Chorea

Chorea" is a borrowed Latin word that derives

from the Greek khoreia, a choral dance. The basic
Greek word for dance (written with the Roman
alphabet) is khoros.

The ad hoc Committee on Classification of the

World Federation of Neurology has defined chorea
as
"a state of excessive, spontaneous
movements, irregularly timed, non-repetitive,
randomly distributed and abrupt in character.
These movements may vary in severity from
restlessness with mild intermittent exaggeration
of gesture and expression, fidgeting movements
of the hands, unstable dance-like gait to a
continuous flow of disabling, violent movements
 Patients with chorea exhibit motor impersistence (ie, they
cannot maintain a sustained posture).
When attempting to grip an object, they alternately
squeeze and release ("milkmaid's grip"). When they
attempt to protrude the tongue, the tongue often pops in
and out ("harlequin's tongue"). Patients often drop objects
involuntarily. Also common are attempts by patients to
mask the chorea by voluntarily augmenting the choreiform
movements with semipurposeful movements (parakinesia)

Chorea involves both proximal and distal muscles.

In most patients, normal tone is noted, but, in some
instances, hypotonia is present.
In a busy movement disorder center, levodopa-induced
chorea is the most common movement disorder, followed
by Huntington disease
 The term athetosis comes from the Greek word athetos (not
fixed).It is a slow form of chorea. Because of the slowness, the
movements have a writhing (ie, squirming, twisting, or
snakelike) appearance. Choreoathetosis is essentially an
intermediate form.

Ballism or ballismus is considered a very severe form of chorea

in which the movements have a violent, flinging quality.
In Greek, ballismos means "a jumping about or
dancing."[2]
Ballism has been defined as "continuous, violent,
coordinated involuntary activity involving the axial and
proximal appendicular musculature such that the limbs are
flung about."
This movement disorder most often involves only one side
of the body (ie, hemiballism or hemiballismus). Occasionally,
bilateral movements occur (ie, biballism or paraballism ). Many
patients with hemiballism have choreiform movements and
vice versa, and hemiballism often evolves into hemichorea.
Schematic diagram of the basal ganglia circuitry. Represented are the following: inhibitory (red
(red arrows)
arrows) and excitatory (green
(green
arrows)
arrows ) projections between the motor cortex, the putamen, the globus pallidus pars externa (GPe) and globus pallidus
pars interna (GPi), the subthalamic nucleus (STN), the substantia nigra pars reticulata (SNr) and substantia nigra pars
compacta (SNc), and the ventrolateral thalamus (VL). D1 and D2 indicate the direct (regulated by dopamine D1

receptors) and indirect (regulated by dopamine D2 receptors) pathways, respectively

Pathophysiology

A simple model of basal ganglia function states that

dopaminergic and GABAergic impulses from the substantia
nigra and motor cortex, respectively, are funneled through the
pallidum into the motor thalamus and motor cortex. These
impulses are modulated in the striatum via two segregated,
parallel, direct and indirect loops through the medial pallidum
and lateral pallidum/subthalamic nucleus. Subthalamic
nucleus activity drives the medial pallidum to inhibit cortex-
mediated impulses, thereby inducing parkinsonism.

Absent subthalamic nucleus inhibition enhances motor

activity through the motor thalamus, resulting in abnormal
involuntary movements such as dystonia, chorea, and tics. A
classic example of loss of subthalamic inhibitory drive is
ballism
History
Patients with chorea
may not initially be aware of the abnormal movements
because they may be subtle.
can suppress the chorea temporarily and frequently
camouflage some of the movements by incorporating them
into semipurposeful activities (ie, parakinesia).
The inability to maintain voluntary contraction (ie, motor
impersistence), as is seen during manual grip (milkmaid
grip) tests or tongue protrusion, is a characteristic feature of
chorea and results in the dropping of objects and clumsiness.
Muscle stretch reflexes are often hung-up and pendular.
In severely affected patients, a peculiar dancelike gait may be
noted.

Depending on the underlying cause of the chorea, other motor

symptoms include- dysarthria, dysphagia, postural
instability, ataxia, dystonia, and myoclonus.
 Laboratory Studies Diagnosis of the primary choreatic
conditions
is based on

history and clinical findings;

several laboratory studies are useful, especially in distinguishing the secondary forms of chorea
from the primary forms.
Huntington disease: The only laboratory study presently available to confirm HD is
genetic testing. It identifies a gene abnormality in the short arm of chromosome 4,
characterized by abnormal repetition of the trinucleotide CAG, the length of which
determines the age of onset (anticipation).
Wilson disease: A low serum ceruloplasmin level and serum copper values showing
increased urinary copper excretion corroborate the diagnosis in most cases.
Liver function test results are usually abnormal.
If the diagnosis is still uncertain, liver biopsy can help confirm the
diagnosis.
Sydenham chorea : The chorea can lag behind the etiologic streptococcal infection
by 1-6 months, sometimes as long as 30 years; therefore, antistreptococcal
antibody titers may no longer be elevated at presentation. Without documentation
of an antecedent streptococcal infection, the diagnosis of Sydenham chorea must
be made by excluding other causes.
Neuroacanthocytosis: The diagnosis is confirmed by the presence of spiky
erythrocytes (acanthocytes) in peripheral blood smears. The serum creatine kinase
level may be elevated.
Other laboratory studies useful in the differential diagnosis

of chorea include complement levels, antinuclear antibody

titers, antiphospholipid antibody titers, amino acid levels in
serum and urine, enzymatic studies from skin fibroblasts,
thyrotropin levels, thyroxine values, and parathormone
levels.
Imaging Studies

MRI
Patients with Huntington disease (HD) and
chorea-acanthocytosis show decreased signal in
the neostriatum, caudate, and putamen . No
significant difference has been observed
between these diseases. The decreased
neostriatal signal corresponds to increased iron
deposition.
Generalized atrophy, as well as focal
atrophy of the neostriatum, predominantly of
the caudate, with resulting enlargement of the
frontal horns, follows the initial findings of
decreased neostriatal signal
Medical Care

Only symptomatic treatment is available for patients

with chorea.
Chorea may be a disabling symptom, leading to
bruises, fractures, and falls, and may impair the ability of
patients to feed themselves.
The most widely used agents in the treatment of chorea are
the neuroleptics. The basis of their mechanism of action is
thought to be related to blocking of dopamine receptors.
Neuroleptics can be classified as typical and
atypical. Typical neuroleptics include haloperidol and
fluphenazine.
Atypical neuroleptics include risperidone, olanzapine,
clozapine, and quetiapine.
Dopamine-depleting agents, such as reserpine and
tetrabenazine, represent another option in the treatment of
chorea.
GABAergic drugs, such as clonazepam, gabapentin, and
valproate , can be used as adjunctive therapy.
 Coenzyme Q10 alone and in combination with minocycline
have been proposed as potential therapies

Intravenous immunoglobulin and plasmapheresis may

shorten the course of the illness and decrease symptom
severity in patients with Sydenham chorea.
Surgical Care

Deep brain stimulation is an emerging technique

that may benefit patients, at least in certain
cases.
Although deep brain stimulation is not yet used
routinely for chorea, as it is for PD, exciting
progress has been made with this modality.
Cell transplantation is controversial and in early
stages of research. It has shown variable results
for HD patient participants.
Causes of Chorea
Inherited
Ataxia-telangiectasia
Benign hereditary chorea
Hallervorden-Spatz disease
Hereditary spinocerebellar ataxias
Huntington disease
Inborn errors of metabolism
Glutaric acidemia, Propionic acidemia ,Homocystinuria Phenylketonuria,Sulfite
oxidase deficiency
Mitochondrial encephalomyopathies
Neuroacanthocvtosis
Paroxysmal disorders
Paroxysmal kinesiogenic choreoathetosis
Paroxysmal nonkinesiogenic choreoathetosis
Pyruvate carboxylase deficiency
Wilson disease
Drugs Antimetabolites
Anticholinergics
Anticonvulsants (eg, phenytoin, carbamazepine, phenobarbital)
Antidopaminergic agents (eg, phenothiazines, haloperidol,
metoclopramide)
Antihistamines
CNS stimulants (eg, amphetamines, methylphenidate, pemoline)
Lithium
Dopamine agonists (eg, levodopa)
Oral contraceptives

Endocrine
Hyperthyroidism
Chorea gravidarum
Hypoparathyroidism, pseudohypoparathyroidism
Immune/infectious
Behet disease
Other infections - Pertussis, diphtheria, varicella
Primary antiphospholipid antibody syndrome
Sydenham chorea
Systemic lupus erythematosus
Bacterial endocarditis
Herpes simplex encephalitis
HIV related
Infectious mononucleosis
Lyme disease
Mycoplasmal pneumonia
Viral meningoencephalitis (eg, mumps, measles, varicella)
Vascular
Arteriovenous malformation
Basal ganglia infarction or hemorrhage
Vasculopathies/vasculitis: Churg-Strauss syndrome[1] , moyamoya
Metabolic
Hypocalcemia
Hypoglycemia and hyperglycemia
Hypomagnesemia
Hyponatremia, hypernatremia, and central pontine myelinolysis
Renal failure
Miscellaneous
Cerebral palsy
Head trauma
Bronchopulmonary dysplasia (infantile chorea)
Cardiopulmonary bypass - "Postpump chorea
Neoplastic
Primary and metastatic brain tumors
Primary CNS lymphoma
Toxins CO, Mg, organophosphate
 Pathophysiology and General Principles in
Treatment of Chorea

Movement disorders (particularly chorea, athetosis, and

dystonia) are thought to result from basal ganglia pathology.

Dopaminergic neurons within the substantia nigra project

rostrally to the neostriatum (caudate and putamen).

Chorea may be viewed as resulting from increased

dopaminergic activity in the projections from the substantia
nigra to the striatum, resulting in decreased GABAergic
projection from the striatum to the globus pallidus.

Most of the drugs used in symptomatic treatment of

chorea act through attenuation of dopaminergic
transmission or enhancement of GABA transmission.
Anticonvulsant drugs may suppress chorea but also may
induce chorea, especially in patients with basal ganglia
dysfunction.
Rheumatic (Sydenham) Chorea
In 1684, Thomas Sydenham described the clinical syndrome that
now bears his name. Originally termed St. Vitus' dance, it now is
referred to as rheumatic chorea. Stoll first proposed a relationship
between Sydenham chorea and rheumatic fever (RF) in 1780.

In 1889, Cheadle described the full rheumatic syndrome of

carditis, polyarthritis, chorea, subcutaneous nodules, and
erythema marginatum.
Several decades later, epidemiologic and microbiologic studies
confirmed the etiological role of streptococcal infection in RF.

More recently, Sydenham chorea (SC) has been linked to

numerous neuropsychiatric disorders, including obsessive
compulsive disorder (OCD), attention deficit-hyperactivity
disorder, depression and anxiety.
Epidemiology

Sydenham chorea is the most common cause of acquired chorea in the

young. During the latter part of the twentieth century the number of
reported cases of RF in the United States increased. This resurgence appears
to be associated with strains of group A beta hemolytic streptococcal
infection that are less likely to cause symptomatic pharyngitis.

In the United States, the incidence of RF is approximately 0.5-2 per 100,000

population per year.

Chorea is a major manifestation of acute RF and

is the only evidence of RF in approximately 20% of cases.

In some outbreaks, chorea has been present in more than 30% of patients
with acute RF.

The female-to-male ratio is approximately 2:1, and most patients present

between 5-15 years of age.
Clinical features and course
SC is a major manifestation of acute rheumatic fever.

According to the 1992 modification of the Jones criteria,

chorea (or indolent carditis) alone is sufficient for diagnosis
of RF, provided other causes have been excluded.

SC typically presents with other manifestations of RF, but in

20% of cases chorea may be the presenting or sole
manifestation of RF.

The main features of SC are involuntary movements,

hypotonia, and mild muscular weakness .
Chorea can be generalized or unilateral, predominantly
involving the face, hands, and arms. Movements are present
at rest, aggravated by stress, and usually cease during sleep.
 In about 20% of patients, only one side of the body may
seem to be affected (hemichorea); however, careful
examination usually reveals some involvement of the
opposite side.
The choreic movements interfere with volitional
movements and result in a clumsy gait, dropping and
spilling, and explosive bursts of dysarthric speech.

Muscular weakness leads to inability to sustain a contraction

(milkmaid's grip).
The pronator sign consists of hyperpronation of the hands,
causing the palms to face outward when the arms are held
over the head. Another sign of weakness and hypotonia is
the so-called choreic handwith the arms extended, the
wrist will flex and the metacarpophalangeal joints
overextend.
 Some children may have such profound weakness that they
appear paralyzed. Not uncommonly, children are restricted to
bed or are unable to attend school for the duration of the
illness. Fortunately, paralytic chorea is uncommon.

Patients with SC may also have psychiatric symptoms such as

depression, anxiety, personality changes, emotional lability,
OCD, and attention deficit disorder (ADD).

Occasionally, these symptoms precede the onset of chorea

 On average, the disease resolves spontaneously in 3-6
months and rarely lasts longer than 1 year.

Mild chorea without functional disability may be found in a

small proportion of patients up to 10 years after the initial
attack of SC.

About 20% of patients experience 2-10 recurrences, usually

within 2 years after the initial attack.
Pathophysiology

Immunology: Evidence suggests that SC may result from the production of

immunoglobin G antibodies that crossreact with antigens in the membrane
of group A streptococci and antigens in the neuronal cytoplasm of the
caudate and subthalamic nuclei, namely intracellular tubulin and
extracellular lysoganglioside.
Antineuronal antibodies have also been found in the cerebrospinal fluid
(CSF) of patients with acute rheumatic chorea. Immunofluorescent staining
has shown that sera from approximately half of the children with SC have
antibodies that react with neuronal cytoplasmic antigens in the caudate and
subthalamic nuclei.

Serum antineuronal antibody titers have been found to decrease as the

chorea improves.

In children who suffer a relapse, the increase in symptom severity correlates

with a rise in these neuronal antibodies.
Neuroimaging

MRI findings in SC are not consistent and may be

normal.

Functional neuroimaging using fluorodeoxyglucose

(FDG) positron emission tomography (PET) has
demonstrated reversible striatal hypermetaboli.
Diagnosis

Diagnosis rests on a combination of clinical manifestations

that can develop in relation to group A streptococcal
pharyngitis. These include chorea, carditis, subcutaneous
nodules, erythema marginatum, and migratory
polyarthritis. Because the inciting infection is completely
treatable, attention has been refocused on prevention .
Diagnosis
Diagnosis of SC may be difficult, because no single, established
diagnostic test is available.

SC usually develops in those aged 3-13 years and is

believed to result from a preceding streptococcal infection.

Infections can be subclinical and often precede the

development of neurologic symptoms by age 1-6 months.
The patient may have no history of rheumatic fever,
and a preceding streptococcal infection cannot always be
documented.
At least 25% of patients with SC fail to have serologic
evidence of prior infection.

Chorea may be the first and only manifestation of rheumatic

fever. However, some patients may have subtle evidence of
carditis by echocardiography despite a normal clinical
examination and ECG. Chorea alone is sufficient for
diagnosis providing other causes of the condition have been
excluded.
 Treatment
Treatment and prevention may involve multiple fields of
discipline, including infectious diseases, cardiology, and
neurology. For this reason, several different classes of
medications are used. These include antibiotic, neuroleptic,
and cardiac medications
(ethiologyc, pathogenic, symptomatic)
A.The primary goal of treating an ARF attack is to eradicate
streptococcal organisms and bacterial antigens from the
pharyngeal region.
Penicillin is the drug of choice in persons who are not at risk
of allergic reaction. A single parenteral injection of benzathine
benzylpenicillin can ensure compliance.
Oral cephalosporins, rather than erythromycin, are
recommended as an alternative in patients who are allergic to
penicillin. However, be cautious of the 20% cross-reactivity of the
cephalosporins with penicillin
 C
SC is usually self-limited, and treatment should be limited to
patients with chorea severe enough to interfere with
function.

Anticonvulsants (valproic acid and carbamazepine) have

been shown to be effective in diminishing choreic
movements at doses normally used for seizure control. In
particular, valproate may be quite helpful in children with SC.
Dopaminergic blockers (pimozide and haloperidol) are
effective and, when used in small doses, are usually well
tolerated.
Neuroleptics such as haloperidol and pimozide remain an
important treatment option, especially in older children
B. Steroids have been used widely, but no controlled studies have
been done to confirm steroid efficacy in chorea.
Patients with carditis require prednisone. The goal is to decrease
myocardial inflammation. May decrease inflammation by reversing
increased capillary permeability and suppressing PMN activity. After

2-3 wk, dosage may tapered, reduced 25% each week.

. Prednisone,

plasma exchange and intravenous immunoglobulin (IVIG) have

been shown to be effective. Case reports have suggested IVIG to
be a safe, effective option in disabling SC.
Immunologic treatment can also be effective but is expensive and
may be associated with significant side effects.

The presence of antineuronal antibodies suggests that intravenous

immunoglobulin (IVIg) and plasma exchange may be effective.

More recent reports have shown IVIG to be an effective safe

option. Because this treatment modality is quite expensive, it
should be reserved for protracted or debilitating cases.
 Parents and school officials should be informed that
emotional lability is characteristic of this organic condition.

Children with SC require prophylaxis against

streptococcal infections until 18 years of age.
 Chorea gravidarum

Background

Chorea gravidarum (CG) is the term given to chorea

occurring during pregnancy. This is not an etiologically
or pathologically distinct morbid entity but a generic
term for chorea of any cause starting during pregnancy.

Chorea gravidarum is regarded as a syndrome rather

than a specific disease entity.
Incidence

Willson and Preece (1932) found that the overall incidence of

chorea gravidarum was approximately 1 case per 300 deliveries.
The condition is much more rare now.
The decline is probably the result of a decline in rheumatic
fever (RF), which was a major cause of chorea gravidarum before
the use of antibiotics for streptococcal pharyngitis.

In recent times, most cases of chorea appearing during

pregnancy are caused by other diseases antiphospholipid
syndrome (APLS), systemic lupus erythematosus [SLE],
Huntington disease).

In general, about half the cases are idiopathic, with rheumatic

fever and antiphospholipid syndrome (APLS) underlying most of
the remainder.
Patient profile

Most patients with chorea gravidarum are young; the

average age is 22 years.

Of initial attacks, 80% occur during first pregnancies,

and one half start during the first trimester.One third
begin in the second trimester.
Of afflicted women, 60% previously had chorea.

Recurrences may occur in subsequent pregnancies,

particularly if antiphospholipid syndrome is the cause.
 Pathophysiology
Several pathogenetic mechanisms for chorea gravidarum have been offered,

but none have been proven.

Willson and Preece noted that nearly 70% of their patients gave a
previous history of either rheumatic fever or chorea .
Of patients who present with chorea and no apparent
carditis, 20% may develop rheumatic heart disease after 20 years.
Interestingly, 50% of patients with oral contraceptive-
induced chorea have a past history of chorea, which in 41% of
cases is of rheumatic origin.

The suggestion is that estrogens and progestational hormones

may sensitize dopamine receptors (presumably at a striatal level)
and induce chorea in individuals who are vulnerable to this
complication by virtue of preexisting pathology in the basal
ganglion.

Pathologic changes found at autopsy in chorea gravidarum include

perivascular degenerative changes in the caudate nucleus.
TREATMENT

CG is not an indication for abortion or premature

interruption of pregnancy
Indicated for patients with disabling severe chorea
Reserpine = CI
Haloperidol effective
Pimozide, valproate, carbamazepine

Discontinue the oral contraceptive pill

2/3 the choreea lasts until puerperium

Mortality 12%
21% have recurrent chorea with subsequent pregnancies
 Huntington disease (HD)

Background

is an incurable,
adult-onset,
autosomal dominant inherited disorder associated with
cell loss within a specific subset of neurons in the
basal ganglia and cortex.
HD is named after George Huntington, the physician who described it as
hereditary chorea in 1872.
Characteristic features of HD include
involuntary movements, dementia, and behavioral
changes.
Pathophysiology

The most striking neuropathology in HD occurs

within the neostriatum, in which gross atrophy of
the caudate nucleus and putamen is accompanied
by selective neuronal loss and astrogliosis.
Marked neuronal loss also is seen in deep layers of
the cerebral cortex.
Other regions, including the globus pallidus,
thalamus, subthalamic nucleus, substantia nigra,
and cerebellum, show varying degrees of atrophy
depending on the pathologic grade.

The extent of gross striatal pathology, neuronal

loss, and gliosis provides a basis for grading the
severity of HD pathology (grades 0-4)
 No gross striatal atrophy is observed in grades 0 and 1.

Grade 1 cases have neuropathologic changes that can

be detected microscopically but without gross atrophy.

In grade 2, striatal atrophy is present, but the caudate

nucleus remains convex.

In grade 3, striatal atrophy is more severe, and the

caudate nucleus is flat.

In grade 4, striatal atrophy is most severe, and the

medial surface of the caudate nucleus is concave.
 The genetic basis of HD

is the expansion of a cysteine-adenosine-guanine (CAG) repeat

encoding a polyglutamine tract in the N-terminus of the protein
product called huntingtin.

The function of huntingtin is not known. Normally, it is located in

the cytoplasm. The association of huntingtin with the cytoplasmic
surface of a variety of organelles, including transport vesicles,
synaptic vesicles, microtubules, and mitochondria, raises the
possibility of the occurrence of normal cellular interactions that
might be relevant to neurodegeneration.

N-terminal fragments of mutant huntingtin accumulate and form

inclusions in the cell nucleus in the brains of patients with HD, as
well as in various animal and cell models of HD.

The presence of neuronal intranuclear inclusions (NIIs) initially

led to the view that they are toxic and, hence, pathogenic
 HD is one of several trinucleotide repeat disorders which are
caused by the length of a repeated section of a gene

exceeding a normal range .

The HTT gene is located on the short arm of chromosome 4 at
4p16.3. HTT contains a sequence of three DNA basescytosine-
adenine-guanine (CAG)repeated multiple times (i.e....
CAGCAGCAG...), known as a trinucleotide repeat.
CAG is the 3-letter genetic code (codon) for the amino acid
glutamine, so a series of them results in the production of a chain
of glutamine known as a polyglutamine tract (or polyQ tract), and
the repeated part of the gene, the PolyQ region.
Classification of the trinucleotide repeat, and resulting disease
status, depends on the number of CAG repeats
people have fewer than 36 repeated glutamines in the polyQ
region which results in production of the cytoplasmic protein
Huntingtin. However, a sequence of 36 or more glutamines results
in the production of a protein which has different characteristics.
This altered form, called mHtt (mutant Htt), increases the decay
rate of certain types of neurons.
Epidemiology
Frequency
United States

Estimates of the prevalence of HD in the United States

range from 4.1-8.4 per 100,000 people. Accurate
estimates of the incidence of HD are not available.

International
The prevalence in most European countries ranges
from 1.63-9.95 per 100,000 people. The prevalence of
HD in Finland and Japan is less than 1 per 100,000
people.
Mortality/Morbidity

HD is a relentlessly progressive disorder, leading to

disability and death, usually from an intercurrent
illness.

The mean age at death in all major series ranges

from 51-57 years, but the range may be broader.
Duration of illness varies considerably, with a
mean of approximately 19 years. Most patients
survive for 10-25 years after the onset of illness.
In a large study, pneumonia and
cardiovascular disease were the most common
primary causes of death.
Juvenile HD (ie, onset of HD in patients younger than 20 years)

accounts for approximately 5-10% of all affected patients.

Most patients with juvenile HD inherit the disease from their
father, whereas patients with onset of the disease after age 20
years are more likely to have inherited the gene from their
mother. Inheritance through the father can lead to earlier onset
through succeeding generations, a phenomenon termed
anticipation. This is caused by greater instability of the HD
allele during spermatogenesis.
CAG repeat length correlates inversely with age of onset, and the
correlation is stronger when the onset of symptoms occurs
earlier.

The length of the CAG repeat is the most important factor in

determining age of onset of HD.
Most studies show a mean age at onset ranging from 35-44
years.
 Huntington DiseaseClinical Presentation

The clinical features of Huntington disease (HD)

include a movement disorder, a cognitive disorder,
and a behavioral disorder. Patients may present with
one or all disorders in varying degrees.

Chorea (derived from the Greek word meaning to

dance) is the most common movement disorder seen
in HD.
 IInitially, mild chorea may pass for fidgetiness.
Severe chorea may appear as uncontrollable flailing
of the extremities (ie, ballism), which interferes with
function.
IIAs the disease progresses, chorea coexists with
and gradually is replaced by
dystonia and parkinsonian
features, such as bradykinesia, rigidity, and postural
instability, which are usually more disabling than the
choreic syndrome per se.
IIIIn advanced disease, patients develop an akinetic-
rigid syndrome, with minimal or no chorea.
IVOther late features are spasticity, clonus, and
extensor plantar responses.
Dysarthria and dysphagia are common.
Abnormal eye movements may be seen early in the
disease.
Other movement disorders, such as -tics and
myoclonus, may be seen in patients with HD.
Juvenile HD (Westphal variant), defined as having an
age of onset of younger than 20 years, is
characterized by parkinsonian features, dystonia,
long-tract signs, dementia, epilepsy, and mild or
even absent chorea.
 Cognitive decline is characteristic of HD, but the rate of
progression among individual patients can vary considerably.
Dementia and the psychiatric features of HD are perhaps the
earliest and most important indicators of functional impairment.

The dementia syndrome associated with HD includes early

onset behavioral changes, such as irritability, untidiness, and
loss of interest. Slowing of cognition, impairment of intellectual
function, and memory disturbances are seen later. This pattern
corresponds well to the syndrome of subcortical dementia, and
it has been suggested to reflect dysfunction of frontal-
subcortical neuronal circuitry.

Early stages of HD are characterized by deficits in short-term

memory, followed by motor dysfunction and a variety of
cognitive changes in the intermediate stages of dementia.[6, 7]
These deficits include diminished verbal fluency, problems with
attention, executive function, visuospatial processing, and
abstract reasoning. Language skills become affected in the final
stages of the illness, resulting in a marked word-retrieval deficit.
 The behavioral disorder of HD is represented
most commonly by affective illness.

Depression is more prevalent, with a small

percentage of patients experiencing episodic
bouts of mania characteristic of bipolar disorder.

Patients with HD and persons at risk for HD may

have an increased rate of suicide.

Patients with HD also can develop psychosis,

obsessive-compulsive symptoms, sexual and
sleep disorders, and changes in personality
 Tendon reflexes are variable in HD, ranging from
reduced in some patients to pathologically brisk
with clonus in other patients. The plantar response
usually is flexor, but it may be extensor in advanced
stages of the illness.

Other hyperkinesias, such as tics and myoclonus,

may be seen in HD.

Eye movement abnormalities can be seen early in

the disease.
Imaging Studies

No single imaging technique is necessary or

sufficient for diagnosis of Huntington disease
(HD).
Measurement of the bicaudate diameter (ie, the
distance between the heads of the 2 caudate
nuclei) by CT scan or MRI is a reliable marker of
HD.
Other Tests

Genetic testing (reported as the CAG repeat number

for each allele) is now commercially available.

Genetic testing may not be necessary in a patient with a

typical clinical picture and a genetically proven family history
of HD.
In the absence of a family history of HD, patients with a
suggestive clinical presentation should undergo genetic testing
to exclude or confirm HD.

If the genetic test is negative for HD, then testing for

systemic lupus erythematosus (SLE), antiphospholipid
antibody syndrome, thyroid disease,
neuroacanthocytosis, DRPLA, Wilson disease, and
other less common causes of chorea may be
reasonable, depending on the individual case
Medication Summary

Although no therapy is currently available to delay the

onset of symptoms or prevent the progression of the
disease, symptomatic treatment of patients with
Huntington disease (HD) may improve the quality of life
and prevent complications. Symptomatic treatment for
HD can be divided into drugs to treat -A.the movement
disorder B.psychiatric or behavioral
problems.

A.Therapeutic options include dopamine-depleting agents

(eg, reserpine, tetrabenazine) and dopamine-receptor
antagonists (eg, neuroleptics).
B.Medical Care

Depression in patients with HD is treatable and should be recognized

promptly. Selective serotonin reuptake inhibitors (SSRIs) should be
considered as first-line therapy. Other antidepressants, including
bupropion, venlafaxine, nefazodone, and tricyclic antidepressants, also
can be used. Electroconvulsive therapy (ECT) can be used in patients
with refractory depression.

Antipsychotic medications may be necessary in patients with

hallucinations, delusions, or schizophrenia-like syndromes. Newer
agents, such as quetiapine, clozapine, olanzapine, and risperidone, are
preferred to older agents because of the lower incidence of
extrapyramidal side effects and the decreased risk for tardive
syndromes.

Irritability may be treated with antidepressants, particularly the SSRIs;

mood stabilizers, such as valproic acid or carbamazepine; and, if
needed, atypical neuroleptics.

Other less frequent aspects of HD that may require pharmacologic

treatment are mania, obsessive-compulsive disorder, anxiety, sexual
disorders, myoclonus, tics, dystonia, and epilepsy.
Wilson Disease
Background

Wilson disease is a rare autosomal recessive inherited

disorder of copper metabolism. The condition is
characterized by excessive deposition of copper in
the liver, brain, and other tissues.
The major physiologic aberration is excessive
absorption of copper from the small intestine and
decreased excretion of copper by the liver.

The genetic defect, localized to arm 13q, has been

shown to affect the copper-transporting adenosine
triphosphatase (ATPase) gene (ATP7B) in the liver.
 Patients with Wilson disease

more often initially present with hepatic manifestations

when identified in the first decade of life
as compared with more neuropsychiatric illness later,
and the latter most commonly occurs during the
third decade.
The diagnosis is established by no individual test but
requires the use of some combination of
serum ceruloplasmin level, urinary copper
excretion, presence of Kayser-Fleischer rings,
and hepatic copper content when biopsy is required.
Etiology

The normal estimated total body copper content is 50-100 mg,

and the average daily intake 2-5 mg, depending on an individuals
intake of legumes, meats, shellfish, and chocolate.
Copper is an important component of several metabolic enzymes ,
including lysyl oxidase, cytochrome c oxidase, superoxide
dismutase, and dopamine beta-hydroxylase.

Around 50-75% of intestinal copper is absorbed and then

transported to the hepatocytes. This pathway is intact in Wilson
disease.
After copper reaches the hepatocyte, it is incorporated into
copper-containing enzymes and copper-binding proteins
(CBPs), including ceruloplasmin, a serum ferroxidase.
Within the liver, the majority of in-infancy (< 6 mo) CBP
granules staining positive may be normal. After 6 months, positive
staining of CBPs for copper is almost exclusively found in association
with liver diseases such as Wilson disease, chronic biliary disorders
(eg, primary biliary cirrhosis, primary sclerosing cholangitis),
cirrhosis/extensive fibrosis, and primary liver tumors (most often
fibrolamellar hepatocellular carcinoma).
 Excess copper may be rendered nontoxic by forming complexes with
apo-metallothionein to produce copper-metallothionein, or it may be
excreted into bile. Normal copper balance is maintained by regulation
of excretion, rather than absorption, and the predominant route of
copper excretion (approximately 95%) is hepatobiliary in nature.

In Wilson disease, the processes of incorporation of copper into

ceruloplasmin and excretion of excess copper into bile are
impaired. The transport of copper by the copper-transporting P-
type ATPase is defective in Wilson disease secondary to one of
several mutations in the ATP7B gene. By genetic linkage studies,
Bowcock and colleagues narrowed the assignment of the Wilson disease
locus to 13q14-q21.
Ceruloplasmin is the major copper-carrying protein in the
blood, and in addition plays a role in iron metabolism =

ferroxidase enzyme

Ceruloplasmin is an enzyme -synthesized in the

liver containing 6 atoms of copper in its structure.
carries more than 95% of the total
copper in healthy human plasma.
Ceruloplasmin exhibits a copper-dependent
oxidase activity, which is associated with possible
oxidation of Fe2+ (ferrous iron) into Fe3+ (ferric
iron),therefore assisting in its transport in the
plasma in association with transferrin, which can
carry iron only in the ferric state
 The excess copper resulting from Wilson disease promotes free
radical formation that results in oxidation of lipids and proteins.
Ultrastructural abnormalities in the earliest stages of
hepatocellular injury, involving the endoplasmic reticulum,
mitochondria, peroxisomes, and nuclei, have been identified.
Initially, the excess copper accumulates in the liver, leading to
damage to hepatocytes.

Eventually, as liver copper levels increase, it increases

in the circulation and is deposited in other organs.
Histologic findings

Histologic findings in the brain include the following:

Copper deposition in the basal ganglia[8]
Opalski cells - Periodic acid-Schiffpositive altered
glial cells
Cavitary degeneration
Gliosis
Neuronal loss
Epidemiology

In the United States, the carrier frequency is 1 per 90

individuals. The prevalence of Wilson disease is 1 per
30,000 individuals.
Worldwide, the incidence of Wilson disease is 10-30
million cases, and the heterozygote carrier rate is 1 case
per 100 persons, with the genetic mutation frequency
varying from 0.3-0.7%.

Age-related presentations

A German study of patients with Wilson disease

illustrated that patients presenting earlier show
predominantly hepatic symptoms , while those presenting
later more often present with neurological symptoms .
 The onset of neurologic symptoms
second / third decade
50% are symptomatic by age 15 years
The initial event is a deposition of copper
in the liver.
 Wilson DiseaseClinical Presentation
History Hepatic dysfunction is the presenting
feature in more than half of patients
Consider hepatic Wilson disease in the differential
diagnosis of any unexplained chronic liver disease,
especially in individuals younger than 40 years.
The condition may also manifest as acute hepatitis.

The 3 major patterns of hepatic involvement are as follows:

(1) chronic active hepatitis,
(2) cirrhosis,
(3) fulminant hepatic failure.
The most common initial presentation is cirrhosis
 Hepatic dysfunction is the presenting feature in more than
half of patients. Although the condition may manifest as
acute hepatitis, the 3 major patterns of hepatic involvement
are as follows:
Chronic active hepatitis
Cirrhosis (the most common initial presentation)
Fulminant hepatic failure
Signs of fulminant hepatic failure include the
following:
Ascites and prominent abdominal veins
Spider nevi
Palmar erythema
Digital clubbing
Hematemesis
Jaundice
Neuropsychiatric features

Most patients who present with neuropsychiatric manifestations have cirrhosis.

The most common presenting neurologic feature is asymmetric tremor,

which is variable in character and may be predominantly resting, postural,
or kinetic.

Frequent early symptoms include the following:

Difficulty speaking
Excessive salivation
Ataxia
Masklike facies
Clumsiness with the hands
Personality changes
Late manifestations (now rare because of earlier diagnosis and treatment)
include the following:
Dystonia
Spasticity
Grand mal seizures
Rigidity
Flexion contractures
Neurologic signs

Neurologic signs of Wilson disease include the following:

Parkinsonian symptoms - Rigidity, bradykinesia

Dysarthria
Tremor at rest or with action
Dystonia, mainly of the face
Dysdiadochokinesia
Poor handwriting
Incoordination
Abnormal eye movements ( slow saccadic movement, limitation of
upgaze)
Respiratory dyskinesia, which can present as an unusual cough[3]
Polyneuropathy, which may be the initial manifestation and may
be reversible with treatment[4]
One study described 4 distinct diagnostic categories based on
patients' major neurologic findings, as follows:
Patients in the parkinsonian group (45%) - Distinguished by
paucity of expression and movement
Patients in the pseudosclerotic group (24%) - Had tremor
resembling multiple sclerosis
Patients in the dystonic group (15%) - Characterized by
hypertonicity associated with abnormal limb movements.
Patients in the choreic group (11%) - Predominantly
characterized by choreoathetoid abnormal movements
associated with dystonia
Psychiatric features (10-20% of patients) include the
following:
Emotional lability
Impulsiveness
Disinhibition
Self-injurious behavior

Psychiatric abnormalities associated with Wilson disease has

been divided into the following 4 basic categories:
Behavioral
Affective
Schizophrenic-like
Cognitive
Psychiatric signs

Psychiatric signs include the following:

Hyperkinetic behavior
Irritability or anger
Emotional lability
Psychosis
Mania
Difficulty concentrating
Abnormal behavior
Personality changes
Depression
Schizophrenia
Musculoskeletal manifestations

The arthropathy of Wilson disease is a degenerative process

that resembles premature osteoarthritis
Symptomatic joint disease usually arises late in the course of
the disease, frequently after age 20 years
The arthropathy generally involves the spine and large
appendicular joints (eg, knees, wrists, hips)
Osteochondritis dissecans, chondromalacia patellae, and
chondrocalcinosis have also been described

Hematologic and renal manifestations

Coombs-negative acute intravascular hemolysis (10-15%)

Urolithiasis
Hematuria
 Clinically, patients may resemble those with Fanconi
syndrome, demonstrating defective renal acidification and
excess renal losses of amino acids, glucose, fructose,
galactose, pentose, uric acid, phosphate, and calcium. The
frequency of renal manifestations is variable.
Urolithiasis, found in up to 16% of patients with Wilson
disease, may be the result of hypercalciuria or poor
acidification.
Hematuria and nephrocalcinosis are reported.
OPHTALMOLOGIC SYMTOMS

Kayser-Fleischer rings

Formed by the deposition of copper in the Descemet membrane in the

limbus of the cornea
The color may range from greenish gold to brown
Well-developed rings may be readily visible to the naked eye or with an
ophthalmoscope set at +40.When not visible to the unaided eye, the
rings may be identified using slit-lamp examination or gonioscopy
Observed in up to 90% of individuals with symptomatic Wilson disease
and almost invariably present in those with neurologic
manifestations
No longer considered pathognomonic of Wilson disease unless
accompanied by neurologic manifestations, as they may also be
observed in patients with chronic cholestatic disorders
Ophthalmic findings

Sunflower cataracts are brilliantly multicolored and are visible

only on slit-lamp examination.
They do not impair vision.

Other relatively uncommon ophthalmic findings include

exotropic strabismus, optic neuritis or pallor of the optic disc
Additional manifestations

Skeletal abnormalities (eg, osteoporosis, osteomalacia,

rickets, spontaneous fractures, polyarthritis)
Cardiac manifestations (eg, rhythm abnormalities,
increased autonomic tone)
Skin pigmentation and a bluish discoloration at the base of
the fingernails (azure lunulae)
Histologic findings

Histologic findings in the brain include the following:

Copper deposition in the basal ganglia[8]
Opalski cells - Periodic acid-Schiffpositive altered
glial cells
Cavitary degeneration
Gliosis
Neuronal loss
 DIAGNOSIS

Approach Considerations

The presence of Kayser-Fleischer rings and ceruloplasmin

levels of less than 20 mg/dL in a patient with neurologic
signs or symptoms suggest a diagnosis of Wilson disease.
If a patient is asymptomatic , exhibits isolated liver
disease, and lacks corneal rings,
the coexistence of a hepatic copper concentration
of more than 250 mg/g of dry weight and a low serum
ceruloplasmin level is sufficient to establish a diagnosis.
Therefore, in the absence of Kayser-Fleischer rings or
neurologic abnormalities, a liver biopsy for quantitative
copper determination is essential to establish the
diagnosis of Wilson disease.
Diagnosis

Considerations in the workup of Wilson disease are as follows:

Serum ceruloplasmin levels are less than 20 mg/dL (reference
range, 20-40 mg/dL) in approximately 90% of all patients with
Wilson disease
The urinary copper excretion rate is greater than 100 mcg/day
(reference range, < 40 mcg/day) in most patients with
symptomatic Wilson disease, but it may also be elevated in other
cholestatic liver diseases
In a patient with Kayser-Fleischer rings, a serum
ceruloplasmin level < 0 mg/dL and 24-hoyr urine copper
excretion >40 mcg/day establish the diagnosis of Wilson
disease
Hepatic copper concentration (criterion standard) on a liver
biopsy specimen is >250 mcg/g of dry weight even in
asymptomatic patients; a normal result (15-55 mcg/g) effectively
excludes the diagnosis of untreated Wilson disease, but elevation
may be found in other chronic hepatic disorders
Radiolabeled copper testing directly assays hepatic copper
metabolism
 Genetic testing is limited to screening of family members
for an identified mutation detected in the index patient
Brain imaging shows characteristic findings; MRI appears to
be more sensitive than CT in detecting early lesions
Abdominal imaging findings are neither sensitive nor
specific
Resting ECG abnormalities include left ventricular or
biventricular hypertrophy, early repolarization, ST segment
depression, T-wave inversion, and various arrhythmias
Electron microscopic detection of copper-containing
hepatocytic lysosomes is helpful in the diagnosis of the
early stages of Wilson disease, in addition to the
quantification of hepatic copper by atomic absorption
spectrophotometry
Genetic diagnosis
Linkage analysis has been used in family studies for
presymptomatic testing; however, the multiplicity of mutations
(>200 mutations of ATP7B have been identified) that require
screening in individuals without affected family members is large,
making such analysis impractical. Therefore, the use of molecular
testing is currently limited to screening of family members for an
identified mutation detected in the index patient.

Abdominal imaging
Computed tomography (CT) scanning, magnetic resonance
imaging (MRI), ultrasonography, and nuclear medicine studies of
the liver have been uninformative, with findings neither specific
nor sensitive for Wilson disease.

Electrocardiography
Resting electrocardiographic abnormalities include left ventricular
or biventricular hypertrophy, early repolarization, ST segment
depression, T-wave inversion, and various arrhythmias.
Serum Ceruloplasmin

Serum ceruloplasmin levels are low in newborns and gradually

rise within the first 2 years of life. Approximately 90% of all
patients with Wilson disease have ceruloplasmin levels of less
than 20 mg/dL (reference range, 20-40 mg/dL). (Ceruloplasmin
is an acute phase reactant and may be increased in response
to hepatic inflammation, pregnancy, estrogen use, or
infection.)

Falsely low ceruloplasmin levels may be observed in any

protein deficiency state, including nephrotic syndrome,
malabsorption, protein-losing enteropathy, and malnutrition.
Ceruloplasmin levels may also be decreased in 10-20% of
Wilson Disease gene heterozygotes, who do not develop
Wilson disease and do not require treatment.
Urinary Copper Excretion and Hepatic Copper
Concentration

Urinary copper excretion

The urinary copper excretion rate is greater than 100
mcg/d (reference range, < 40 mcg/d) in most patients
with symptomatic Wilson disease. The rate may also be
elevated in other cholestatic liver diseases.

Hepatic copper concentration

This test is regarded as the criterion standard for

diagnosis of Wilson disease. A liver biopsy with
sufficient tissue reveals levels of more than 250 mcg/g
of dry weight even in asymptomatic patients.
Brain MRI

MRI of the brain appears to be more sensitive than CT scanning in

detecting early lesions of Wilson disease.
MRI studies have identified focal abnormalities in the white matter,
pons, and deep cerebellar nuclei. These lesions, measuring 3-15 mm in
diameter, are typically bilateral, appearing with low signal intensity on
T1-weighted images and with high signal intensity on T2-weighted
images, representing cell loss and gliosis. Other studies describe
decreased signal intensity in the putamen and other parts of the basal
ganglia, which may represent either copper or iron ferritin deposition.

A characteristic "face of the giant panda" sign has been described,

formed by high signal intensity in the tegmentum (except for the red
nucleus), preserved signal intensity of the lateral portion of the pars
reticulata of the substantia nigra, and hypointensity of the superior
colliculus.
PET Scanning

Positron emission tomography (PET) scanning

reveals a significantly reduced regional cerebral
metabolic rate of glucose consumption in the
cerebellum, striatum, and, to a lesser extent, in
the cortex and thalamus.

PET scan analyses of patients with Wilson disease

have also demonstrated a marked reduction in
the activity of dopa-decarboxylase, indicative of
impaired function of the nigrostriatal
dopaminergic pathway.
Management

Features of treatment of Wilson disease are as

follows:
The mainstay of therapy is lifelong use of
chelating agents (eg, penicillamine, trientine)
Symptoms, particularly neurologic ones, may worsen with
initiation of chelation
Surgical decompression or transjugular
intrahepatic shunting (TIPS) is reserved for
recurrent or uncontrolled variceal bleeding
unresponsive to standard conservative
measures
Orthotopic liver transplantation is
curative
Other treatments for Wilson disease include the
following:

Anticholinergics, baclofen, GABA antagonists, and levodopa

to treat parkinsonism and dystonia
Antiepileptics to treat seizures
Neuroleptics to treat psychiatric symptoms
Protein restriction, lactulose, or both to treat hepatic
encephalopathy
 After the initiation of therapy with a chelating agent , the
patient needs to be aware of potential adverse effects of
the agents with which he or she is being treated.
For instance, some of the concerning adverse
effects are those commonly associated with penicillamine
use.

In addition, a patient must also be aware of the potential to develop

worsening of some symptoms when chelation is started; in particular,
patients with neurologic signs and symptoms can see worsening of
these with chelation, and, in some instances, therapy needs to be
reduced or stopped.
Laboratory tests in patients started on penicillamine should include
hematology and biochemical monitoring, as well as urinalysis.
 With clinical progression, acute liver failure, or
worsening hepatic function, the patient must be
evaluated at a center with expertise in Wilson disease
and the capability to perform liver transplantation.

Orthotopic liver transplantation is curative treatment

for Wilson disease.
Diet

Patients should generally avoid eating foods with a

high copper content, such as liver, chocolate, nuts,
mushrooms, legumes, and shellfish (especially
lobster). Drinking water from atypical sources (eg,
well water) should be analyzed for copper content
and replaced with purified water if the copper
content is greater than 0.2 parts per million.
Medication Summary

The mainstay of therapy for Wilson disease is the use

of chelating agents and
medications that block copper absorption from
the gastrointestinal (GI) tract.

Zinc and penicillamine are lifelong medications for patients with

Wilson disease. Dosages vary with the severity of the disorder.
Another chelating agent is trientine, which may be more easily
tolerated than penicillamine.[1] Patients who do not respond to
zinc therapy and who have increased activities of liver enzymes
should be identified so that chelating agents may be added to
the therapeutic regimen.
Class Summary

Chelating agents bind excess copper. Ammonium tetrathiomolybdate is an

investigational chelating drug used at the University of Michigan as an initial treatment
for patients who present with neurologic or psychiatric manifestations. This drug works
as a chelating agent and as an inhibitor of copper absorption from the GI tract.[17]

Penicillamine (Cuprimine, Depen)

Penicillamine forms soluble complexes with metals excreted in urine. It was the drug of
choice before newer regimens were available. Because of extensive toxicities,
alternative agents are used. It must be administered with pyridoxine 25 mg by mouth
daily.

Trientine (Syprine)

Trientine is an effective oral chelator used to induce cupruresis. It is useful for patients
who cannot tolerate penicillamine. It is indicated in Wilson disease if the initial
presentation is hepatic. It should be administered with zinc

Zinc (Galzin)

Zinc is a cofactor for more than 70 types of enzymes. It is approved for patients
initially treated with a chelating agent. It should be used for maintenance after initial
chelation therapy. Zinc acetate is the drug of choice in presymptomatic, pregnant,
pediatric populations, and in some instance for maintenance in compliant patients who
have undergone copper chelation therapy
 Generally, penicillamine is the first treatment used

. Penicillamine is not without problems: about 20% experience a side

effect or complication of penicillamine treatment, such as drug-
induced lupus (causing joint pains and a skin rash) or myasthenia
(a nerve condition leading to muscle weakness). In those who
presented with neurological symptoms, almost half experience a
paradoxical worsening in their symptoms. While this phenomenon
is observed in other treatments for Wilson's, it is usually taken as
an indication for discontinuing penicillamine and commencing
second-line treatment.
Those intolerant to penicillamine may instead be commenced on
trientine hydrochloride, which also has chelating properties. Some
recommend trientine as first-line treatment, but experience with
penicillamine is more extensive.
A further agent with known activity in Wilson's disease is
tetrathiomolybdate. This is regarded as experimental
Once all results have returned to normal, zinc (usually in the form of a zinc
acetate prescription called Galzin) may be used instead of chelators to
maintain stable copper levels in the body. Zinc stimulates metallothionein,
a protein in gut cells that binds copper and prevents their absorption and
transport to the liver. Zinc therapy is continued unless symptoms recur or if
the urinary excretion of copper increases.

In rare cases where none of the oral treatments are effective, especially in
severe neurological disease, dimercaprol (British anti-Lewisite) is
occasionally necessary. This treatment is injected intramuscularly (into a
muscle) every few weeks and has unpleasant side effects such as pain.[12]

People who are asymptomatic (for instance, those diagnosed through family
screening or only as a result of abnormal test results) are generally treated,
as the copper accumulation may cause long-term damage in the future. It
is unclear whether these people are best treated with penicillamine or zinc
acetate
Transplantation

Liver transplantation is an effective cure for

Wilson's disease but is used only in particular
scenarios because of the risks and
complications associated with the procedure.
It is used mainly in people with fulminant liver
failure who fail to respond to medical
treatment or in those with advanced chronic
liver disease.
Liver transplantation is avoided in severe
neuropsychiatric illness, in which its benefit
has not been demonstrated
 Prognosis

Important clues for the diagnosis of Wilson disease that a clinician

must recognize are a younger patient with hemolytic anemia, impaired
hepatic synthetic function, and normal alkaline phosphatase values.
Left untreated, Wilson's disease tends to become progressively worse and is
eventually fatal.
With early detection and treatment, most of those affected can live relatively normal
lives.
Liver and neurologic damage that occurs prior to treatment may improve, but it is
often permanent
 Complications

The major complications in patients with untreated Wilson disease

are those associated with acute liver failure, chronic hepatic
dysfunction with either portal hypertension or hepatocellular
carcinoma, and the sometimes-relentless course to cirrhosis, which
is characterized by a progressive lassitude, fatigue, anorexia,
jaundice, spider angiomas, splenomegaly, and ascites. Bleeding
from varices, hepatic encephalopathy, hepatorenal syndrome, and
coagulation abnormalities occur as liver failure ensues. Death
occurs, generally at age 30 years, if emergent liver transplantation
is not performed.