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CASE OF THE MONTH
Prepared by : Dr. Abhishek Garg
M.D Resident 3rd year
Edited by : Dr. Arun kumar sharma
PARTICULARS OF PATIENT
Miss PRAGYA DHITAL,
10 Years old girl
From Gorkha , Nepal
Admitted on 7/4/062
at KCH / BED NO- 321
IP NO- 10112
Presented with
• Abdominal swelling --- 1 month
• Progressive pallor------ 1 month
• Pain abdomen off and on
History of Present Illness
• She was apparently well 1 month back when
she
started
developing
progressively
increasing abdominal swelling mainly in left
upper abdomen associated with off and on
mild pain.
• This was associated with
without any major bleeds.
progressive pallor
History of Present Illness..
• Occasionally had bleeding from nose in
small amounts
• No h/o jaundice
• No h/o hematemesis, melena, hemoptysis.
• No h/o blood transfusions in the past.
• No h/o fever, rash
• No h/o high colored urine
• No h/o any joint pains/chest pain
Past medical history
•
•
•
•
•
•
No history of any long term illness
No history of drug intake
No history of TB contact
No bleeding disorders in the family
Home delivered
Prenatal / intranatal / postnatal period uneventful
(according to mother)
• Immunized as per national schedule, no
hepatitis B vaccine given
FAMILY HISTORY
• FATHER - 35 years
• MOTHER - 30 years
• 4 SIBLINGS
o 1ST
o 2nd
o 3rd
o 4th
– 12 years/female
– 10 years/female
– 8 years/male
– 6 years/male
healthy
patient
healthy
healthy
• No other members symptomatically ever
jaundiced
GENERAL EXAMINATION
•
•
•
•
•
Temp- 98 * F
Pulse- 120 /min
BP- 120/60 mmHg
RR- 19 / min
Pallor- present
•
•
•
•
Icterus- absent
Edema - absent
Cyanosis- absent
Lymphadenopathyabsent
• Clubbing-absent
•Height-129 cms (94.1% of median for age)
•Weight- 29.5 kg (89.3% of median for age)
Abdominal examination
• Distended with everted umbilicus
• Non tender to palpation, spleen was palpable 16
cms below left costal margin, hard in
consistency with smooth and regular surface,
liver was not appreciably enlarged
• Percussion showed no free fluid in abdomen
• Auscultation revealed no appreciable bruit
Other systemic examination
• Respiratory examination was
unremarkable.
• Cardiovascular examination was
unremarkable.
• Neurological examination showed no
abnormalities.
• Musculoskeletal examination showed no
abnormalities
INVESTIGATIONS
Investigations were done to evaluate these etiologies of
splenomegaly
•
•
•
•
•
•
•
•
Hb = 8 gm%
TLC = 2500/ul
DLC =N 60 L40 M0 E 0
Platelet = 30,000
ESR =45
Retics = 0.2%
PT =19 sec ,Control =13 sec
Peripheral smear = Normocytic, Hypochromic, Atypical
lymphocytes few.
Investigations contd.
• Bone marrow = Normocellular marrow.
Erythroid hyperplasia
• Urine R/M= normal
• Stool r/m- normal
• X-Ray Chest PA = normal
Investigations contd
• USG Abdomen= Liver Normal, dilated
portal vein(12mm), Grossly enlarged
spleen with normal parenchymal echo
density , No SOL. Doppler study of portal
system showed portal vein to measure
10.8 mm in caliber and show normal ante
grade blood flow. Intrahepatic portal vein
tributaries are distorted, hepatic veins are
normal. Splenic vein is dilated and
measures 9.0-9.4 mm in diameter with
normal ante grade flow
Investigations contd
• Upper GI Endoscopy:Grade IV esophageal varices
Discussion
Minor nose bleeds common problem in children
Most prominent problem in this patient is
massive splenomegaly
Causes of massive splenomegaly
• Congestive splenomegaly due to cirrhotic or non
cirrhotic portal hypertension or splenic vein
obstruction
• Hemolytic anemias due to extramedullary
hematopoiesis
• Chronic infections especially malaria and kalaazar in endemic areas
• Malignancies
• Storage disorders ,especially Gaucher’s, and
Niemann-pick disease
• Anatomical
lesions
like
splenic
cysts,
hemangiomas or hamartomas
Discussion (contd)
These findings confirmed the portal hypertension
of cirrhotic etiology for splenomegaly.
Causes of cirrhosis in children:
•
Hepatits B and C,
•
Bilirary cirrhosis,
•
Autoimmune cirrhosis,
•
Inherited disease (Wilson disease, cystic fibrosis,
alpha-1 antitrypsin deficiency, hemochromatosis,
galactosemia, and glycogen storage disease. )
(Absence of jaundice as the presentation:
unlikely of first three )
Further investigations
for this patient and led to the etiological investigations
• Serum Copper Level:- 53 micro mole/liter (normal:-11-24
micro mole/liter)
• Ceruloplasmin level:- 20 micro mole/litre (normal:-62140)
• Ophthalmologic examination:- KF (Kayser-Fleischer
ring) Ring with sub capsular brownish opacity.
Kayser-Fleischer ring) Ring with
sub capsular brownish opacity.
FINAL DIAGNOSIS
• WILSONS DISEASE + CIRRHOSIS OF
LIVER + PORTAL HYPERTENSION
Treatment
• Patient was started on D-Pencillamine
20mg/kg/day
• Patient was also referred to surgery unit
for sclerotherapy for esophageal varices.
• And was asked to follow up after 1 month
WILSON’S DISEASE
• Wilson disease (WD) is an inherited disease of
copper metabolism characterized by cirrhosis and
degenerative central nervous system disorder first
described an American neurologist Samuel
Alexander Kinnier Wilson in 1912
• WD is inherited as an autosomal recessive disorder
linked to a locus on the long arm of chromosome
13.
• 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.
• 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. The
excess copper acts as a promoter of free
radical formation and causes oxidation of
lipids and proteins.
• Organ dysfunction in patients with WD results
from inadequate biliary excretion of copper
and subsequent copper deposition, most
notably in the liver and central nervous
system.
Demography
It occurs world-wide with an estimated prevalence of 1 in
30–50 000. No data exists on prevalence in Nepal
Case series of 19 patients has been published recently
(Nepal Journal of Neuroscience, Volume 1, Number 2,
2004)
Certain features of Wilson's disease (WD) in Asia
have been found to be different from those in other
continents.
In many case series from india, this disease is noted to
manifest at a younger age in Indian children. The
average intake of copper in India ranges from 5.7-7.1
mg/day and is higher than the reported 0.34-1.1
mg/day in Western countries. The practice of cooking
food in copper/copper alloy pots might be contributory.
Presentation of the disease
• The clinical presentations can be extremely varied viz: all
forms of acute and chronic liver disease, minimal to
severe neurological disease, psychiatric problems, bony
deformities,
hemolytic
anemia
and
endocrine
manifestations.
• Age of presentation varies from 4 to 60 years though
majority present before the age of 30 years. The younger
the patient, the more likely is the hepatic involvement
and after 20 years of age neurological symptoms
predominate. KF ring may be absent in young patient
with liver disease but are always present in patient with
neurological symptoms.
• Untreated WD is uniformly fatal. Death results from
hepatic, renal, or hematological complications, generally
at the age of 30 years.
Gastrointestinal System
• Hepatic presentation:
– Most patients including asymptomatic demonstrate
some degree of hepatic damage. Anorexia, vague
abdominal pain, lethargy and epistaxis are non
specific symptoms.
– Most common presentation is that of chronic liver
disease with signs of liver cell failure and portal
hypertension
– Some patients present as acute hepatitis causing
initial diagnostic confusion with infective hepatitis
– Hepatic insufficiency may develop rapidly and result
in signs of fulminant hepatic failure
• Gallstones have been associated with WD in children
Neuro-psychiatric manifestations
Central nervous system pathology in WD results from copper
deposition in the basal ganglia.
Patients may report central nervous system signs and
symptoms, such as drooling, speech changes, incoordination,
tremor, difficulty with fine motor tasks, and gait difficulties.
Psychiatric manifestations include compulsive behavior,
aggression, depression, impulsive behavior, and phobias.
The patient or parent often reports deterioration in school or job
performance. Intellect is unchanged.
KF rings and WD
Kayser-Fleischer rings are 1-3 mm and consist of
copper granules in the stromal layer of the eye.
Color changes are visible only in the Descemet
membrane and typically are described as a golden
brown, brownish green, bronze, or tannish green
color seen in the limbic area of the eye.
No visual impairments are associated with the color
changes, which may be detected with the naked eye,
although slit lamp examination is mandatory for
confirmation.
KF rings are seen in 90% of children with neurological
symptoms, 50-60% without neurological symptoms
and in 10% of siblings with asymptomatic disease.
KF rings start as a small crescent at the top of the
limbus and spread inferiorly then laterally and finally
medially to become circumferential.
The rings fade and disappear with appropriate chelation
therapy in 3-5 years in the reverse order of
appearance.
Renal disease
The product of the WD gene is expressed in renal
tissue, but whether the renal symptoms are primary
or secondary to release of copper from the liver is
unknown.
Renal complications tend to be functional changes
unrelated to identifiable histologic findings.
Rarely, patients with WD develop renal stones and
associated
symptoms.
Renal
stones
are
precipitated by hypercalciuria and poor urine
acidification. Therapy with copper-chelating agents
can improve renal function
Muskuloskeletal system
• Skeletal abnormalities in patients with WD are also
highly
variable
and
include
osteoporosis,
osteomalacia, rickets, spontaneous fractures, and
polyarthritis.
• Knock knees presenting as refractory rickets is
considered common presentation of WD in India.
Cardio vascular disease in WD
• Disorders such as rhythm abnormalities and
increased autonomic tone, have been described in
patients with WD.
• Autopsy findings have included hypertrophy, small
vessel disease, and focal inflammation.
Hematological
• Patients with WD exhibit signs of anemia,
presumably due to oxidative injury of the cell
membrane by excess copper.
• Acute or recurrent coomb’s negative hemolytic
anemia is sometimes a presenting feature which
may or may not be associated with liver dysfunction.
Skin
• Skin
pigmentation
and
a
bluish
discoloration at the base of the fingernails
(azure lunulae) have been described in
patients with WD.
Diagnosis
No single test is diagnostic by itself, and a group of tests
needs to be done
Laboratory results in patients with WD include the
following:
Serum ceruloplasmin levels lower than 20 mg/dL(but
5-40%of patients have normal ceruloplasmin)
Low total serum copper levels(but are seldom
diagnostic, The levels may be low, normal or high in
WD)
Increased urinary copper excretion: >100 mcg/d
(increased excretion after penicillamine dose is more
diagnostic)
Hepatic copper is the single best predictive marker for
WD and considered the gold standard, with values
usually above 250 mcg/g dry weight of liver ( this
facility is seldom available in country like ours)
A complete Kayser–Fleischer (KF) ring indicates longstanding disease and severe Cu overload.
Other findings
• Results of copper stain testing often are negative early in
the disease. Negative results of copper staining of liver
biopsy specimens do not exclude the diagnosis, since
stored copper may be distributed heterogeneously.
• The following laboratory results may be observed in
patients with WD:
– Elevated aminotransferase levels
– Abnormal results on coagulation tests
– Hemolytic anemia
– Aminoaciduria, glycosuria, uric aciduria, and calciuria
• Mutational analysis and haplotype analysis is being
pursued for diagnosis as well as carrier state detection in
the siblings.
Neuroimaging studies
• CT scans of the brain in patients with WD reveal
hypodense regions in the basal ganglia (caudate
nucleus, putamen, globus pallidus). Ventricular
dilatation, brainstem atrophy, and posterior fossa
atrophy are other possible findings. Extent of
involvement as demonstrated on CT scans does not
provide prognostic information.
• Radiographs are not uniformly recommended as
part of the workup for WD in children because
musculoskeletal abnormalities rarely are identified in
the pediatric population.
Diagnostic approach
In a neurological setting, diagnosis of WD is easier, as a
KF ring would be positive in almost all cases and along
with either a low ceruloplasmin or high urinary copper,
would be diagnostic. In liver disease, diagnosis can be
more complex. WD is strongly suggested by any two of
the following – low ceruloplasmin, high urinary copper,
presence of KF rings, and confirmed by a high hepatic
Cu. If a liver biopsy is not possible due to coagulopathy,
but other investigations are suggestive of WD, chelation
therapy can be started immediately. Liver biopsy must
then be done at the earliest opportunity, as hepatic copper
may remain elevated despite years of therapy and clinical improvement
Medical care
Once the diagnosis of WD is made, treatment is
crucial to avoid fatal outcome. Medical treatment
consists of dietary restriction coupled with various
copper-chelating medications.
• Dietary restriction alone doesn’t prevent or control
wilson’s disease, high amount of copper containing
foods( nuts ,meat and fish ,chocolates, spinach etc)
should be avoided .
• Continuous life long drug therapy is essential
;initially to reduce copper to sub toxic levels and
subsequently to maintain a negative copper
balance.
Current drug therapy for wilsons disease
Chelating Drug
Usual dose
Common side effects
D-penicillamine
Start 10mg/kg/day
increase to 2030mg/kg/day in 2-3
divided doses
Zinc
25-30 mg of elemental Abdominal discomfort
zinc 3 times a day
Trientene
25mg/kg/day in 3
divided doses
Ammonium
120 mg/kg/day in six
tetrathiomolybdate divided doses
Thrombocytopenia, bone
marrow depression,
proteinuria, autoimmune
conditions,worsening of
neurological symptoms
Same as penicillamine
Anemia , thrombocytopenia ,
bone marrrow depression
and hepatotoxicity
Further care
• Clinical evaluation, liver function tests, 24 hour
urinary copper, KF rings must be monitored six
monthly initially and yearly thereafter.
• Scholastic and vocational rehabilitation is required
for neurological handicaps along with considerations
for social problem of costly treatment.
• Liver transplant is indicated in patients with WD with
fulminant hepatic failure and/or disease that is
worsening despite chelation therapy. Prognostic
criteria has been set for patients presenting with
fulminant hepatitis.
• Sibling evaluation is mandatory for occult WD or
carrier status of WD gene.
Prognostic Scores for Wilson’s Disease with fulminant hepatiits
Bilirubin
micro mole/l)
Aspartate amino
transferase
(U/l )
Prothrombin time
prolongation
(second)
Prognostic
Score
<100
<100
4
0
101-150
101-150
4 –8
1
151 -200
151 -200
9 -12
2
201 -300
201 -300
13 -20
3
>300
>300
>20
4
Score <6: Recovery likely with treatment
Score>7: List for emergency liver transplantation
Score 6 or 7: Regular review with list for emergency liver
transplantation
Outcome in wilson disease
• Despite adequate chelation therapy the outcome is
unpredictable with 48% mortality in hospital series.
Common outcome seen are:
– Rapid and complete improvement of hepatic
lesions including early cirrhosis
– Initial deterioration of neurological symptoms but
with eventual improvement with few residual
handicaps (speech and handwriting)
– Relentless progression and death as in fulminant
hepatic failure
– Relentless progression and death in advanced
cirrhosis
– Normal healthy outcome in asymptomatic siblings
of index patient who take regular chelation
therapy
• A poor prognosis (i.e. rapid fulminant
hepatic failure) has been reported in
patients who discontinue chelation
therapy.
• Relatively favorable outcome has been
reported after liver transplant, with
reported
decrease
in
neurologic
symptoms. Continued chelation therapy
was not necessarily required post
transplantation.