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Considerations for the Cost-Effective Management of Hepatic Encephalopathy
Steven L. Flamm, MD

Considerations for the Cost-Effective Management of Hepatic Encephalopathy

Steven L. Flamm, MD
Hepatic encephalopathy (HE) is a neuropsychiatric complication commonly associated with liver disease, namely cirrhosis. The inability of the liver to metabolize ammonia results in a buildup of ammonia, which can cross the blood–brain barrier and cause significant neurocognitive impairment. Up to 80% of patients with cirrhosis will experience HE and a large proportion of these patients are at high risk of recurrent HE. There are several factors to consider when developing a cost-effective approach to managing HE, such as patient compliance, the adverse event (AE) profile of drug therapy, efficacy of drug therapy, and relative cost–benefits of drug therapy. Pharmacologic agents used for HE treatment and prevention are commonly associated with gastrointestinal AEs, namely diarrhea. While these AEs are mild in nature, they can be bothersome and lead to patient noncompliance, which increases the patient’s risk of HE. Furthermore, the complex dosing schedule and self-titration requirement of lactulose, a first-line agent, can be confusing to a patient. A patient’s noncompliance with self-titration may result in underuse, increasing the patient’s risk of HE, or overuse, increasing the patient’s risk of severe AEs. HE imposes a significant economic burden to the patient, patients’ caregivers, healthcare systems, and society. HE not only negatively impacts a patient’s morbidity and mortality, but also impacts the patient’s psychological and social functioning and overall quality of life. HE can impact the patient’s ability to work, resulting in reduced productivity and lost wages. A patient with HE may require hospitalization, which accounts for a substantial proportion of costs associated with HE. Given the social and financial burden of HE, cost-effective management of HE is crucial. Early prevention is important to minimize the societal and economic costs associated with HE.
Am J Manag Care. 2018;24:-S0
Hepatic encephalopathy (HE) is a neuropsychiatric condition that is usually associated with acute or chronic liver disease. The overall prevalence of HE among patients admitted to the hospital is approximately 0.3% in the United States, but the incidence and prevalence are much higher in some patient populations, such as those with cirrhosis.1 Cirrhosis is the most common cause of HE. In an analysis of National Health And Nutrition Examination Survey data from 1999 and 2010, the estimated prevalence of cirrhosis was 0.27% in American adults, corresponding to more than 630,000 adults.2  However, this may be a large underestimate of the affected population as 69% of cirrhotic cases are undiagnosed.2 As many as 80% of patients with cirrhosis will experience some form of HE during their lifetime, with an estimated nationwide incidence of 115,814 affected patients in 2009.1,3,4 HE poses a substantial economic burden; factors contributing to the total cost of HE include medication cost, morbidity and mortality, quality of life, cost of treatment,  marketing, and research and development. Over the last 2 decades, hospitalization costs associated with HE have been rapidly increasing. From 1994 to 2003, hospitalization costs associated with HE totaled $5.9 billion, while hospitalization costs in 2003 alone totaled $1.3 billion.5 HE-related hospitalization costs have continued to rise; these costs escalated from $4.68 billion in 2005 to $7.25 billion in 2009.1

Classification

HE is classified into types A, B, and C based on the etiology. Type A HE is secondary to acute liver failure; Type B is associated with portosystemic bypass without liver disease; and type C is secondary to chronic liver disease.3 Clinical severity of HE is graded by the West Haven Criteria (Grades I through IV) (Table 13) and neurocognitive impairment is graded by the Spectrum of Neuro-Cognitive Impairment in Cirrhosis (SONIC).3 HE can be broadly categorized as covert hepatic encephalopathy (CHE), which includes subclinical or minimal HE (MHE) and grade I HE, or the more severe overt hepatic encephalopathy (OHE), which encompasses grades II through IV HE. Patients with HE may experience episodic bouts, developing over a short time period and exerting sporadic effects, or persistent HE, impairing daily function.6

Risk Factors

Several risk factors and predictive factors are associated with the development of HE. Among patients with cirrhosis, between 20% and 80% will experience CHE and 30% will experience OHE during their course of disease.3,4 Moreover, OHE is present in approximately 14% of all patients at the time of cirrhosis diagnosis; between 16% and 21% of patients diagnosed with decompensated cirrhosis and between 10% and 50% of patients with a transjugular intrahepatic portosystemic shunt (TIPS) will have OHE at the time of diagnosis.3 Other risk factors associated with OHE include diabetes and hepatitis C infection, as well as complications of cirrhosis including CHE, infection, variceal bleeding, and ascites.3

Clinical Presentation

The clinical presentation of HE varies widely by disease severity and neurocognitive impairment. In MHE, patients might not have obvious clinical changes but instead may have abnormal psychometric tests indicating mild neurocognitive decline. Grade I HE is marked by subtle behavioral changes, such as sleep disturbances, inattention, and moodiness. Upon progressing to OHE, patients may exhibit drastic personality changes, irritability, motor impairment, speech slowness, and excessive daytime sleepiness.3,7,8

OHE has a high risk of recurrence within a short time period, even if the patient has mild symptoms or is receiving treatment. Within 1 year of an OHE episode, patients have a 40% cumulative risk of another recurrence. Despite treatment with lactulose, patients who have had recurrent episodes of OHE have a 40% risk of recurrence within 6 months. For patients with mild cognitive dysfunction, approximately 1 episode of OHE will occur for every 3 years of survival.3 With this degree of recurrence, cost-effective management becomes imperative.

Pathogenesis

Under normal physiologic conditions, nitrogen compounds are typically derived from the gut and transported via portal circulation to the liver, where they then enter the urea cycle. The end product of ammonia metabolism is urea, which is excreted through urine. In advanced liver disease, damaged hepatocytes and portosystemic shunts are unable to properly metabolize and excrete nitrogen compounds, leading to a buildup of ammonia in extrahepatic tissues. Ammonia crosses the blood–brain barrier following the increased systemic concentration and is metabolized by glutamine synthetase in astrocytes, which causes morphologic abnormalities, such as astrocyte swelling.7

Furthermore, to adequately treat HE, the following provocative factors must be identified and corrected: increased nitrogen load (eg, gastrointestinal bleeding, renal failure), metabolic disorders (eg, hyponatremia, hypokalemia, dehydration), medications (eg, benzodiazepines, diuretics), bacterial infections, and TIPS.9 Beyond ammonia dysregulation, other pathologic mechanisms of HE include blood–brain barrier disruption and neurotransmission abnormalities in GABAergic and benzodiazepine pathways.9

The Impact of HE on Clinical Outcomes

Patients who develop HE are at risk for poor clinical outcomes and reduced survival. Among patients with decompensated cirrhosis, the median survival is 2 years for a patient with OHE compared with 12 years for patients without OHE.10 In an analysis of 271 patients with hepatic decompensation, OHE was associated with a significantly increased risk of mortality in patients with TIPS and grade III or IV HE compared with patients with grade 0 HE (HR, 3.68; 95% CI, 1.85-7.30; P = .0002). Increased risk of mortality in patients with  TIPS and grade II HE was intermediate compared with patients with grade 0 HE (HR, 1.56; 95% CI, 0.98-2.50; P = .06). Even after adjustment for Model for End-Stage Liver Disease (MELD) scores, OHE remained significantly associated with risk of death (HR, 2.55; 95% CI, 1.72-3.78; P <.01).11

HE also negatively impacts transplant survival. In a retrospective analysis of approximately 60,000 patients who underwent a liver transplant between 2003 and 2013, grade III or IV HE was associated with significantly lower survival at 1 year compared with patients without HE. The survival rate for patients with grade III or IV HE was 82.5% compared with 90.3% in patients without HE (P <.001) at 1-year post transplant. The survival rate 5 years post transplant was 69.1% in patients with grade III or IV HE compared with 74.4% in patients without HE (P <.001). After multivariate regression adjusting for sex, age at time of transplant, comorbidities, and MELD scores, the presence of HE was associated with worse posttransplant survival (HR, 1.27; P <.001).12

MHE and grade I HE are associated with poor clinical outcomes as well. In part, this may be due to the approximately 2-fold increased risk of OHE among this population.13 In a prospective analysis of 170 patients with cirrhosis, survival was compared between patients with and without CHE. Compared with patients without CHE, those with CHE were at increased risk for hospitalization (HR, 2.5; 95% CI, 1.4-4.5; P = .002) and the composite outcome of death or transplant (HR, 3.4; 95% CI, 1.2-9.7; P = .01).13 At 4-year follow-up, 75.6% of patients who experienced CHE died or underwent a transplant compared with 22.5% of patients without CHE.13

Available Management Strategies for Outpatient Care

The 2014 American Association for the Study of Liver Diseases and European Association for the Study of the Liver (AASLD/EASL) practice guidelines on hepatic encephalopathy in chronic liver disease currently recommend that only OHE should be routinely treated. Nonetheless, primary prophylaxis for HE is recommended in certain circumstances, in which patients may be at increased risk for the development of OHE. Other factors that might lead to treatment in patients with CHE include those with impairments in daily living, such as deficiencies in driving or poor work performance.3  Precipitating factors for OHE should also be identified and treated preemptively.3

Pharmacologic Treatments

Lactulose

Lactulose, a nonabsorbable disaccharide, is among the most common treatments for OHE. Since lactulose is synthesized by fructose and galactose, it is not digestible in mammals and passes unabsorbed to the large intestine.14 Metabolism of lactulose by colonic bacteria to produce lactic, acetic, and formic acids acidifies the colonic contents, preventing the growth of ammonia-producing bacteria, promoting the growth of beneficial microorganisms, and decreasing ammonia load by changing ammonia to ammonium, which is not absorbed.15 Lactulose syrup (25 mL) is typically given every 1 to 2 hours until at least 2 soft or loose bowel movements are produced per day, at which time dosing is titrated to maintain 2 to 3 bowel movements per day. Overusing lactulose can potentially lead to dehydration, hypernatremia, or aspiration, and may even precipitate HE.3

The efficacy of lactulose was assessed by a Cochrane review meta-analysis of 1415 patients enrolled in 22 randomized controlled trials (RCTs). The meta-analysis included both primary and secondary prophylaxis studies which were conducted internationally between the years 1969 and 2014. Results indicated that nonabsorbable disaccharides were associated with improvement or resolution of HE when compared with placebo or no intervention (risk ratio [RR], 0.58; 95% CI, 0.50-0.69).16 Lactulose reduced adverse events (AEs) of underlying liver disease, which included liver failure, hepatorenal syndrome, and variceal bleeding (RR, 0.47; 95% CI, 0.36-0.60).16 In a separate meta-analysis of 9 RCTs, lactulose significantly lowered the mean number of abnormal neuropsychological tests compared with placebo or no intervention (weighted mean difference [WMD]: –1.76; 95% CI, –1.96  to –1.56; P <.00001).17 Furthermore, lactulose was associated with significantly reduced blood ammonia levels (WMD: –9.89 mmol/L; 95% CI, –11.01 to –8.77 mmol/L; P <.00001).17

 
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