Review article
Covert and Overt Hepatic Encephalopathy: Diagnosis and Management

https://doi.org/10.1016/j.cgh.2015.06.039Get rights and content

Hepatic encephalopathy (HE) is part of a spectrum of neurocognitive changes in cirrhosis. HE is divided into 2 broad categories based on severity: covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). CHE has a significant impact on a patient’s quality of life, driving performance, and recently has been associated with increased hospitalizations and death. Likewise, OHE is associated with increased rates of hospitalizations and mortality, and poor quality of life. Given its significant burden on patients, care takers, and the health care system, early diagnosis and management are imperative. In addition, focus also should be directed on patient and family member education on the disease progression and adherence to medications. Treatment strategies include the use of nonabsorbable disaccharides, antibiotics (ie, rifaximin), and, potentially, probiotics. Other therapies currently under further investigation include L-ornithine-L-aspartate, ornithine phenylacetate, glycerol phenylbutyrate, molecular adsorbent recirculating system, and albumin infusion.

Section snippets

Pathophysiology

The pathophysiology of HE (overt and covert) is complex, with multiple components, which act alone or in combination (Figure 2), with an end product of functional neuronal impairment. These components include ammonia, inflammatory cytokines, benzodiazepine-like compounds, and manganese deposition.19

Covert Hepatic Encephalopathy: Diagnosis

CHE is a challenging diagnosis to make given that there is no disorientation or asterixis on examination. However, patients with grade 1 West Haven Criteria (WHC) HE, who are currently included in the realm of CHE, may have self-reported cognitive complaints or issues noticed by their companions. Patients with CHE have abnormalities on psychometric testing, particularly in areas of attention, executive functions, visuospatial coordination, and psychomotor speed/reactions times.26 Thus, testing

Pragmatic Approach to Covert Hepatic Encephalopathy Screening and Diagnosis

Although most of the tests mentioned earlier have been validated, they often are difficult to perform in clinical practice. Therefore, pragmatic cognitive solutions that potentially can be administered and interpreted by medical assistants, nurses, or allied health practitioners are a potential vital sign and could be relevant. It also is important to note that cognitive testing also could be performed outside the clinic at a separate appointment, such as before an ultrasound, and so forth, to

Overt Hepatic Encephalopathy: Diagnosis

The diagnostic strategies for OHE are inconsistent given its subjectivity, and thus require careful attention in each case. Traditionally, OHE severity is graded by the WHC,14 which now consists of stages 2 to 4 in the new classification. OHE usually is associated with a precipitating factor(s) such as gastrointestinal bleeding, acute kidney injury, infection, constipation, electrolyte imbalances, and other forms of liver injury (alcoholic injury, portal vein thrombosis, hepatocellular

Management of Covert Hepatic Encephalopathy and Overt Hepatic Encephalopathy

The treatment and management of HE depend on its severity and acuity. Patients with CHE are managed mostly as outpatients using nonabsorbable disaccharides, antibiotics (ie, rifaximin), and other agents. Based on its severity, OHE can be managed both as an outpatient or inpatient with similar agents. Goals of therapy for CHE include the prevention of OHE and OHE-related hospitalizations, to improve HRQOL, and to prevent hospitalizations and mortality. The goals of therapy for OHE episodes are

Nonabsorbable Disaccharides

Lactulose and lactitol are common nonabsorbable disaccharides used for HE treatment. When administered, they are degraded by microbiota in the colon to short-chain organic acids, creating both an acidic environment and an osmotic gradient in the intestinal lumen.20 The acidic environment created is hypothesized to reduce ammoniagenic bacteria and to convert ammonia to nonabsorbable ammonium. In addition, the increased osmolality also causes intestinal cleansing via removal of excess fecal

Covert Hepatic Encephalopathy Management

It is important to note that most studies in CHE have not measured outcomes data such as hospitalizations, OHE prevention, or death, but rather had end points such as improvement in HRQOL and cognitive testing.

Numerous controlled trials comparing lactulose or lactitol with placebo have shown improvement in the psychometric and neurophysiologic variables for CHE, but did not show any improvement in mortality15, 42, 43, 44, 45 (Table 2). In a meta-analysis including 9 randomized controlled trials

Overt Hepatic Encephalopathy Management

The use of lactulose or lactitol for OHE has been the mainstay of therapy despite its variable efficacy in trials54, 55, 56, 57 (Table 2). It also should be noted that these studies were small and underpowered. In a meta-analysis by Als-Nielsen et al,58 when compared with placebo or no intervention, nonabsorbable disaccharides had no statistically significant effect on mortality, but did show to reduce the risk of no improvement of OHE. Thus far, there is insufficient evidence showing that

Secondary Prevention of Overt Hepatic Encephalopathy

Data for nonabsorbable disaccharides for the secondary prevention of OHE have been sparse. In an open-label RCT, Sharma et al70 showed that lactulose was able to prevent recurrent OHE. However, in the real world this often is not tolerated in the US population, in which 46% of recurrences were caused by lactulose misuse.71

Bass et al66 showed that rifaximin (vs placebo, >90% on lactulose) was more effective in preventing OHE over 6 months compared with placebo. In a follow-up, long-term,

L-Ornithine-L-Aspartate, Ornithine Phenylacetate, and Glycerol Phenylbutyrate

L-ornithine-L-aspartate (not available in the United Stated) can reduce blood ammonia levels via stimulating both the urea cycle and glutamine synthesis.19 It has been studied extensively with better results with its intravenous rather than oral formulation across the HE spectrum.77, 78, 79, 80, 81, 82

Ornithine phenylacetate83 and glycerol phenylbutyrate84 are drugs that have been shown to reduce ammonia levels and have shown promise for the treatment of both OHE and secondary prevention.

Nutritional Management

The American Association for the Study of Liver Diseases and the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recommend that patients with cirrhosis should have 1.2 to 1.5 g/kg of protein daily to maintain muscle mass.3, 89 In addition, increasing intake of branched-chain amino acids may be beneficial for HE, but did not show any mortality benefit and improvement in HRQOL. Branched-chain amino acids are not readily available in the United States.

Management of Refractory Hepatic Encephalopathy

There are rare instances in which a patient will have continued recurrences of OHE despite optimal medical management and compliance. Here, it is imperative to search for other possible reasons such as spontaneous portosystemic shunts (Figure 3). In patients in whom HE does not improve despite aggressive medical therapies, liver transplant is the definitive treatment.

Future Directions

Future directions for the study of HE include convenient, rapid, and validated methods to diagnose CHE, as well as better objective methods to diagnose the severity of OHE. This is paramount because early recognition could impact morbidity and mortality, and HRQOL. At this time, therapy for CHE can be used in selected cases for psychosocial purposes because further trials are needed to substantiate the role of therapy in routine clinical practice. Clinicians also should be meticulous in the

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    Conflicts of interest This author discloses the following: Jasmohan Bajaj has served as a consultant for Salix, Merz, and Norgine. The remaining author discloses no conflicts.

    Funding This study was supported in part by VA Merit Review (CX001076), the National Institute on Alcohol Abuse and Alcoholism (RO1AA020203), and by the National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK087913).

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