Resident Version
Hepatic Encephalopathy Module
Created by Dr. Greg Fotieo
Objectives:
1) Review the clinical presentation and staging of hepatic encephalopathy
2) Review what is known about the pathogenic mechanism of hepatic
encephalopathy
3) Recognize the precipitants of hepatic encephalopathy
4) Discuss treatment of hepatic encephalopathy
References:
1. Fitz, GJ, Chapter 89 – Hepatic Encephalopathy, Hepatopulmonary Syndromes,
Hepatorenal Syndromes and Other Complications of Liver Disease, Feldman:
Sleisenger & Fordtran’s Gastroenterology and Liver Disease, 8th ed.
2. www.uptodate.com: Pathogenesis of hepatic encephalopathy, Clinical
manifestations and diagnosis of hepatic encephalopathy, Treatment of hepatic
encephalopathy.
3. Als-Nielsen et al, Nonabsorbable disaccharides for hepatic encephalopathy.
Cochrane Database Syst Rev 2004
Case:
Mr. Jones is a 64 yo man with a history of cirrhosis due to Hepatitis C and alcohol. He is
brought to the ED by his daughter because he is confused. The last time the daughter
spoke to him was a week ago and he seemed to be his usual self. However, when she
went to visit him today, he was confused and disoriented.
Meds: Spironolactone 100 mg po qd
Lasix 40 mg po qd
Exam:
VS: afebrile, lying BP 110/66 HR 102
seated BP 90/62 HR 120
General- patient is lying in bed asleep, he is arousable but falls right back to sleep, he has
slurred speech and cannot answer questions
Mouth- dry mucous membranes
Eyes- no scleral icterus
Neck- no nodes, supple
Chest- faint crackles in bases B, multiple spider telangectasias
CV- regular, tachycardic, nl S1 and S2, no murmur
Abd- scaphoid, normoactive BS, no rigidity, no guarding, unable to palpate liver edge,
spleen tip palpable 5 cm below L costal margin
Ext- muscle wasting, no edema
Rectal- dark brown stool, guaiac +
Neuro- difficult exam due to patient’s somnolence, diffuse hyporeflexia, + clonus
Lab:
WBC- 2.0 ( 70% PMN’s)
H/H 10/30
Platelets- 43 K
Na 134 K+ 2.4 Cl 92 HCO3 30 BUN 20 Creat 0.5
TP 8.1 alb 2.5 AST 99 ALT 110 Alk P 188 Bili 2.8/1.3
Question #1: What is your differential for the patient’s decline in neurologic
function?
Question #2: How would you proceed with your work up?
Question #3: Would you be less confident in your diagnosis if the ammonia level
was normal?
Question #4: How would you grade the severity of the patient's HE?
Question #5: What are the factors that may have precipitated the patient’s
development of HE?
Question #6: How would you manage this patient?
Discussion/Answers to questions 1-6
Question 1): Unfortunately, we are not able to get much history from the patient or
family. Therefore, a broad differential needs to be considered. Although hepatic
encephalopathy (HE) is a strong consideration given his underling advanced chronic liver
disease, other possible etiologies for the mental status changes include metabolic
derangements, infectious processes, endocrine abnormalities, primary CNS events, and
intoxication.
Question 2): A non-contrasted head CT was done and was unremarkable other than
diffuse cerebral atrophy. ETOH level was 0. Urine tox screen was negative. CXR and
urinalysis were unremarkable. His ammonia level came back elevated at 105. An
abdominal ultrasound showed a small liver, enlarged spleen and no ascites.
You feel confident that the patient’s depressed mental status is due to HE. Hepatic
encephalopathy or portosystemic encephalopathy is defined as a spectrum of potentially
reversible neuropsychiatric abnormalities in patients with liver dysfunction. The
diagnosis can only be made after exclusion of other causes of mental dysfunction. It can
occur with either acute liver failure or cirrhosis.
Question 3): Most patients with HE will have elevated ammonia levels, however an
elevated ammonia level is not required to make the clinical diagnosis of HE.
Approximately 20-40% of patient with HE will have normal ammonia levels. Ammonia
levels can be elevated in non-hepatic conditions as well and are not diagnostic of HE.
The precise pathogenic mechanism of HE is not fully understood. A number of
metabolic factors contribute to HE. The responsible toxins include short chain fatty
acids, mercaptans, false neurotransmitters, manganese, ammonia and gammaaminobutyric acid. The accumulation of these neurotoxic substances results in
morphologic changes in astrocytes. Cerebral edema also appears to play a role.
Ammonia appears to be the major toxin responsible for HE. The GI tract is the primary
source of ammonia production. It is produced by colonic bacterial degradation of
nitrogenous compounds and by enterocytes which convert glutamine into glutamate and
ammonia. Ammonia is absorbed into the portal circulation where ammonia levels are 510 fold higher than in mixed venous blood. A healthy, functioning liver is able to convert
ammonia to glutamine prior to its entry into the systemic circulation. In patients with
advanced liver disease, both hepatic dysfunction (impaired metabolism of ammonia) and
shunting of blood around the liver (diversion of ammonia rich blood into the systemic
circulation) result in elevated systemic ammonia levels.
Ammonia and other toxins interfere with brain function at a number of levels. Elevated
ammonia levels appear to increase the cerebral uptake of neutral amino acids which
affects the synthesis of various neurotransmitters. Hyperammonemia also causes brain
edema and decreased cerebral glucose oxidation.
Question 4): Grading is based on clinical neuropsychatric findings. The most common
system grades HE from stages 1-4 (Table 1). Our patient would be graded as Stage 3.
The onset of HE can be insidious. Subclinical or minimal HE occurs in patients with
liver disease and very subtle changes in mental function. Subclinical HE is a common
entity that usually can only be diagnosed with psychometric tests. Studies have shown
that up to half of compensated cirrhotic patients who appear to have normal mental status
have subclinical HE when formal psychometric testing is done. These patients may also
have an impaired ability to drive.
Table 1. Clinical Stages of Hepatic Encephalopathy
Impairment
Clinical
Stage
Intellectual Function
Subclinical Normal examination findings,
but work or driving may be
impaired
Neuromuscular Function
Subtle changes on psychometric or number
connection tests
Stage 1
Impaired attention, irritability, Tremor, incoordination, apraxia
depression, or personality
change
Stage 2
Drowsiness, behavioral
changes, poor memory and
computation, sleep disorders
Asterixis, slowed or slurred speech, ataxia
Stage 3
Confusion and disorientation,
somnolence, amnesia
Hypoactive reflexes, nystagmus, clonus,
and muscular rigidity
Stage 4
Stupor and coma
Dilated pupils and decerebrate posturing;
oculocephalic (“doll's eye”) reflex; absence
of response to stimuli in advanced stages
Question 5): It is estimated that precipitating factors are responsible for 80% of episodes
of HE. The most common precipitants of HE are GI bleeding, increased protein intake,
infection, constipation, hypokalemia, metabolic alkalosis, sedatives, uremia, dehydration
and portosystemic shunting.
Hypokalemia causes intracellular K+ to be exchanged for extracellular H+. The
intracellular acidosis in renal tubular cells results in an increase ammonia production.
Metabolic alkalosis promotes the conversion of ammonium (NH4+) into ammonia
(NH3). Hypokalemia and metabolic alkalosis are often the result of diuretics used to
manage patients with advanced liver disease and ascites.
Uremia results in urea diffusing into the colon where colonic bacteria convert it into
ammonia. Increased protein intake, constipation and GI bleeding also increase delivery
of nitrogenous substances to the GI tract resulting in increased absorption of ammonia.
HE occurs in about 30% of patients who undergo portosystemic shunt surgery. It can
even occur in patients with no underlying liver disease who undergo portosystemic
shunting.
In this case, the patient’s HE was likely precipitated by multiple factors. The patient has
a hypokalemic, metabolic alkalosis with evidence of dehydration likely due to his
diuretics. The elevated BUN and guaiac + stool are consistent with an upper GI bleed.
Question 6): The first step in managing HE is to identify and correct the precipitating
causes. Mr. Jones should have an NG tube placed and lavage performed. He should be
rehydrated and have his potassium repleted.
Once precipitating factors have been addressed, ammonia lowering therapy should be
initiated. Synthetic disaccharides (lactulose is most commonly used) are the mainstays of
therapy for HE. Disaccharides are metabolized by bacterial flora to short chain fatty
acids. This lowers the colonic pH which favors the conversion of ammonia (NH3) to
nonabsorbable ammonium ( NH4+) which is trapped in the colon. Lactulose should be
given to achieve 2-3 loose bowel movements per day with a pH below 6. The typical
dose of lactulose required to achieve this goal is 45 to 90 g per day. It can be given
through a nasogastric or by enema in patients who are unable to take it orally. There have
been numerous small clinical studies over the years showing the efficacy of disaccharides
for the treatment of HE. Approximately 70 to 80% of patients with hepatic
encephalopathy improve with lactulose treatment although mortality benefit has not been
shown.
Antibiotics have also been used to treat HE. They are felt to work by decreasing the
concentration of colonic bacteria. Neomycin has been used to treat HE but no controlled
studies have demonstrated efficacy. Other antibiotics are better tolerated and less toxic
than neomycin but also do not have strong evidence for efficacy and can lead to bacterial
overgrowth. Ornithine-aspartate has been demonstrated to decrease ammonia levels. It
appears to be more effective than placebo but has not been compared to lactulose therapy.
These alternative therapies are usually reserved as second line agents and are limited to
use in patients that do not respond to disaccharides.
Test Questions:
1) A 47 yo woman with primary biliary cirrhosis presents to your clinic with complaints
of insomnia, irritability and trouble with concentration. You suspect mild HE. Your next
step should be:
A. Perform an EEG
B. Place the patient on a protein restricted diet
C. Give a trial of a benzodiazepine
D. Give an empiric trial of lactulose
2) Which of the following is NOT true about serum ammonia levels:
A. Ammonia levels may be helpful in elucidating the cause of worsening mental
function in patients with chronic liver disease
B. Some patients with elevated ammonia levels may have normal mental
functioning
C. Serial ammonia levels are the best way to assess the clinical response to treatment
D. Ammonia levels are affected by phlebotomy technique
Post Module Evaluation
Please place completed evaluation in an interdepartmental mail envelope and address to
Dr. Wendy Gerstein, Department of Medicine, VAMC (111).
1) Topic of module:__________________________
2) On a scale of 1-5, how effective was this module for learning this topic? _________
(1= not effective at all, 5 = extremely effective)
3) Were there any obvious errors, confusing data, or omissions? Please list/comment
below:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
4) Was the attending involved in the teaching of this module? Yes/no (please circle).
5) Please provide any further comments/feedback about this module, or the inpatient
curriculum in general:
6) Please circle one:
Attending
Resident (R2/R3)
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