HEPATIC ENCEPHALOPATHY

DEFINITION

Syndrome observed in patients with cirrhosis of the liver. characterized by personality changes,

intellectual impairment, and a depressed level of consciousness.

What is Hepatic Encephalopathy?

Broadly defined: All neurological and psychological symptoms in patients with liver disease that

cannot be explained by presence of other pathologies

Brain and nervous system damage secondary to severe liver dysfunction (most often chronic

disease) resulting from failure of liver to remove toxins

Multifactorial pathogenesis with exact cause unknown

Symptoms vary from nearly undetectable, to coma with decerebration

Characterized by various neurologic symptoms

Cognitive impairment

Neuromuscular disturbance

Altered consciousness

Reversible syndrome

INTRODUCTION

Hepatic encephalopathy (HE) It represents a reversible decrease in neurologic

function, based upon the disorder of metabolism which are caused by severe decompensate liver

disease

Portal-systemic encephalopathy patients with portal hypertension abnormal shunting of blood

Subclinical or latent HE diagnosed only by using precise mental tests or EEG no obvious

clinical and biochemical abnomalities

Incidence & Prognosis

Incidence

10-50% of cirrhotic pts and portal-systemic shunts (TIPS) experience episode of overt hepatic

encephalopathy

True incidence/prevalence of HE unknown

Lack of definitive diagnosis

Wide spectrum of disease severity

Prognosis

40% survival rate 1 year following first episode

15% survival rate 3 years following first episode

Variants of Hepatic Encephalopathy

Acute HE

Associated with marked cerebral edema seen in patients with the acute onset of hepatic failure

(FHF)

Hormonal disarray, hypokalemia, vasodilation (ie, vasopressin release)

Quick progression: coma, seizures, and decerebrate rigidity

Altered mental function attributed to increased permeability of the blood-brain barrier and

impaired brain osmoregulation

Results in brain cell swelling and brain edema

Can occur in cirrhosis, but usually triggered by precipitating factor

Precipitating factors usually determine outcome

Precipitants of Hepatic Encephalopathy

Drugs

• Benzodiazepines

• Narcotics

• Alcohol

Dehydration

• Vomiting

• Diarrhea

• Hemorrhage

• Diuretics

• Large volume paracentesis

Portosystemic Shunting

• Radiographic or surgically placed shunts

• Spontaneous shunts

• Vascular Occlusion

• Portal or Hepatic Vein Thrombosis

Increased Ammonia Production,

Absorption or Entry Into the Brain

• Excess Dietary Intake of Protein

• GI Bleeding •Infection

• Electrolyte Disturbances (ie., hypokalemia)

• Constipation •Metabolic alkalosis

Variants of Hepatic Encephalopathy

Chronic HE

Occurs in subjects with chronic liver disease such as cirrhosis and portosystemic shunting of

blood (Portal Systemic Encepalopathy [PSE])

Characterized by persistence of neuropsychiatric symptoms despite adequate medical therapy.

Brain edema is rarely reported

Refractory HE

Recurrent episodes of an altered mental state in absence of precipitating factors

Persistent HE

Progressive, irreversible neurologic findings: dementia, extrapyramidal manifestations,

cerebellar degeneration, transverse cordal myelopathy, and peripheral neuropathy

Subclinical or “Minimal HE

Most frequent neurological disturbance

Not associated with overt neuropsychiatric symptoms

Subtle changes detected by special psychomotor tests

Stages of Hepatic Encephalophay

Stage Symptoms

I Mild Confusion, agitation, irritability, sleep disturbance, decreased attention

II Lethargy, disorientation, inappropriate behavior, drowsiness

III Somnolent but arousable, slurred speech, confused, aggressive

IV Coma

Propossed theories of hepatic encephalopathy

Ammonia hypothesis

produced in the G.I. tract by bacterial degradation of amines, amino acids, purines, and urea.

Normally, ammonia is detoxified in the liver by conversion to urea and glutamine by the Krebs-

Henseleit cycle.

In liver disease or in the presence of portosystemic shunting, portal blood ammonia is not

efficiently converted to urea.

Increased levels of ammonia may enter the systemic circulation

Normal skeletal muscle aids in the metabolism of ammonia in the conversion of glutamate to

glutamine.

The muscle wasting that is observed in patients with advanced cirrhosis may potentiate

hyperammonemia.

multiple neurotoxic effects:

altering the transit of amino acids, water, and electrolytes across the neuronal membrane. can

also inhibit the generation of both excitatory and inhibitory postsynaptic potentials.

clinical observation: strategies designed to reduce serum ammonia levels tend to improve hepatic

encephalopathy.

An argument against the ammonia hypothesis includes the observation that approximately 10%

of patients with significant encephalopathy have normal serum ammonia levels.

many patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy

Ammonia does not induce the classic electroencephalographic (EEG) changes associated with

hepatic encephalopathy when it is administered to patients with cirrhosis.

GABA hypothesis

GABA is a neuroinhibitory substance produced in the gastrointestinal tract. Of all brain nerve

endings, 24-45% may be GABAergic. Increased GABAergic tone is observed in patients with

cirrhosis, perhaps because of decreased hepatic metabolism of GABA.

When GABA crosses the extrapermeable blood-brain barrier of patients with cirrhosis, it

interacts with supersensitive postsynaptic GABA receptors. The GABA receptor, in conjunction

with receptors for benzodiazepines and barbiturates, regulates a chloride ionophore.

Binding of GABA to its receptor permits an influx of chloride ions into the postsynaptic neuron,

leading to the generation of an inhibitory postsynaptic potential. Administration of

benzodiazepines and barbiturates to patients with cirrhosis increases GABAergic tone and

predisposes to depressed consciousness.

Clinical features

Asterixis- flapping hand tremors ---early sign

ÜLOC – lethargy progressing to coma

Ü mental status, confusion, disorientation

dullness, slurred speech

behavioral changes, lack of interest in grooming/ appearance

twitching, muscular incoordination, tremors

Fetor hepaticus

elevated serum ammonia level

Symptoms of Hepatic encephalopathy

Changes in mental state, consciousness

Confusion, disorientation

Delirium

Dementia (loss of memory, intellect)

Mood swings

Decreased altertness, responsiveness

Coma

Course muscle tremors

Muscle stiffness or rigidity

Loss of small hand movements (handwriting)

Seizures (rare)

Decreased self-care ability

Speech impairment

Flapping Tremor

LABORATORY ABNORMALITIES IN HEPATIC ENCEPHALOPATHY

An elevated blood ammonia level is the classic laboratory abnormality reported in patients with

hepatic encephalopathy. This finding may aid in correctly diagnosing patients with cirrhosis who

present with altered mental status

EEG

EEG changes are high-amplitude low-frequency waves and triphasic waves. However, these

findings are not specific for hepatic encephalopathy. When seizure activity must be ruled out, an

EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental status.

CT and MRI

Computed tomography and magnetic resonance imaging studies of the brain may be important in

ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question.

MRI

additional advantage of being able to demonstrate hyperintensity of the globus pallidus on T1-

weighted images, a finding that is commonly described in hepatic encephalopathy.

Drawing Tests

Common precipitating factors

Renal failure: Renal failure leads to decreased clearance of urea, ammonia, and other nitrogenous

compounds.

Common precipitating factors

Gastrointestinal bleeding: The presence of blood in the upper gastrointestinal tract results in

increased ammonia and nitrogen absorption from the gut. Bleeding may predispose to kidney

hypoperfusion and impaired renal function.

Blood transfusions may result in mild hemolysis, with resulting elevated blood ammonia levels.

Infection: Infection may predispose to impaired renal function and to increased tissue

catabolism, both of which increase blood ammonia levels.

Constipation: Constipation increases intestinal production and absorption of ammonia.

Medications: Drugs that act upon the central nervous system, such as opiates, benzodiazepines,

antidepressants, and antipsychotic agents, may worsen hepatic encephalopathy.

Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion

of NH4+ to NH3.

Dietary protein overload: This is an infrequent cause of hepatic encephalopathy.

DIFFERENTIAL DIAGNOSIS FOR HEPATIC ENCEPHALOPATHY

Intracranial lesions such as subdural hematoma, intracranial bleeding, stroke, tumor, and abscess

Infections such as meningitis, encephalitis, and intracranial abscess

Metabolic encephalopathy such as hypoglycemia, electrolyte imbalance, anoxia, hypercarbia,

and uremia

Hyperammonemia from other causes such as secondary to ureterosigmoidostomy and inherited

urea cycle disorders

Toxic encephalopathy from alcohol intake, such as acute intoxication, alcohol withdrawal, and

Wernicke encephalopathy

Toxic encephalopathy from drugs such as sedative hypnotics, antidepressants, antipsychotic

agents, and salicylates

Organic brain syndrome

Postseizure encephalopathy

Management of Hepatic Encephalopathy

First and foremost control the underlying precipitant(s).

Medical therapy - optimal agent is controversial (see meta-analysis)

Lactulose - has multiple actions including cathartic, acidification of the colon to

“ion-trap” ammonia as NH4+, and reduces inoculum of urea-splitting bacteria.

Drawbacks include osmotic diarrhea with hypernatremia due to free water loss

and gaseous bowel distension.

Neomycin - non-absorbed aminoglycoside which reduces colon bacterial burden. Dose

at 2-6 grams orally per day. Small incidence of ototoxicity and nephrotoxicity with

prolonged usage.

Metronidazole - oral dosing at 800 mg/day. No large scale reported experience. Is

associated with neurotoxicity in hepatic failure due to accumulation.

Flumazenil - benzodiazepine receptor (GABA) antagonist.

Encephalopathy Treatment

Step 1 requires attempts to identify the precipitating cause – three most common include

azotemia secondary to aggressive diuresis, and/or persistent vomiting or diarrhea; overuse of

tranquillizers, sedatives, or analgesics; and GI bleeding, other causes include increased dietary

protein intake, alkalosis, infection and hypokalemia

Step 2 requires interventions to reduce the production and absorption of gut-mediated ammonia

and other toxins which is accomplished through reduction and modification of dietary protein,

altering the enteric bacteria and the colonic environment through the use of antibiotics and

lactulose

Step 3 requires the use of agents such as bromocriptine and flumazemil that directly modify

neurotransmitter balance, currently these therapies are not widely used, and have not been shown

to be highly effective

Nursing care

Interventions:

a. ) Ü ammonia production

Üdietary protein to 20-40 g/day, maintain adequate calories

Ü ammonia formation in the intestine – give laxative, enema as ordered and

Neomycin - Ü bacterial ammonia production

b.) Protect pt. from injury

side rails up

turning to side

assess mental status, LOC

proper positioning (semi-Fowler’s)

prevent aspiration

c.) Prevent further episodes of encephalopathy

low protein diet

prescribed medications

avoid constipation ( to Ü ammonia production by bacteria in the GIT)

early signs of encephalopathy (restlessness, slurred speech, dec. attention span)

HEPATIC FAILURE

Introduction

Liver failure is the inability of the liver to perform its normal synthetic and metabolic function

as part of normal physiology. Liver failure occurs when large parts of the liver become damaged

beyond repair and the liver is no longer able to function.

Liver failure is a life-threatening condition that demands urgent medical care. Most often liver

failure occurs gradually and over many years. However, a more rare condition known as acute

liver failure occurs rapidly (in as little as 48 hours) and can be difficult to detect initially.

Two forms are recognized

Acute liver failure - development of hepatic encephalopathy (confusion, stupor and coma) and

decreased production of proteins (such as albumin and blood clotting proteins) within four weeks

of the first symptoms (such as jaundice) of a liver problem. "Hyperacute" liver failure is said to

be present if this interval is 7 days or less, while "subacute" liver failure is said to be present if

the interval is 5-12 weeks.

Chronic liver failure usually occurs in the context of cirrhosis, itself potentially the result of

many possible causes, such as excessive alcohol intake, hepatitis B or C, autoimmune, hereditary

and metabolic causes (such as iron or copper overload or non-alcoholic fatty liver disease)

Fulminant hepatic failure

FHF - acute liver failure & encephalopathy within 8 weeks of signs and symptoms & without

history or physical evidence of chronic liver disease

Subfulminant HF- acute liver failure & encephalopathy 8 and 24 weeks after the onset of signs &

symptoms

A Classification based on the time interval from the onset of jaundice to the development of

encephalopathy

Hyperacute LF - within 7days

Acute LF - within 8 to 28 days

Subacute LF - between 5 to 28 weeks

Causes of liver failure

There are several causes of liver failure. The most common causes of liver failure are:

Hepatitis B

Hepatitis C

Long term, excessive alcohol consumption

Cirrhosis

Hemochromatosis

Malnutrition

Acetaminophen (Tylenol) overdose

Reaction to a prescribed medication

Ingestion of poisonous wild mushrooms

Molecules implicated in the pathogenesis of acute liver failure

The main cause of mortality in patients with acute hepatic failure is brain edema. Ammonia is

perhaps the most thoroughly studied molecule that has been implicated in the Pathogenesis of

hepatic encephalopathy and brain edema.

Effect of ammonia

Ammonia was converted to glutamine by astrocytes

Intracellular glutamine increasing intracellular osmolarity and causing cell swelling

Extracelluar glutamine stimulates n-NOS, causing vasodilatation.

Increases the cerebral uptake of the albumin-bound neutral amino acids, including tyrosine,

phenylalanine, and tryptophan.

An accumulation of endogenous benzodiazepines, GABA-like molecules, or both also

impairs neurotransmission

Symptoms of liver failure

The early symptoms of liver failure are similar to symptoms of many other conditions. Because

of this, liver failure may initially difficult to diagnose. Some of the most common initial

symptoms of liver failure are:

Nausea

Loss of appetite

Fatigue

Diarrhea

As liver failure progresses, the symptoms become more serious. The most common symptoms of

advanced liver failure include:

Jaundice

Bleeding easily

Swollen abdomen

Mental disorientation or confusion

Sleepiness

Coma  

Management

Goal: To remove toxin

Blood and blood component treatments

Hemodialysis

Hemodiafiltration

Plasmapheresis

Albumin dialysis

Blood and blood component treatments

By 1965, it was generally accepted that acute hepatic failure was a disease of metabolic origin.

Success of exchange transfusions in treating hemolytic disease of the newborn, carbon monoxide

poisoning, and acute renal failure led clinicians to apply exchange transfusions to acute liver

failure.

5-50 L of whole blood were used.

Cross-circulation.

Total body washout.

Hemodialysis

Although ammonia is removed with dialysis, serum ammonia levels are not substantially

lowered with hemodialysis.

Sorbent hemoperfusion:

Charcoal-based sorbents: not effectively remove protein-bound material and ammonia.

Synthetic resins: removing lipid-soluble molecules and protein-bound molecules

Anion exchange resins

Hemodiafiltration

Hemodiafiltration combines charcoal hemoperfusion with a cation exchange resin for improved

clearance of positively charged molecules.

Some improvement in neurologic function.

Did NOT to show any improvement in survival rate for patients with liver failure and

encephalopathy.

Plasmapheresis

Plasma exchange has been used sporadically in the management of acute liver failure during the

past 30 years.

Small series reported some benefit for patients with acute failure secondary to toxic ingestions.

The rationale for treatment is to prevent life-threatening complications.

Total plasma exchange can correct the bleeding diathesis associated with acute liver failure.

Plasma exchange did NOT significantly affect graft survival in patients with primary graft

dysfunction.

Intracellular, protein- and tissue-bound toxins were NOT effectively removed, and there was a

theoretic risk of removing unidentified hepatotrophic molecules from the circulation.

Complications of plasmapheresis included pulmonary edema, infection, and hypocalcemia from

citrate intoxication.

Albumin dialysis

Albumin synthesis was inhibited in ALF.

Some components is elevated in patient of ALF.

Bilirubin, aromatic amino acids, endogenous benzodiazepines, mercaptans, nitric oxide,

prostacyclins, and tryptophan.

Elevated toxic substance may be correlated with clinical status.

The Molecular Absorbent and Recirculating System (MARS)

Ameliorate hepatic encephalopathy and decrease the elevations of intracranial pressure (ICP).

Decrease in cerebral oxygen extraction concurrent with a clinical improvement in neurologic

status.

The effect is independent of plasma ammonia levels or hemodynamic status.

Large increases in factor VII levels, albumin levels, and the ratio of branched-chain amino acids

to aromatic amino acids (phase I trial).

A notable decrease in patient mortality seen with MARS treatment (30-day mortality :8.3% and

50% with MARS or medical treatment alone; p=0.0027) (a prospective RCT,2002).

MARS treatment did result in a marked increase in mean survival time in patient of hepatorenal

syndrome. (25.2 ±34.6 days in the MARS versus 4.6 ± 1.8 days in the hemodiafiltration alone

group,2000).

Nursing management

1. Activity intolerance related to fatigue, anemia from poor nutrition and bleeding,

ascites, dysponea from pressure of ascites to diaphragm, muscle wasting

Alternate rest & activity

Monitor hemoglobin and hematocrit to rule out any bleeeding.

Assist with daily living activities to conserve energy.

Administer iron supplements or blood transfusion as ordered to treat anemia.

Assist with measures to decrease edema and ascities to increase the lung capacity.

2. Ineffective protection related to decrease filtering of bacteria by liver and impaired

synthesis of clotting factors.

Monitor for manifestations of hemorrhage

Provide assistance with ambulation and activities of daily living.

Use small-gauge needles for injections and apply prolonged pressure after injection

Recommend soft – bristle toothbrush.

Teach to avoid vigorous blowing of nose or straining at stool.

Administer vitamin K as orederd.

Follow infection control procedures

3. Imbalanced nutrition: less than body requirements related to impaired utilization

and storage of nutrients from vomiting

Weigh daily

Provide oral hygiene before meals.

Administer antiemetic as ordered.

Provide small and frequent meals

Determine food preferences and assist in selection of those that contain low or no protein

and low salt.

Prevent constipation.

4. Acute confusion related to portal systemic encephalopathy occuring in conjunction

with gastrointestinal bleeding and accumulation of ammonia in the bloodstream.

Monitor manifestations of encephalopathy such as disorientation, changes in handwriting

or speech, or coma.

Encourage fluids

Give laxatives and enemas

Provide low-protein diet ; reduces generation of ammonia.

Limit activity.

Treat GI bleeding

5. Ineffective breathing pattern related to pressure on diaphragm and reduced lung

capacity.

Place the client in semi-fowlers or fowler position with arms supported with pillows.

Assess manifestations such as crackles or increased respirations.

Administer oxygen

6. Fluid volume excess related to retention of fluids secondary to decreased serum

albumins, increased sodium and water, portal hypertension, and possible shunting

procedures causing hemodilutaion of blood

Follow sodium and fluid restrictions

Administer diuretics

Weigh daily

Measure abdominal girth every day or shift

Monitor intake/output.

Monitor electrolytes, hemoglobin and hematocrit.

Implement measures to prevent skin breakdown

Administer albumin

Assist with paracentesis procedure.

References:

1 Black M. Joyce “Medical-Surgical Nursing” Ed.6th; Saunders publication; 2007; (2); 1330-

60.

2 Nettina M.S. “Lippincot Manual of Nursing practices” Ed. 8th; Lippincot; 2006; 562-80.

3 Robbins “Pathologic basis of disease” Ed. 7th; Saunders Elsevier; 2006; 643-46.

4 Smeltzer Suzanne “Brunner & Suddarth’s Textbook of medical surgical nursing” Ed 11th;

Lippincot; 2008; 1039-42

5 www.mayoclinic.com