What is the pathophysiology and treatment of progression from hepatitis to hepatic encephalopathy?

Pathophysiology of Hepatic Encephalopathy in Chronic Liver Disease

Hepatic encephalopathy develops when chronic liver disease (hepatitis leading to cirrhosis) causes both hepatocellular dysfunction and portosystemic shunting, resulting in accumulation of neurotoxic substances—primarily ammonia—that cross the blood-brain barrier and cause astrocyte swelling, neuroinflammation, and progressive neuropsychiatric dysfunction. 1, 2

Core Pathophysiological Mechanisms

Liver Dysfunction and Portosystemic Shunting

The progression from hepatitis to encephalopathy occurs through two fundamental mechanisms:

• Hepatocellular failure reduces the liver's capacity to detoxify ammonia and other gut-derived neurotoxins through the urea cycle 2
• Portosystemic shunting (either spontaneous collaterals in cirrhosis or surgical/TIPS shunts) allows neurotoxic substances to bypass hepatic metabolism and enter systemic circulation directly 1
• Type C hepatic encephalopathy specifically results from cirrhosis, while Type B results predominantly from portosystemic bypass 1

Ammonia and Neuroinflammation

The central pathophysiological cascade involves:

• Ammonia accumulation remains the primary neurotoxin, though blood ammonia levels correlate imperfectly with encephalopathy severity in cirrhosis 3, 2
• Astrocyte dysfunction occurs when ammonia crosses the blood-brain barrier, causing astrocyte swelling and impaired neurotransmission 2
• Synergistic inflammation amplifies ammonia neurotoxicity—infection and systemic inflammation are profound determinants for developing severe hepatic encephalopathy 3
• Gut microbiome perturbation and impaired gut epithelial barrier facilitate bacterial translocation, inducing systemic inflammation that worsens encephalopathy 3

Etiology-Specific Considerations

While the European Association for the Study of the Liver states that patients should not be classified based on liver disease etiology 1, certain causes have additional pathophysiological implications:

• Alcohol is directly neurotoxic, making it difficult to distinguish contributions from liver dysfunction versus direct toxicity 1
• Hepatitis C may cause neuropsychiatric symptoms independent of disease severity through viral replication in brain endothelial cells and glia, causing neuroinflammation 1
• Metabolic dysfunction-associated fatty liver disease can show hyperammonemia and astrocytic activation even before cirrhosis develops 1

Clinical Progression and Risk Factors

Epidemiology of Progression

• The risk for first overt hepatic encephalopathy episode is 5-25% within 5 years after cirrhosis diagnosis 1
• Risk factors include minimal/covert hepatic encephalopathy, infections, variceal bleeding, ascites, diabetes, and hepatitis C 1
• After one episode, 40% cumulative risk of recurrence at 1 year; recurrent episodes carry 40% risk of another recurrence within 6 months despite lactulose 1
• After TIPS placement, median cumulative 1-year incidence is 10-50% 1

Clinical Spectrum

The neuropsychiatric manifestations progress through a continuum 1:

• Minimal/Covert HE (20-80% of cirrhosis patients): Only detectable on psychometric testing affecting attention, working memory, psychomotor speed, and visuospatial ability 1
• Early overt HE: Personality changes (apathy, irritability, disinhibition), sleep-wake disturbances with excessive daytime sleepiness, and asterixis 1
• Progressive overt HE: Disorientation to time and space, inappropriate behavior, acute confusional state with agitation or somnolence 1
• Advanced stages: Stupor and coma with motor abnormalities including hypertonia, hyperreflexia, positive Babinski sign 1

The onset of disorientation or asterixis marks the transition to overt hepatic encephalopathy 1

Treatment Approach

Identify and Treat Precipitating Factors

Nearly 90% of patients can be treated solely by correcting the precipitating factor 4:

• Infections (urinary, pneumonia, spontaneous bacterial peritonitis) 1, 5, 4
• Gastrointestinal bleeding 5, 4
• Electrolyte disturbances, particularly hyponatremia <130 mmol/L 5, 4
• Constipation 5, 4
• Medication non-compliance 5, 4
• Proton pump inhibitors should be restricted to strict validated indications 5, 4
• Benzodiazepines are contraindicated in decompensated liver cirrhosis 5, 4

Pharmacological Management

First-line therapy is lactulose 25 mL syrup every 12 hours, titrated to achieve 2-3 soft stools per day 5, 6:

• Lactulose reduces blood ammonia levels by 25-50%, with clinical response in approximately 75% of patients 6
• The mechanism involves acidification of colonic contents, reducing ammonia absorption and altering gut microbiome 6, 3

Add rifaximin 550 mg twice daily when lactulose alone is insufficient or for prevention after a second episode 5, 7:

• Rifaximin is indicated for reduction in risk of overt hepatic encephalopathy recurrence in adults 7
• In trials, 91% of patients used lactulose concomitantly with rifaximin 7
• Rifaximin modulates gut microbiome and reduces bacterial translocation 3

Critical Care Considerations

For severe encephalopathy (Grade III-IV):

• Intensive care unit monitoring is required for patients who cannot protect their airways 5, 4
• Intubation is recommended for Grade III-IV hepatic encephalopathy 4
• Elevate head of bed 30 degrees to reduce intracranial pressure 4
• Avoid sedatives whenever possible as they impair neurological assessment 4

Secondary Prophylaxis

After an episode of hepatic encephalopathy, continue lactulose indefinitely; add rifaximin for recurrent encephalopathy 5, 4:

• Patient and caregiver education on medication effects, adherence, and early signs of recurrence is essential 5
• Nutritional support is critical—provide adequate protein and energy to favor positive nitrogen balance and increase muscle mass, as sarcopenia worsens encephalopathy 5

Liver Transplantation

Recurrent, treatment-refractory hepatic encephalopathy combined with liver failure is an indication for liver transplantation 4:

• Transplantation leads to significant improvement in most cognitive functions 4
• However, some mental deficits may persist after transplantation, and episodes of overt HE may be associated with persistent cumulative deficits in working memory and learning 1

Common Pitfalls

• Do not assume asterixis is pathognomonic—it can occur in uremia and other conditions 1
• Blood ammonia levels correlate poorly with encephalopathy severity in cirrhosis, unlike in acute liver failure 3, 2
• Always perform diagnostic workup to exclude alternative causes: infections, stroke, subdural hematoma, non-convulsive seizures, meningitis/encephalitis 1
• Hepatic encephalopathy was previously considered fully reversible, but research shows persistent cognitive deficits may occur after repeated episodes 1
• MELD scores >25 have not been adequately studied with rifaximin, and systemic exposure increases with severe hepatic dysfunction 7