Hepatic Encephalopathy

 

1. Pathophysiology of hepatic encephalopathy:

a) Definitive answer unclear, but likely related to impaired clearance of culprit substances resulting from hepatic dysfunction

b) Ammonia hypothesis: primary source of amomonia is breakdown of protein and urea by colonic bacteria, which is subsequently absorbed by enterocytes

      - Under normal circumstances, first-pass metabolism is extensive, with 80% cleared by liver

      - With liver disease, decreased metabolism and porto-systemic shunts (from portal hypertension) lead to increased circulating levels of ammonia

      - Ammonia crosses blood-brain barrier, where it has multiple effects:

         - Increased intracellular osmolarity of astrocytes, leading to cell swelling

         - Activation of GABA (inhibitory) pathways

         - Impairment of glutamine and catecholamine (excitatory) pathways

 

 

2. Clinical manifestations and grading of hepatic encephalopathy:

a) Manifests as reversible neuropsychiatric abnormalities

b) Findings can be subtle, thus requiring high index of suspicion

c) Many patients with cirrhosis have persistent, mild cognitive impairment

d) One of earliest clinical symptoms is disturbance in diurnal sleep patterns

e) Spectrum of presentation is broad, but some signs to be aware of are: bradykinesia, asterixis, hyperreflexia, ataxia, clonus

f) Loss of time typically preceeds loss of place

g) Grading system exists (West Haven), progressing from grade I (mild sx) to grade IV (frank coma)

 

 

3. Diagnosis of hepatic encephalopathy:

a) Ammonia levels are neither sensitive nor specific, and do not correlate with the effectivness of therapy or resolution of symptoms

b) Thus, role in diagnosis and monitoring of treatment is limited

c) One potential setting is in the initial evaluation of patient with AMS and no known history

 

 

4. Precipitants of hepatic encephalopathy:

a) In patient in whom HE is suspected, key is to identify precipitating factor and treat this

b) While ammonia hypothesis is not completely established, it is helpful to use as a framework to think about precipitants:

      - Increased ammonia production/absorption:

         - Excess dietary protein

         - GI bleed (protein load)

         - Electrolytes (hypokalemia): leads to compensatory intracellular shift of hydrogen ions and increased production of ammonia in renal tubules

         - Constipation: Increased transit time leads to increased ammonia production by GI flora

         - Infection: Inflammatory catabolic state

      - Increased diffusion of ammonia across blood-brain barrier

         - Dehydration --> contraction alkalosis --> conversion of ammonium to ammonia, which more readily crosses blood-brain barrier

      - Decreased ammonia clearance

         - Worsening hepatic insufficiency

         - Increased portosystemic shunting (e.g. TIPS)

         - AKI (e.g. HRS)

 

 

5. Treament of hepatic encephalopathy

a) Nonabsorbable disaccharides (lactulose): Historically, data supporting this has not been robust, but recent trial showed efficacy (see attached).

      - Enterocytes lack disaccharidase to break down lactulose down, allowing it to reach colon, where it is broken down into fatty acids by bacteria

         - Resultant decrease pH converts ammonia to ammonium, thus trapping it in the colonic lumen

      - Displaces urease-producing bacteria (Klebsiella, Proteus) with Lactobacillus species

      - Cathartic effects increase nitrogen clearance

b) Antibiotics: Decrease ammonia production by reducing intestinal flora

      - Neomycin: effective, but absorbed systemically, so concern for traditional side effects of aminoglycosides

      - Rifaximin: non-absorbable broad-spectrum antibiotic, shown recently to be superior to lactulose (see attached)

c) Other:

      - Zinc: repletes possible deficiency in glutamatergic neurons, but evidence insufficient to support use

 

 

(Christopher Woo MD, 7/27/10)