The clinical features (as seen in R.C.) include altered mental state and asterixis.
He is classified as having OHE, Type C, Grade III, Episodic, Precipitated (by upper
Asterixis can be demonstrated by having the patient hyperextend his or her wrist
with the forearms outstretched and fingers separated. It is characterized by bilateral,
synchronous, repetitive arrhythmic motions occurring in bursts of one flap (twitch)
1 to 2 seconds. Asterixis is not specific for HE and may also be present in uremia,
hypokalemia, heart failure, ketoacidosis, respiratory failure, and sedative
As discussed in the questions that follow, the pharmacologic management of HE is
guided by both an understanding of the pathogenesis of this disorder and the stage of
severity demonstrated by the individual patient. In most cases, HE is fully reversible;
therefore, it is likely a metabolic or neurophysiologic rather than an organic
144 Severe, progressive HE can lead to irreversible brain damage (caused
by increased intracranial pressure), brain herniation, and death.
CASE 25-3, QUESTION 2: What is the pathogenesis of hepatic encephalopathy?
Several theories exist about the pathogenesis of HE. The most widely referenced
theories involve abnormal ammonia metabolism; altered ratio of branched chain to
aromatic amino acids; imbalance in brain neurotransmitters, such as γ-aminobutyric
acid (GABA) and serotonin; derangement in the blood brain–barrier; and exposure of
the brain to accumulated “toxins.”
148 The pathogenesis of HE is likely multifactorial.
Ammonia is a byproduct of dietary protein metabolism or digestion of protein-rich
blood in the GI tract (e.g., from bleeding esophageal varices). Bacteria present in the
GI tract digest protein into polypeptides, amino acids, and ammonia. These
substances are then absorbed across the intestinal mucosa. Ammonia is readily
metabolized in the liver to urea, which is then renally eliminated. However, when
blood flow and hepatic metabolism are impaired by cirrhosis, serum and CNS
concentrations of ammonia are increased. The ammonia that enters the CNS combines
with α-ketoglutarate to form glutamine, an aromatic amino acid. Ammonia has been
considered central to the pathogenesis of HE. An increased ammonia level raises the
amount of glutamine within astrocytes, causing an osmotic imbalance, cell swelling,
and ultimately brain edema. Although high serum ammonia and cerebrospinal
glutamine concentrations are characteristic of encephalopathy, they may not be the
actual cause of this syndrome.
147,149 According to the AALSD/EASL guidelines, high
ammonia levels alone may not add any diagnostic, staging, or prognostic value.
However, if a level is normal, the diagnosis of HE should be questioned. In the case
where ammonia-lowering drugs are used (e.g., lactulose), repeated measurements of
ammonia would be beneficial to assess their efficacy.
In both acute and chronic liver failure, the ratio of the branched chain to aromatic
amino acids is altered. Because of the higher permeability of aromatic amino acid
across the blood–brain barrier and into the cerebrospinal fluid, some aromatic
compounds can lead to production of “false neurotransmitters” that can lead to
hepatic encephalopathy with altered mental status (see Chapter 38, Adult Parenteral
150 proposed that in liver disease, gut-derived GABA escapes hepatic
metabolism, crosses the blood–brain barrier, binds to its postsynaptic receptor sites,
and causes the neurologic abnormalities associated with HE. Others hypothesize that
endogenous benzodiazepine-like substances, via their agonist properties, contribute
to the pathogenesis of hepatic encephalopathy by enhancing GABA-ergic
neurotransmission. The role of GABA and endogenous benzodiazepines in HE is still
Of all the toxins suspected to cause hepatic coma, ammonia and certain aromatic
amino acids are most commonly studied. Other precipitating factors include
infections, electrolyte disorders, GI bleeding, constipation, and over diuresis. These
factors may increase the serum ammonia and precipitate an exacerbation of
CASE 25-3, QUESTION 3: What are the probable precipitating causes of hepatic encephalopathy in R.C.?
The main precipitating cause of HE in R.C. was the sudden onset of upper GI
bleeding. The bacterial degradation of blood in the gut results in absorption of large
amounts of ammonia and possibly other toxins into the portal system. Other important
contributory factors in this case are diuretic-induced hypovolemia (BUN:SCr ratio
>20), hypokalemia (potassium, 3.1 mEq/L), and potentially metabolic alkalosis
(continuous NG suctioning and furosemide). Overzealous diuretic therapy increases
HE by inducing pre-renal azotemia, hypokalemia, and metabolic alkalosis. Alkalosis
promotes diffusion of nonionic ammonia and other amines into the CNS. The
associated intracellular acidosis “traps” the ammonia by converting it back to
Sedating drugs such as opioids (e.g., morphine, methadone, meperidine, codeine),
sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate), and tranquilizers
(e.g., phenothiazines) can also precipitate HE. Encephalopathy precipitated by most
drugs can be explained by increased CNS sensitivity and decreased hepatic
clearance with subsequent drug and, in some cases, active metabolite accumulation.
For R.C., the morphine and prochlorperazine might have contributed to the worsening
of his HE. Although not applicable to this case, excessive dietary protein, infections,
and constipation can also contribute to excess nitrogen load and hepatic coma.
Treatment and General Management
CASE 25-3, QUESTION 4: What nondrug steps should be taken to manage R.C.’s hepatic encephalopathy?
Correcting the precipitating factor underlying the episode of OHE can improve
mental status in 90% of patients.
144 After identifying and removing precipitating
causes of HE, therapeutic management is aimed primarily at reducing the amount of
ammonia or nitrogenous products in the circulatory system. The 2013 ISHEN
guidelines recommend an energy intake of 35 to 40 kcal/kg of body weight/day and a
protein intake of 1.2 to 1.5 g/kg of ideal body weight/day for cirrhotic patients and
those awaiting liver transplantation surgeries.
157–160 A study conducted by Cordoba et
randomized patients with cirrhosis and HE to two dietary groups for 14 days.
The first group followed a progressive increase in the dose of protein receiving 0 g
of protein for the first 3 days, then the protein was increased progressively every 3
days (12, 24, and 48 g) up to 1.2 g/kg/day for the last 2 days. The second group
received 1.2 g/kg/day from the first day. Results showed that the course of HE was
not significantly different between groups. The patients in the first group, however,
experienced a higher degree of protein breakdown.
R.C. is a cachectic male, and care should be taken in providing nutrition to
malnourished patients. The 70-g protein, 2,000-kcal diet ordered for R.C. is
appropriate because it falls within the recommended weight-based ranges
established by the ISHEN guidelines. R.C. should be offered small meals or liquid
nutritional supplements evenly distributed throughout the day along with a late-night
CASE 25-3, QUESTION 5: Which pharmacologic interventions are appropriate to manage R.C.’s hepatic
Lactulose is broken down by GI bacteria to form lactic, acetic, and formic acids,
which acidify colonic contents converting ammonia into the less readily absorbed
ammonium ion. Back diffusion of ammonia from the plasma into the GI tract can also
occur. The net result is a lower plasma-ammonia concentration. The absorption of
other protein breakdown products (e.g., aromatic amino acids) may also be reduced.
Lactulose-induced osmotic diarrhea decreases intestinal transit time available for
ammonia production and absorption, and it may help clear the GI tract of blood.
Lactulose syrup (10 g/15 mL) has been used successfully for the treatment of HE. For
OHE, lactulose 25 mL is administered every 1 to 2 hours until catharsis occurs.
Doses are then titrated downward to maintain 2 to 3 bowel movements daily and
clear mentation in order to avoid complications of overuse of lactulose (aspiration,
dehydration, severe perianal skin irritation, and precipitation of HE).
oral route of administration is not possible, as in the treatment of a comatose patient,
it may be necessary to administer the drug through an NG tube. Alternatively, a rectal
retention enema compounded with 300 mL of lactulose in 700 mL water can be
prepared. The lactulose water mixture (125 mL) is retained for 30 to 60 minutes,
although this is difficult in patients with altered mental status. The beneficial clinical
effect of lactulose occurs within 12 to 48 hours. Patients may need long-term
administration of lactulose as maintenance therapy, especially in patients with
recurring HE. For prevention of recurrence of OHE, oral daily prophylactic dosing
of lactulose should be maintained. If precipitating factors have been removed or liver
function improved, prophylactic therapy may be tapered and potentially
144 The administration of lactulose permits better dietary protein
tolerance and is well tolerated if dosages are kept sufficiently low to avoid
Although lactulose is the mainstay of HE treatment,
144,163 very limited data exist
evaluating its efficacy. Care should be taken not to induce excessive diarrhea that
could lead to dehydration and hypokalemia, both of which have been associated with
exacerbation of HE. Although lactulose is generally well tolerated, 20% of patients
may complain of gaseous distention, flatulence, or belching. Dilution with fruit juice,
carbonated beverages, or water can reduce the excessive sweetness of the syrup.
Rifaximin is a synthetic antibiotic structurally related to rifamycin. It has a wide
spectrum of antibacterial activity against gram-negative and gram-positive bacteria,
164 Of note, 96.6% of the drug is recovered in the feces as
unchanged drug, and what is absorbed undergoes metabolism with minimal renal
It was introduced in the United States for the
treatment of travelers’ diarrhea,
166 but also is indicated for HE.
used in HE trials ranged from 550 mg twice daily to 400 mg every 8 hours,
FDA-approved dose for HE is 550 mg twice daily.
165 Rifaximin is well tolerated, but
can cause flatulence, nausea, and vomiting. Some urticarial skin reactions have been
169 Bacterial superinfections (Clostridium difficile—
associated diarrhea) with >2 months of rifaximin have also been reported.
Neomycin is also an antibiotic effective in reducing plasma-ammonia concentrations
(presumably by decreasing protein-metabolizing bacteria in the GI tract).
Approximately 1% to 3% of the neomycin dose is absorbed. Chronic use in patients
with severe renal insufficiency can cause ototoxicity or nephrotoxicity. Routine
monitoring of serum creatinine, presence of protein in the urine, and estimation of
creatinine clearance are advisable for patients receiving high dosages for more than
162 Neomycin therapy can also produce a reversible malabsorption syndrome
that not only suppresses the absorption of fat, nitrogen, carotene, iron, vitamin B12
xylose, and glucose but also decreases the absorption of some drugs, such as digoxin,
146 Typical HE dosage for neomycin ranges from 500 to
1,000 mg 4 times daily, or as a 1% solution (125 mL) given as a retention enema
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