144

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

GI bleed; see Question 3).

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)

every

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p. 552

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

overdose.

144

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

disorder.

144 Severe, progressive HE can lead to irreversible brain damage (caused

by increased intracranial pressure), brain herniation, and death.

144,146,147

Pathogenesis

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

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.

144

AMINO ACID BALANCE

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

Nutrition).

148,149

γ-AMINOBUTYRIC ACID

Schafer et al.

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

not clearly defined.

151,152

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

HE.

144,153,154

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

ammonium ion (NH4

+

).

155,156

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

al.

161

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.

161

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

snack.

157,158

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CASE 25-3, QUESTION 5: Which pharmacologic interventions are appropriate to manage R.C.’s hepatic

encephalopathy?

LACTULOSE

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).

144 When the

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

discontinued.

144 The administration of lactulose permits better dietary protein

tolerance and is well tolerated if dosages are kept sufficiently low to avoid

diarrhea.

162

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.

146

RIFAXIMIN

Rifaximin is a synthetic antibiotic structurally related to rifamycin. It has a wide

spectrum of antibacterial activity against gram-negative and gram-positive bacteria,

both aerobic and anaerobic.

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

excretion of unchanged drug.

82,165

It was introduced in the United States for the

treatment of travelers’ diarrhea,

166 but also is indicated for HE.

165 Although dosages

used in HE trials ranged from 550 mg twice daily to 400 mg every 8 hours,

167,168

the

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

reported with prolonged use.

169 Bacterial superinfections (Clostridium difficile—

associated diarrhea) with >2 months of rifaximin have also been reported.

82,165

NEOMYCIN

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

2 weeks.

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,

penicillin, and vitamin K.

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

(retained for 30–60 minutes) 4 times daily.