Hepatic encephalopathyK72.9

Reversible dysfunction of the central nervous system due to liver failure.

Hepatic encephalopathy is classified as follows:

• Type A (in acute liver failure)
• Type B (for portal-systemic shunt without hepatocellular disease)
• Type C (for liver cirrhosis and portal hypertension).

The cause is a deficient "detoxification" of CNS toxic substances such as ammonia, mercaptans, phenols, fatty acid, gamma-aminobutyric acid (GABA) accumulate these in the CNS. Ammonia plays a leading role in the pathophysiology of HE. Due to inadequate metabolism by the liver, blood is enriched with ammonia in the intestinal tract and enters the CNS through the blood-brain barrier. Astrocytes metabolize the ingested ammonia to glutamine; this leads to an osmotic effect with swelling of astrocytes, stimulation of depressing and inhibition of excitatory neurons (Classen M et al. 2008).

HE can be triggered in liver cirrhotic patients by:

• increased protein catabolism during infections(urinary tract infections or pneumonia)
• medication: therapy with benzodiazepines, sedatives, analgesics.
• increased ammonia formation in the intestine (e.g. due to acute bleeding into the digestive tract)
• excessive consumption of animal proteins, especially red meat
• due to overdosed diuretic therapy (Hahn JM 2013)

West-Haven classification: HE is classified into five severity levels according to the West-Haven classification.

• Stage 0 (Asymptomatic HE): Minimal HE represents the least severe form of hepatic encephalopathy. In this form, no clinical symptoms are evident, but patients show initial cognitive deficits of mild severity, which may adversely affect quality of life. Especially complex activities requiring attention, information processing and psychomotor skills are limited. Validated psychometric tests may provide an indication of minimal HE.
• Stage 1 (Subclinical HE): Mild reduction in level of consciousness with increasing need for sleep, mood swings, irritability, marked impulsivity, and decline in intellectual performance. Noticeable disturbances in fine motor skills with a change in writing pattern, onset of tremor, and slowed movement.
• Stage 2 (Manifest HE): Significant reduction in level of consciousness with orientation disorders, marked memory impairment, impoverishment of emotional life, and delayed response to address. Slurred speech (dysarthria), flapping tremor and increased muscle tension.
• Stage 3 (Manifest HE): High-grade disturbance of consciousness (usually asleep but can be awakened), loss of orientation, confusion, incoherent speech, decreased response to painful stimuli. Increased muscle tension to the point of muscle stiffness (spasticity), flapping tremor, fecal and urinary incontinence, unsteadiness of gait and stance (ataxia). Severe drowsiness (somnolence).
• Stage 4 (hepatic failure coma - coma hepaticum): Unconsciousness without response to painful stimuli . Foetor hepaticus (smell of raw liver). Extinction of muscle reflexes, corneal reflex; continued muscle rigidity with flexion and extension. EEG changes: delta activity.

Note: Minimal HE and stage 1 of the West Haven classification are also grouped under the term Covert HE, while stages 2 - 4 are also referred to as Overt HE.

Ammonia > 100ug/l

In patients with chronic liver disease, the occurrence of conspicuous neurological symptoms such as disorders of cognition, attention, concentration, memory and problem solving. Use of simple psychometric tests (frequently used are the "Psychometric Hepatic Encephalopathy Score" (PHES), which includes the number connection tests A and B as well as the line tracing test and the number symbol test)

Furthermore the "critical flicker frequency" can be checked. For this purpose, the patient is exposed to high-frequency light through special glasses, which initially appears to the patient as continuous light. Then the frequency is gradually reduced until he can perceive a flicker. This "critical transition frequency" is above 39 Hz in healthy people, but is significantly lower in patients with HE.

Primary therapy is the elimination of predisposing factors. These include:

• Normalization of water and electrolyte balance
• elimination of gastrointestinal bleeding
• Oral or parenteral nutrition
• Treatment of coagulation disorders Infection prophylaxis (antibiotic therapy)
• General treatment of cirrhosis of the liver
• From stage III intensive medical monitoring

A further aim is either to reduce ammonia synthesis in the gastrointestinal tract or to promote ammonia detoxification in the liver.

Non-absorbable disaccharides such as lactulose (e.g. bifeteral 2-3x10-50ml/day p.o.- in comatose patients 100 ml administered through a stomach tube) inhibit the production and absorption of ammonia; used as first-line therapy of HE.

If there is no improvement, start treatment with a non-resorbable antibiotic. Previously established was the aminoglycoside neomycin (routine use is not recommended due to possible nephro- and ototoxicity). Alternatively, the non-absorbable antibiotic rifaximin (xifaxan) is available; dosage: 2x 550 mg/day or 3x 400 mg/day. Rifaximin significantly reduces the relative risk of recurrent episodes of hepatic encephalopathy and improves the quality of life of patients.

Other therapies that may be used in HE are L-ornithine L-aspartate (LOLA), zinc, sodium benzoate, dopamine receptor agonists, benzodiazepine antagonists, acarbose and prokinetics. L-Ornithine L-Aspartate (LOLA) supports ammonia detoxification (activates the disturbed formation of urea in the liver as well as glutamine synthesis in the liver, muscles and brain).

In somnolent patients flumazenil can be applied in vivo (Goh ET et al. 2017).

Calorically adequate nutrition (39kcal/kgKG/day. The protein intake should not fall below 0.8 g/kg KG per day.

Note: The HE tends to recur! Recurrences lead to a deterioration of cognitive damage. Therefore a long-term consistent recurrence prophylaxis is important (current guideline of the EASL and AASLD).

Ultima ratio is the liver transplantation (LTX).

1. Classen M et al (2008) Repetitorium Internal Medicine. Urban&Fischer Publisher Munich S 287-288
2. Goh ET et al (2018) L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 5:CD012410.
3. Goh ET et al (2017) Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev 26:CD002798.
4. Hahn JM (2013) Checklist Internal Medicine. Georg Thieme Publishing House, Stuttgart S 426-427
5. Herold G (2016) Internal Medicine. 2016, S. 561-563
6. Suraweera D et al (2016) Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions. Well Liver 10:509-519.
7. Wijarnpreecha K et al (2017) Association of Helicobacter pylori with the Risk of Hepatic Encephalopathy. Dig Dis Sci 62:3614-3621.
8. Wu KC et al (2018) Effect of sirolimus on liver cirrhosis and hepatic encephalopathy of common bile duct-ligated rats. Eur J Pharmacol 824:133-139.