Is It Covert or Overt Hepatic Encephalopathy?

Rowen K. Zetterman, MD


November 21, 2016

Definition and Classification

Hepatic encephalopathy is typically considered a reversible neuropsychiatric complication that occurs in patients with end-stage liver disease. The neuropsychiatric change is recognized in the absence of a structural brain disorder, is related to the severity of the underlying acute or chronic liver injury, and is associated portosystemic shunting. The spectrum of abnormalities can range from minimal changes in cognition that are clinically unrecognized to coma.[1] Overt hepatic encephalopathy develops in approximately 40% of patients with cirrhosis during their clinical care.[2] A first episode of overt encephalopathy predicts recurrence in 40% of patients. Aggravating factors for the development of hepatic encephalopathy in advanced liver disease include infection, gastrointestinal bleeding, metabolic disturbance, and receipt of sedative medications. Genetic abnormalities affecting ammonia metabolism can also play a role.[3]

The associated underlying disease is used to classify hepatic encephalopathy: type A is related to acute liver injury, type B is related to portosystemic shunting, and type C is related to cirrhosis. It is then subdivided by severity: minimal hepatic encephalopathy is associated with abnormalities in psychometric testing and slow response time; stage I is associated with day–night sleep reversal, poor attention span, and impaired mathematic ability; stage II is associated with asterixis, apathy, disorientation, and inappropriate behavior; stage III is associated with marked disorientation and somnolence; and stage IV is marked by coma.

Patients with minimal hepatic encephalopathy might not be clinically identified as having altered mental function because of a lack of asterixis and other overt signs, whereas patients with stage I encephalopathy can have cirrhosis-related complications that require hospitalization.[4]

Guidelines from the Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL)[1] have proposed using the term "covert encephalopathy" to combine minimal and stage I encephalopathy into one diagnosis, because the presence of the distinguishing characteristics of each is difficult to establish, and "overt encephalopathy" for hepatic encephalopathy of stage II (presence of asterixis[5]) or greater.

Clinical Features

Clinical manifestations of altered mental status in patients with hepatic encephalopathy range from findings so minimal that they go unrecognized by the patient and the clinician to deep coma. Patients with clinically evident hepatic encephalopathy have a poor prognosis and increased risk for mortality.[6] More than 50% of patients with an episode of clinically evident encephalopathy will die within a year. For patients with encephalopathy, quality of life can be affected by any degree of altered mental function and can create care issues for the patient or family members.

Although it was initially thought that the resolution of encephalopathy meant complete reversal of the neuropsychiatric condition, recent studies have suggested that this is not the case. Despite continued lactulose or rifaximin therapy, cirrhotic patients with a previous episode of overt hepatic encephalopathy will have a persistent loss of learning capacity[7] and memory[8]; after multiple episodes, they will have even greater difficulty with mentation.

Covert or minimal hepatic encephalopathy is common, develops in up to 60% of patients with cirrhosis,[9] and is associated with a greater likelihood of eventual overt hepatic encephalopathy.[10] Compared with cirrhotic patients who lack minimal hepatic encephalopathy, those with minimal or covert encephalopathy have a greater likelihood of hospitalization, transplantation, and death[11], especially when associated with a more advanced Child–Pugh score.[9] In addition, cirrhotic patients with minimal hepatic encephalopathy have a greater likelihood of developing overt encephalopathy after a transjugular intrahepatic portosystemic shunt (TIPS) procedure.[12]

Clinical findings include impaired concentration, reduced attention span, delayed reaction time,[13] and the inability to perform simple mental tasks, such as balancing a checkbook. There are also personality changes, a reduction of fine motor skills,[14] and a greater likelihood of falling.[15] An even greater risk of falling exists for patients receiving psychotropic medications, and hospitalization after a fall can lead to overt encephalopathy.[15] Patients with unrecognized covert encephalopathy have an increased risk for auto accidents and poor driving habits that result in traffic tickets.[16] A day–night reversal of sleeping has been ascribed to covert encephalopathy, although it might be a consequence of other metabolic abnormalities.[17]


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