE.31,60,69 The most widely used regimen during hospital inpatient admission uses the nonabsorbable disaccharide lactulose in addition to rifaximin in some cases.31,71–79 Treatment modalities, mechanism of action, and side effects are summarized in Table 2.
Nonabsorbable disaccharides
Lactulose (b-galactosidofructose) and lactitol (b-galactosidosorbitol) reduce ammonia levels by acidification of the colon with resultant conversion of ammonia to ammonium, shifting the colonic flora from urease-producing to non–urease-producing bacterial species, and by its cathartic effect. Clinical guidelines recommend lactulose or lactitol as first-line therapy because of their proven efficacy over the years. The results of a large meta-analysis in 2004 showed that nonabsorbable disaccharides were superior to placebo and were associated with beneficial effects on HE, mortality, and serious adverse events.31,40,60 Nonabsorbable disaccharides are administered orally, by mouth or through a nasogastric tube, or via retention enemas1,2 initiated at 25 mL every 1 to 2 hours to achieve greater than or equal to 2 soft or loose stools per day.31
Rifaximin
Rifaximin a poorly absorbed antibiotic that works by altering the gut microbiota and theoretically decreasing the numbers of ammonia-producing microorganisms. Rifaximin is approved by the US Food and Drug Administration (FDA) for secondary prophylaxis of HE. Secondary prophylaxis is important and appropriate management to reduce the risk of another recurrence in all patients recovering from an episode of OHE. AASLD/EASL recommend secondary prophylaxis with rifaximin to reduce the risk of another OHE recurrence while on lactulose.34 A 2016 consensus statement on management of HE published in the European Journal of Gastroenterology & Hepatology additionally supports the AASLD/EASL guidelines, highlighting that prompt initiation of appropriate management can reduce the duration of admission and reduce the risk of subsequent readmission.34,69,70 Studies to date are still unable to elucidate the role of rifaximin monotherapy for OHE.31,42,48–51,82–94 A few clinical trials show that rifaximin is as efficacious as lactulose in the treatment of OHE; however, those clinical trials have not been replicated to date and there is a lack of real-world data.31,60 The increased use of rifaximin for episodic HE is supported by 1 clinical trial to date that compared lactulose plus placebo with lactulose plus rifaximin in patients hospitalized for HE and showed that 80% of patients had severe HE, grade III or IV, and 70% were Child class C, with the remainder Child class B.31,33,35,82 Patients in the lactulose and rifaximin group had a higher proportion of complete reversal of HE (76% vs 50.8%; P<.004), shorter hospital stays, and a striking improvement in 10day mortality (49.1% vs 23.8%; P<.05).31,82 The very high mortality in the lactulose plus placebo arm raises some concerns about the validity of this study, which should be repeated in a larger number of patients at multiple sites. Clinical guidelines recommend rifaximin as prophylactic therapy for secondary prevention of HE.
Neomycin
Neomycin should be avoided in the routine treatment of HE. However, it may be considered in select patients with refractory HE. Neomycin is a poorly absorbed aminoglycoside used to decrease gut bacteria–derived ammonia. It is FDA approved for use in acute(episodic), OHE but not chronic HE. Real-world studies do not show much efficacy in the use of neomycin. In general, the evidence for neomycin in episodic OHE is weak, and its use is complicated by the risk of ototoxicity and nephrotoxicity. Although FDA approved, the decreased efficacy and high side effect profile compared with other therapies limit its clinical utility.31,32,60,69,70,80,81 The risk of side effects hinders this agent’s use in the armamentarium for HE.31,32,60,69,70,80,81
Zinc
Zinc is considered nonstandard therapy for HE, but it may be considered in patients not responsive to initial therapy trials. Ammonia is converted to urea by ornithyl transcarbamylase in the liver and is combined with glutamate by glutamine synthetase in the skeletal muscle to form glutamine.31 Both ammonia-reduction pathways are impaired by zinc deficiency. Treatment with zinc has been shown to enhance the formation of urea from ammonia and amino acids. Studies show that zinc improved HE in 54% of patients with HE grade I to II that was previously refractory to standard therapy. Overall, there are insufficient data to define the optimal dose of zinc; however, the most frequently used dose was noted to be in zinc sulfate form at 600 mg/ d.31,32,60,69,70,80–82,95,96 Zinc is fairly well tolerated, with the rare side effects of dyspepsia and copper deficiency (with chronic, high-dose use), and it can decrease the effectiveness of ciprofloxacin if taken at the same time, which may pose a problem for patients undergoing spontaneous bacterial peritonitis prophylaxis with ciprofloxacin.31,96
L-Ornithine L-aspartate
LOLA is a compound salt that stimulates ornithine transcarbamoylase and carbamoyl phosphate synthetase, and is a substrate for the formation of urea. LOLA also works by stimulating glutamine synthesis in the skeletal muscle and consequently decreasing ammonia levels. The data for the use of this medication are scarce but some small randomized controlled trials show that patients with grade II HE or greater had improvement in HE grade on standard medical therapy (SMT) plus LOLA (79%) versus SMT plus placebo (55%), which was significant (P 5 .019).31,33
Sodium benzoate
Small studies show that sodium benzoate may be effective in a select group of patients with HE. Sodium benzoate is thought to be a metabolically active agent in which benzoate is first conjugated by coenzyme A to form benzoyl coenzyme A, which then conjugates with glycine in liver and kidney mitochondria to form hippurate (hippuric acid, N-benzoylglycine), which, in turn, is rapidly excreted by the kidneys via glomerular filtration and tubular secretion.12,58,59 One mole of hippurate contains 1 mol of waste nitrogen. Thus, 1 mol of nitrogen is removed per mole of benzoate when it is conjugated with glycine (one-half as much nitrogen as is excreted in urea).31 The data for the use of sodium benzoate are scarce to date. The largest study evaluating the effectiveness of sodium benzoate versus lactulose was a prospective, randomized, double-blind study involving 74 consecutive patients with cirrhosis or surgical portosystemic anastomosis and HE of fewer than 7 days’ duration.70 Recovery was achieved in 80% of patients receiving sodium benzoate after lactulose failure. The limitation of this study is that the number of participants was 74 patients.
Branched-chain amino acids
BCAAs have been previously used as salvage therapy. In theory, the plasma amino acid profile in patients with cirrhosis is altered with a decrease in BCAAs and increase in aromatic amino acids. The BCAAs are a source of glutamate, which helps to metabolize ammonia in skeletal muscle, therefore decreasing systemic ammonia waste. Two randomized controlled trials showed that BCAAs improved important composite end points of death/hospitalization metrics (in 1 study) and hepatic failure, variceal bleeding, HCC, and mortality.44,45 At present, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommend use of 1.2 g/kg/d of protein for compensated cirrhosis, and 1.5 g/kg/d in decompensated cirrhosis. This recommendation was based on the results of a randomized controlled trial of a normal protein diet (1.2 g/kg/d) versus a restricted diet showing no effect on the outcome of episodic HE, but increased muscle breakdown in the low protein diet group.56
Molecular adsorbent recirculating system
MARS is based on the concept of albumin dialysis. This system was designed to remove protein/albumin-bound toxins such as bilirubin, bile acids, nitrous oxide, and endogenous benzodiazepines, and it also removes the non–protein-bound ammonia that accumulates in liver failure.31 One of the largest trials for the MARS system (RELIEF trial) enrolled 189 patients with acute-on-chronic liver failure and evaluated MARS plus SMT versus SMT alone, on the primary end points of 28-day and 90-day liver transplant–free survival.31,34 Survival end points were not met, but safety was established. There was a higher proportion of patients with MELD greater than 20 (78.9% vs 69.7%; P 5 .16) and Spontaneous bacterial Peritonitis (14.4% vs 6.7%; P 5 .94) at baseline in the MARS treatment group.31,34 The proportion of patients with HE grade III to IV HE improvement to HE grade 0 to I was higher in MARStreated patients (15 out of 24; 62.5%) compared with SMT (13 out of 34; 38.2%) which trended toward statistical significance (P 5 .07).31
Shunt embolization
Large portosystemic shunts cause escape of ammonia-rich blood through the shunt to the systemic circulation without liver detoxification, therefore causing HE or worsening existing HE Therefore, embolization of large shunts may be an option for a select group of patients with refractory HE. Two large retrospective series have been published showing the efficacy and safety of embolization of large portosystemic shunts in medically refractory HE. In a European multicenter cohort study (n 5 37), 59% of patients were free of HE within 100 days and 48% were HE free over an average of 2 years after embolization.58 The median MELD in both studies was 13.31,35 Logistic regression performed in the European study suggested that patients with MELD greater than 11 were at risk of HE recurrence after shunt embolization.31,35
There are emerging data on the techniques, safety, and efficacy of this modality, but more data are needed before solidifying the role of this treatment in the management paradigm. Some series have reported an increased risk of portal hypertensive bleeding after embolization of large shunts, whereas others have suggested poor outcomes with mortality within 3 months.34 In the series with high mortality, it was postulated that these outcomes were related to candidate selection because patients undergoing embolization had Child-Pugh class C cirrhosis. The ideal candidates for shunt embolization are currently not well defined and must be highly selected.31–35,60,69,70,80–82,95,96
SUMMARY
HE poses a large burden on the patients and the health care system because of the high costs associated with admissions, work-up needed to reach the diagnosis, and high rate of readmission. Patient L-Ornithine L-aspartate and family education is a key component in early recognition, treatment, and prevention of hospital admission. Despite the best efforts of health care professionals, HE remains a devastating complication of liver cirrhosis and portal hypertension. Larger multicenter studies are needed to reach a consensus on the approach to making the diagnosis, defining refractory HE, and management.
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