Hepatic encephalopathy

In medicine, hepatic encephalopathy is "syndrome characterized by central nervous system dysfunction in association with liver failure, including portal-systemic shunts. Clinical features include lethargy and confusion (frequently progressing to coma); asterixis; nystagmus, pathologic; brisk oculovestibular reflexes; decorticate and decerebrate posturing; muscle spasticity; and bilateral extensor plantar reflexes . Electroencephalography may demonstrate triphasic waves." The Babinski sign demonstrates abnormal plantar reflexes.

Classification and grading

In the World Congress of Gastroenterology 1998 in Vienna, a proposed classification of hepatic encephalopathy was presented to standardize the subclasses. According to this classification, hepatic encephalopathy is subdivided in type A, B and C.

• Type A (=acute) describes hepatic encephalopathy associated with acute liver failure;
• Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease;
• Type C (=cirrhosis) occurs in patients with cirrhosis.

In addition, the duration and characteristics of hepatic encephalopathy were classified into episodic, persistent and minimal. The term minimal encephalopathy (MHE) is defined by patients with cirrhosis who do not demonstrate clinically overt cognitive dysfunction, but who show a cognitive impairment on neuropsychological studies. This is still an important finding, as minimal encephalopathy has been demonstrated to increase the rate of road traffic accidents and violations.

The evaluation of severity of persistent hepatic encephalopathy is based on the West Haven Criteria for semi-quantitative grading of mental status, referring to the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy..

• Grade 1 (also called minimal hepatic encephalopathy - MHE)- Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of addition. 67% of cirrhotic patients in one study of outpatients at a liver clinic had MHE.
• Grade 2 - Lethargy or apathy; Minimal disorientation for time or place; Subtle personality change; Inappropriate behavior; Impaired performance of subtraction
• Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation
• Grade 4 - Coma (unresponsive to verbal or noxious stimuli)

Etiology / cause

There may be a genetic propensity to hepatic encephalopathy.

Diagnosis

The inhibitory control test (ICT) may be a faster way to diagnose hepatic encephalopathy than standard psychometric tests (average administration time of 15 minutes versus 37 minutes)

Asterixis

Asterixis, which are "abnormal involuntary movements which primarily affect the extremities, trunk, or jaw that occur as a manifestation of an underlying disease process," may help diagnose hepatic encephalopathy. In unresponsive patients, asterixis can be checked by flexing the hips.

Blood tests

Ammonia

The normal plasma level of ammonia is 12 - 48 μmol/L.

Venous ammonia and level of encephalopathy.
Number (%) of patients.

NH3 level	Grade 0 (no encephalopathy)	Grade 1	Grade 2	Grade 3	Grade 4
> 50	10 (33%)	18 (67%)	14 (52%)	25 (89%)	12 (92%)
25-20	12 (40%)	9 (33%)	5 (19%)	3 (11%)	0
< 25	8 (27%)	0 (0%)	4 (15%)	0 (0)%)	1* (8%)
Total patients	30 (100%)	27 (100%)	2 (100%)3	28 (100%)	13 (100%)
*This patient's ammonia level was approximately 20 μmol/L.

The ammonia level can help diagnose encephalopathy.

Accuracy of the venous ammonia

	sensitivity	specificity
> 50 μmol/L	76%	67%
> 25 μmol/L	93%	27%

Newer blood tests

A study concluded that the "determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values.". This study reported a sensitivity and specificity of 94% and 83%, respectively. In populations similar to those in this study which had a prevalence of minimal hepatic encephalopathy of 35%, the probabilities of minimal hepatic encephalopathy among patients with an abnormal and normal serum 3-nitro-tyrosine above 14 nM were 75.0% and 4.0%, respectively.

Treatment

Even 'minimal hepatic encephalopathy' may benefit from treatment.

Reduce protein intake

The role of protein restriction is controversial.

Correction of hypokalemia

Concommittent hypokalemia should be corrected as hypokalemia increases renal ammonia production and may promote conversion of ammonium into ammonia which can cross the blood-brain barrier.

Lactulose

Lactulose is a compound that will cause osmotic diarrhoea, thus lessening the time available for intestinal bacteria to metabolise protein into ammonia within the bowel. Further, it acidifies the environment in the lumen of the bowel. This promotes the conversion of lumenal ammonia (NH₃) to ammonium (NH₄⁺) which, by which virtue of its net charge, should be less readily absorbed into the bloodstream from the bowel lumen. Despite this theoretical and appealing mechanism, a meta-analysis of [[randomized controlled trial]s] by the international Cochrane Collaboration found benefit, but suggests there is little evidence for its preferred use to treat hepatic encephalopathy. Indeed, any drug (laxative) which speeds up transit through the bowel thereby lessening the time available for bacteria to metabolize protein into ammonia, works just as well.

Lactulose can be given rectally for patients who cannot take oral medications. One regimen is 300 mL (200 gm) of lactulose syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.

Antibiotics

Antibiotics may be given to kill bacteria present in the bowel thereby decreasing bacterial conversion of protein to ammonia (and other toxic substances) there. Although effective, neomycin, a non-absorbable aminoglycoside antibiotic, is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased gut permeability, thus increasing the risk of renal failure and hearing loss (i.e. two of the potential side effects of neomycin). The former side-effect, in particular, is especially worrisome given the already increased likelihood of renal failure in cirrhosis and portal hypertension (i.e. hepatorenal syndrome). Metronidazole 200 mg four times a day by mouth was similar to neomycin in short a randomized crossover trial.

Rifaximin

Rifaximin (Xifaxan®), received orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo. Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms. Similarly, rifaximin was as effective as neomycin and paromomycin. Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A number of concerns remain regarding rifaximin's role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose. There are also concerns regarding the cost-effectiveness of the medication.

Rifaximin may add to lactulose in preventing episodes of encephalopathy.

Benzodiazepine receptor antagonists

A meta-analysis of randomized controlled trials by the Cochrane Collaboration found benefit from flumazenil. The doses of flumazenil varied around a median of 2 milligrams over 10 minutes: 'Flumazenil was given as a continuous infusion (12 trials), preceded by bolus injections in two trials. One trial used only bolus injections. Patients received flumazenil at a total dose ranging from 0.2 to 19.5 milligram (median 2 milligram). The median duration of treatment was 10 minutes (range one minute to 72 hours)'. However, the benefit was short.

L-ornithine-L-aspartate

L-ornithine-L-aspartate stimulates the urea cycle, and has shown encouraging results in randomized controlled trials.

Assessment fitness for automobile driving

Hepatic encephalopathy, even minimal encephalopathy, can impair driving.

Six states madate that physicians report drivers with medical impairments (California, Delaware, Nevada, New Jersey, Oregon, and Pennsylvania). These states and 25 others grant immunity to physicians who report impaired drivers.