Understanding the impact of neurologic complications in patients with cirrhosis.

Patients with cirrhosis may experience neurologic complications, including hepatic encephalopathy. Hepatic encephalopathy may be classified as covert (mild symptoms (e.g. lack of awareness)) or overt (moderate to severe symptoms (e.g. confusion or coma)), and symptoms may overlap with other neurologic conditions (e.g. epilepsy, stroke). Managing hepatic encephalopathy includes identifying and treating precipitating factors (e.g. dehydration). First-line treatment for patients with overt hepatic encephalopathy is typically lactulose; to reduce the risk of overt hepatic encephalopathy recurrence, lactulose plus the nonsystemic antibiotic rifaximin is recommended. Rifaximin reduced the risk of breakthrough overt hepatic encephalopathy by 58% versus placebo over 6 months (p < 0.001; 91% of patients in each group were on concomitant lactulose). However, neither pharmacologic hepatic encephalopathy treatment nor liver transplantation may completely reverse neurologic impairment in patients with hepatic encephalopathy. Additional neurologic considerations for patients with cirrhosis include preventing falls, as well as managing sleep-related issues, hyponatremia, and cerebral edema. Thus, monitoring neurologic impairment is an important component in the management of patients with cirrhosis.

Rifaximin has the potential to prevent complications of cirrhosis.

BACKGROUND: Cirrhosis-related complications are associated with poor prognosis. With our analyses, we examined the potential benefit of rifaximin in reducing the risk of developing cirrhosis-related complications. METHODS: Adults with cirrhosis and hepatic encephalopathy (HE) in remission were randomly assigned to receive rifaximin 550 mg twice daily or placebo for 6 months with concomitant lactulose permitted. Post hoc analyses examined time to cirrhosis-related complications (HE, spontaneous bacterial peritonitis (SBP), variceal bleeding, acute kidney injury/hepatorenal syndrome). Subgroup analyses evaluated efficacy for select baseline disease characteristics. RESULTS: Of patients receiving rifaximin (n = 140) and placebo (n = 159), 53.6% and 49.1%, respectively, had baseline Model for End-Stage Liver Disease (MELD) score ⩾ 12 and international normalized ratio (INR) ⩾ 1.2. Baseline ascites was observed in 36.4% (rifaximin) and 34.6% (placebo) of patients. In patients with MELD score ⩾ 12 and INR ⩾ 1.2, rifaximin reduced the relative risk (RR) of any first complication experienced during trial by 59% [hazard ratio (HR) = 0.41, 95% confidence interval (CI): 0.25-0.67; p < 0.001] versus placebo. For patients with baseline ascites, rifaximin reduced the RR of any first complication experienced during trial by 42% versus placebo (HR = 0.58, 95% CI: 0.34-1.0; p = 0.045). For some subgroups, there was a decrease in RR of complications of SBP, variceal bleeding, and acute kidney injury/hepatorenal syndrome with rifaximin versus placebo, although there were few events reported in the study. CONCLUSION: Rifaximin may reduce the incidence of cirrhosis-related complications and the recurrence of overt HE.[ClinicalTrials.gov identifier: NCT00298038.].

Practical Issues in the Management of Overt Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a condition that encompasses a range of neuropsychiatric abnormalities in patients with significant liver disease. Overt HE occurs in approximately 30% to 45% of patients with cirrhosis. This article discusses practical issues in the management of patients with overt HE and cirrhosis, including a recently developed 4-pronged approach that consists of identifying and correcting precipitating factors, recognizing and treating concomitant medical conditions, commencing empiric treatment, and caring for the unconscious patient. Following recovery from overt HE, a plan of action should be developed to prevent readmissions.

A New Look at Precipitants of Overt Hepatic Encephalopathy in Cirrhosis.

BACKGROUND AND AIMS: Overt hepatic encephalopathy (HE) is a major cause of significant morbidity and mortality in patients with liver cirrhosis. We examined the frequency and profile of the precipitating factors resulting in hospitalizations for overt HE. METHODS: We conducted both retrospective and prospective studies to identify clinical precipitants of overt HE in patients with cirrhosis. The retrospective study patients were hospitalized at a large urban safety-net hospital, and the prospective study included the patients admitted at a liver transplant center. RESULTS: There were a total of 149 patients with cirrhosis and overt HE (91 males, mean age 55.3 ± 8.6 years) in the retrospective group and 45 patients (27 males, mean age 58.3 ± 8.2 years) in the prospective group of the study. The average MELD score was 16 ± 6.8 in the retrospective group and 22.7 ± 7.2 in the prospective group. Dehydration (46-76%), acute kidney injury (32-76%), lactulose nonadherence (about 50%), constipation (about 40%), and infections (20-42%) were the most frequently identified precipitants for hospitalization in retrospective and prospective groups. Multiple precipitants were identified in 60 (40.3%) patients in the retrospective group and 34 (76%) patients in the prospective group. CONCLUSIONS: Multiple concurrent precipitating factors were identified in the majority of patients with overt HE requiring hospitalization. Dehydration due to various causes was the most common precipitant of overt HE, followed by acute kidney injury (AKI), constipation, and infections. Prevention of dehydration, AKI, and constipation by close outpatient monitoring may be an effective measure to prevent hospitalization for overt HE in patients with cirrhosis.

Hepatic Encephalopathy Is Associated with Persistent Learning Impairments Despite Adequate Medical Treatment: A Multicenter, International Study.

BACKGROUND: Hepatic encephalopathy (HE) is considered reversible regarding mental status but may not be cognitively in single-center studies. AIM: To evaluate persistence of learning impairment in prior HE compared to those who never experienced HE (no-HE) in a multicenter study. METHODS: A total of 174 outpatient cirrhotics from three centers (94 Virginia, 30 Ohio, and 50 Rome; 36 prior HE) underwent psychometric hepatic encephalopathy score (PHES) and inhibitory control (ICT) testing at baseline and then at least 7 days apart. ICT learning (change in 2nd half lures compared to 1st half) was compared between patient groups at both visits. Change in the PHES individual sub-tests and total score between visits was compared in both groups. US versus Italian trends were also analyzed. RESULTS: HE patients had worse PHES and ICT results compared to no-HE patients at baseline. Significant improvement (1st half 7.1 vs. 2nd half 6.2, p < 0.0001) was observed in no-HE, but not in HE (1st half 7.9 vs. 2nd half 7.8, p = 0.1) at baseline. At retesting (median 20 days later), no-HE patients continued with significant learning (1st half 6.0 vs. 2nd half 5.4, p < 0.0001), while HE patients again did not improve (1st half 7.8 vs. 2nd half 6.9, p = 0.37). Between visits, no-HE patients improved significantly on four PHES sub-tests and overall score, while HE patients only improved on two sub-tests with similar overall PHES score. Trends were similar between US and Italian subjects. CONCLUSION: In this multicenter study, prior HE patients showed persistent significant learning impairment compared to those without prior HE, despite adequate medical therapy. This persistent change should increase efforts to reduce the first HE episode.

Optimal treatment of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome associated with decompensated liver disease. The spectrum of disease ranges from trivial abnormalities in complex decision-making and prolonged reaction time to coma in its most severe form. The very initial stages, recently termed covert hepatic encephalopathy, can only be diagnosed with the help of neuropsychiatric testing, while the later and more severe forms, termed overt hepatic encephalopathy, can be diagnosed clinically. Management of HE is very critical as it can dramatically increase morbidity and mortality. This leads to financial hardships, which tend to make matters worse. Timely management of HE will help diminish the disease burden and thus decrease morbidity and mortality. It is thus crucial that liver cirrhosis and HE are managed aggressively to try and lower the need for transplantation and other aggressive treatment measures.

Long-Term Management of Alcoholic Liver Disease.

The key to management of alcoholic liver disease (ALD) is early recognition by the patient and physician. Excessive alcohol consumption, ranging from drinking more than recommended amounts to abuse, is one of the most preventable causes of death and disability. The US Preventive Services Task Force guidelines recommend screening for alcoholism in the primary care setting. Abstinence is the cornerstone of therapy and it decreases mortality and morbidity significantly. Alcoholic cirrhosis can cause varices that need to be followed closely with upper endoscopy to prevent or treat hemorrhage. In this review, we describe an approach to long-term management of ALD.

Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy.

BACKGROUND & AIMS: Rifaximin is a gut-selective, oral antimicrobial agent shown to reduce the recurrence of overt hepatic encephalopathy (HE) and HE-related hospitalizations in a 6-month, randomized, controlled trial (RCT). We performed a phase 3, open-label maintenance study to assess the safety and rate of hospitalization with long-term rifaximin use. METHODS: We conducted a 24-month, open-label maintenance study of rifaximin (550 mg, twice daily) in patients with HE who participated in the previous RCT of rifaximin or new patients enrolled from March 2007 to December 2010. Safety was assessed (adverse events, clinical laboratory parameters) for the integrated population of all patients, who were given rifaximin 550 mg twice daily (all-rifaximin population, N = 392). Safety and hospitalization data were compared between the group given placebo in the original RCT (n = 159) and those given rifaximin (n = 140). RESULTS: In the all-rifaximin population, the median exposure to rifaximin was 427.0 days (range, 2-1427 d), with 510.5 person-years of exposure. The profile and rate of adverse events with long-term rifaximin treatment were similar to those of the original RCT. There was no increase in the rate of infections, including with Clostridium difficile, or development of bacterial antibiotic resistance. Rates of hospitalizations with long-term rifaximin administration remained low: the HE-related hospitalization rate, normalized for exposure (0.21; all-rifaximin population), was similar to that of the rifaximin group in the original RCT (0.30), and lower than that for the placebo group (0.72). CONCLUSIONS: Long-term treatment (≥24 mo) with rifaximin (550 mg, twice daily) appears to provide a continued reduction in the rate of HE-related and all-cause hospitalization, without an increased rate of adverse events. ClinicalTrials.gov number: NCT00686920.

Evolving concepts: the negative effect of minimal hepatic encephalopathy and role for prophylaxis in patients with cirrhosis.

BACKGROUND: Hepatic encephalopathy (HE), which may be categorized as minimal or overt, is a serious and progressive neuropsychiatric condition that occurs in patients with liver disease or portosystemic shunting. Overt HE (OHE) presents as a wide spectrum of clinical signs and symptoms, ranging in severity from mild confusion to life-threatening coma. Minimal HE (MHE) is a more subtle form of the condition; it is characterized by deficits in cognitive function in patients with a normal clinical examination. OBJECTIVE: The purpose was to review the effect of MHE on patients and caregivers, as well as its currently available diagnostic and treatment options. METHODS: A MEDLINE search of published diagnostic assessments, clinical trials, and guidelines from 1985 to 2012 were reviewed and analyzed to assess the potential effect of MHE in the clinical practice setting. RESULTS: Accumulating evidence suggests that MHE has a substantial negative effect on patient quality of life, particularly in activities that require attention, motor skills, and visuospatial ability. Because MHE lacks obvious clinical signs, specialized testing is required for diagnosis, although there is no consensus on the most appropriate assessment tools or treatment algorithms. Compounds derived from bacterial activities in the gut can cause neurochemical changes in the brain. These gut-derived toxins (eg, ammonia, benzodiazepine-like substances) are implicated in the pathophysiology of OHE. In patients with liver disease or portosystemic shunting, these toxins are inefficiently detoxified, accumulate in the blood, cross the blood-brain barrier, and result in abnormalities such as altered neurotransmission, astrocyte swelling, and impaired energy metabolism. Therefore, treatments have focused on toxin removal and the management of gut flora levels. Several studies have indicated that probiotics, nonabsorbable disaccharides, and nonsystemic antibiotics can all be effective in improving the symptoms of MHE. Furthermore, prophylaxis for MHE in patients with cirrhosis could serve to improve patient quality of life while preventing its transition to OHE. CONCLUSIONS: Although MHE detection and treatment is not currently the standard of care, several therapies have been reported to improve cognitive function and quality of life. Interest is increasing in the proactive diagnosis and management of MHE in the clinical practice setting. However, research is required to determine the conditions under which the putative benefits of prophylactic MHE therapy outweigh the costs.

Bleeding risk in patients with esophageal varices undergoing transesophageal echocardiography.

BACKGROUND: Bleeding from esophageal varices is a major potential concern during transesophageal echocardiography (TEE) in patients with cirrhosis of the liver. As there are limited data on its risk in these patients, this was retrospectively assessed at our institution. METHODS: The hospital electronic medical record database at our university affiliated teaching hospital was searched for all patients with esophageal varices undergoing TEE from 2000 to 2012 and patient charts were reviewed for procedure-related bleeding complications. RESULTS: Twenty-four patients with esophageal varices were found (18 men, 57 ± 14 years). Nine patients had grade 2 esophageal varices, 15 patients had grade 1 varices, and 12 patients had portal hypertensive gastropathy. Alcoholic liver disease (9) and hepatitis C (8) were the most common etiologies of the cirrhosis with an average MELD score of 15. The most common indication for TEE was for possible endocarditis (15). Medications potentially increasing bleeding risk included warfarin in 2 and aspirin in 7 patients. Twelve patients were taking ß-blockers for portal hypertension. There were no immediate bleeding complications and none of these patients were readmitted with bleeding. CONCLUSIONS: TEE can be performed without serious bleeding risk in patients with grade 1 or 2 esophageal varices.

Cognitive dysfunction is associated with poor socioeconomic status in patients with cirrhosis: an international multicenter study.

BACKGROUND & AIMS: In patients with cirrhosis, cognitive dysfunction most often results from covert hepatic encephalopathy (HE). These patients are not tested routinely for cognitive dysfunction despite single-center evidence that it could be associated with poor socioeconomic status (SES). We investigated the association between SES and cognition in a multicenter study of cirrhosis. METHODS: In a cross-sectional study, 236 cirrhotic patients from 3 centers (84 subjects from Virginia, 102 from Ohio, and 50 from Rome, Italy; age 57.7 ± 8.6 y; 14% with prior overt HE) were given recommended cognitive tests and a validated SES questionnaire that included questions about employment, personal and family income, and overall financial security. Comparisons were made among centers and between subjects who were employed or not. Regression analysis was performed using employment and personal income as outcomes. RESULTS: Only 37% of subjects had been employed in the past year. Subjects had substantial financial insecurity-their yearly personal income ranged from $16,000 to $24,999, and their family income ranged from $25,000 to $49,999. They would be able to maintain a residence for only 3 to 6 months if their income stopped, and their current liquid assets were $500 to $4999 (<$500 if debt was subtracted). Cognition and SES were worst in Ohio and best in Virginia. Cognition correlated with personal and family income, within and between centers. On regression analysis, cognitive performance (digit symbol, lures, and line tracing) was associated with personal yearly income, after controlling for demographics, country, employment, and overt HE. Unemployed subjects had a higher rate of overt HE, worse cognition, and lower personal income than employed subjects. On regression analysis, performance on digit symbol, line tracing, inhibitory control test lures, and serial dotting tests remained associated with employment, similar to income. CONCLUSIONS: In an international multicenter study of patients with cirrhosis, socioeconomic condition, based on employment and personal income, was associated strongly with cognitive performance, independent of age, education, and country.

New perspectives in hepatic encephalopathy.

The terminology of hepatic encephalopathy (HE) remained poorly defined for decades. One major problem was the lack of definition of what constituted acute versus chronic HE. Chronic HE caused more confusion because it was proposed to signify any bout of HE in patients with chronic liver disease, whereas others thought it denoted a protracted period of loss of consciousness. Numerous other versions were rampant. This mass confusion was solved by the report of the Hepatic Encephalopathy Consensus Group at the World Congress of Gastroenterology in 1998. This new multi-axial definition led to standardization of diagnosis and explosion in the field of research in HE.

Theories of the pathogenesis of hepatic encephalopathy.

The earliest hypothesis of the pathogenesis of HE implicated ammonia, although effects of appreciable concentrations of this neurotoxin did not resemble HE. Altered eurotransmission in the brain was suggested by similarities between increased GABA-mediated inhibitory neurotransmission and HE, specifically decreased consciousness and impaired motor function. Evidence of increased GABAergic tone in models of HE has accumulated; potential mechanisms include increased synaptic availability of GABA and accumulation of natural benzodiazepine receptor ligands with agonist properties. Pathophysiological concentrations of ammonia associated with HE, have the potential of enhancing GABAergic tone by mechanisms that involve its interactions with the GABAa receptor complex.