Hepatic encephalopathy: Suspect it early in patients with cirrhosis
ABSTRACTAs viral hepatitis and nonalcoholic fatty liver disease continue to increase in prevalence, we will see more cases of hepatic encephalopathy. Primary care physicians are often the first to suspect it, as they are familiar with the patient’s usual mental and physical status. This serious complication typically occurs in patients with severe comorbidities and requires multidisciplinary evaluation and care.
KEY POINTS
- Hepatic encephalopathy should be considered in any patient with cirrhosis who presents with neuropsychiatric manifestations in the absence of another brain disorder, such as stroke or brain tumor.
- “Minimal” hepatic encephalopathy may not be obvious on clinical examination but can be detected with neurophysiologic and neuropsychiatric testing.
- Every cirrhotic patient is at risk; potential precipitating factors should be addressed during regular clinic visits.
- Management requires prompt identification of precipitating factors and initiation of empiric medical therapy. Current treatments include drugs to prevent ammonia generation in the colon.
- Long-acting benzodiazepines should not be used to treat sleep disorders in patients with cirrhosis, as they may precipitate encephalopathy.
Hyponatremia
Hyponatremia (a serum sodium concentration < 130 mmol/L) is increasingly being recognized as an independent predictor of overt hepatic encephalopathy and is reported to increase the risk by a factor of eight.17
Neuronal dysfunction
Astrocytes are integral to the physiologic functioning of the neurons, and it is becoming clear that both neurons and astrocytes are affected in hepatic encephalopathy.
Additionally, neuroinflammation and a decrease in energy metabolism by the brain are described during episodes of hepatic encephalopathy.18
Amino acid imbalance
An imbalance between aromatic amino acids (ie, high levels of tyrosine and phenylalanine) and branched-chain amino acids (leucine, isoleucine, and valine) has been linked with encephalopathy in patients with liver disease, 19–21 but it is not totally clear whether this imbalance contributes to hepatic encephalopathy or is a consequence of it.
Low-grade brain edema
Edema of the brain occurs in all forms of hepatic encephalopathy, but in cirrhosis it is characteristically of low grade. The mechanism behind this low-grade edema is not clear. Studies have shown that swelling of astrocytes is not global but involves certain areas of the brain and is associated with compensatory extrusion of intracellular myoinositol.22 This, in combination with a mild degree of brain atrophy23 observed in patients with chronic liver disease, is thought to keep the brain from extreme swelling and herniation, a phenomenon usually seen in acute hepatic failure.24,25
Transjugular intrahepatic portosystemic shunting and encephalopathy
The incidence rate of hepatic encephalopathy after placement of a portosystemic shunt to treat portal hypertension ranges from 30% to 55% and is similar to the rate in cirrhotic patients without a shunt.26 In 5% to 8% of patients, the hepatic encephalopathy is refractory and requires intentional occlusion of the shunt.26,27 An elevated serum creatinine level appears to be a risk factor for refractory hepatic encephalopathy in patients with a portosystemic shunt.26
In one study,28 when transjugular intrahepatic portosystemic shunting was done early in the treatment of cirrhotic patients with acute variceal bleeding, the rates of treatment failure and death were significantly less than in a control group that received endoscopic therapy, and no significant difference was noted in the rate of encephalopathy or of serious adverse effects between the groups.
Whether to place a portosystemic shunt in a patient with cirrhosis and a history of hepatic encephalopathy depends on the possible underlying causes of the encephalopathy. For example, if encephalopathy was precipitated by variceal bleeding, shunt placement will prevent further bleeding and will make a recurrence of encephalopathy less likely. However, if the encephalopathy is persistent and uncontrollable, then shunt placement is contraindicated.27
A SPECTRUM OF SYMPTOMS
The spectrum of symptoms extends from a subclinical syndrome that may not be clinically apparent (early-stage or “minimal” hepatic encephalopathy) to full-blown neuropsychiatric manifestations such as cognitive impairment, confusion, slow speech, loss of fine motor skills, asterixis, peripheral neuropathy, clonus, the Babinski sign, decerebrate and decorticate posturing, seizures, extrapyramidal symptoms, and coma.4 The clinical manifestations are usually reversible with prompt treatment, but recurrence is common, typically induced by an event such as gastrointestinal bleeding or an infection.
Minimal hepatic encephalopathy is important to recognize
Although this subclinical syndrome is a very early stage, it is nevertheless associated with higher rates of morbidity and can affect quality of life, including the patient’s ability to drive a car.29,30
Abnormal changes in the brain begin at this stage and eventually progress to more damage and to the development of overt clinical symptoms.
The exact prevalence of minimal hepatic encephalopathy is not known because it is difficult to diagnose, but reported rates range between 30% and 84% of patients with cirrhosis.31 Progression from minimal to overt hepatic encephalopathy is 3.7 times more likely than in patients without the diagnosis of minimal hepatic encephalopathy.32
Thus, minimal hepatic encephalopathy is important to identify,29 so that treatment can be started.
Overt encephalopathy and survival
The prevalence of overt encephalopathy in cirrhosis ranges from 30% to 40% and is even higher in the advanced stages. Once encephalopathy develops, the prognosis worsens rapidly. In patients who do not undergo liver transplantation, the survival rate at 1 year is 42%, and the survival rate at 3 years is 23%.33
These rates are worse than those after liver transplantation, and the American Association for the Study of Liver Diseases recommends that patients with cirrhosis who develop a first episode of encephalopathy be considered for liver transplantation and be referred to a transplantation center.34
CHALLENGES IN DIAGNOSIS
Since the symptoms of hepatic encephalopathy are not specific and can be subtle in the early stage, its diagnosis may be a challenge. It is important to recognize that this neuropsychiatric complication occurs in people with severe comorbidities and requires dedicated time for evaluation and management.
