Prepared by : Dr. Abhishek Garg

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CASE OF THE MONTH

• Prepared by Dr. Abhishek Garg
• M.D Resident 3rd year
• Edited by Dr. Arun kumar sharma

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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

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Presented with

• Abdominal swelling --- 1 month
• Progressive pallor------ 1 month
• Pain abdomen off and on

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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 progressive pallor
  without any major bleeds.

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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

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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

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FAMILY HISTORY

• FATHER - 35 years
• MOTHER - 30 years
• 4 SIBLINGS
• 1ST 12 years/female healthy
• 2nd 10 years/female patient
• 3rd 8 years/male healthy
• 4th 6 years/male healthy
• No other members symptomatically ever jaundiced

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GENERAL EXAMINATION

• Temp- 98 F
• Pulse- 120 /min
• BP- 120/60 mmHg
• RR- 19 / min
• Pallor- present

• Icterus- absent
• Edema - absent
• Cyanosis- absent
• Lymphadenopathy- absent
• Clubbing-absent

• Height-129 cms (94.1 of median for age)
• Weight- 29.5 kg (89.3 of median for age)

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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

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Other systemic examination

• Respiratory examination was unremarkable.
• Cardiovascular examination was unremarkable.
• Neurological examination showed no abnormalities.
• Musculoskeletal examination showed no
  abnormalities

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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.

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Investigations contd.

• Bone marrow Normocellular marrow. Erythroid
  hyperplasia
• Urine R/M normal
• Stool r/m- normal
• X-Ray Chest PA normal

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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

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Investigations contd

• Upper GI Endoscopy-
• Grade IV esophageal varices

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• Discussion
• Minor nose bleeds common problem in children
• Most prominent problem in this patient is massive
  splenomegaly

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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
  kala-azar in endemic areas
• Malignancies
• Storage disorders ,especially Gauchers, and
  Niemann-pick disease
• Anatomical lesions like splenic cysts,
  hemangiomas or hamartomas

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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 )

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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-62-140)
• Ophthalmologic examination- KF (Kayser-Fleischer
  ring) Ring with sub capsular brownish opacity.

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Kayser-Fleischer ring) Ring with sub capsular
brownish opacity.
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FINAL DIAGNOSIS

• WILSONS DISEASE CIRRHOSIS OF LIVER PORTAL
  HYPERTENSION

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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

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WILSONS 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.

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• 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.

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Demography

• It occurs world-wide with an estimated prevalence
  of 1 in 3050 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.

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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.

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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

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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.

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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.

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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

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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.

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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.

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Hematological

• Patients with WD exhibit signs of anemia,
  presumably due to oxidative injury of the cell
  membrane by excess copper.
• Acute or recurrent coombs negative hemolytic
  anemia is sometimes a presenting feature which
  may or may not be associated with liver
  dysfunction.

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Skin

• Skin pigmentation and a bluish discoloration at
  the base of the fingernails (azure lunulae) have
  been described in patients with WD.

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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 5-40of 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 gt100 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 KayserFleischer (KF) ring indicates
  long-standing disease and severe Cu overload.

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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.

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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.

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In a neurological setting, diagnosis of WD is
easier, as aKF ring would be positive in almost
all cases and alongwith either a low
ceruloplasmin or high urinary copper,would be
diagnostic. In liver disease, diagnosis can
bemore complex. WD is strongly suggested by any
two ofthe following low ceruloplasmin, high
urinary copper,presence of KF rings, and
confirmed by a high hepaticCu. If a liver biopsy
is not possible due to coagulopathy,but other
investigations are suggestive of WD,
chelationtherapy can be started immediately.
Liver biopsy mustthen be done at the earliest
opportunity, as hepatic copper may remain
elevated despite years of therapy and clin-ical
improvement
Diagnostic approach
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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 doesnt prevent or
  control wilsons 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.

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• Current drug therapy for wilsons disease

Chelating Drug Usual dose Common side effects
D-penicillamine Start 10mg/kg/day increase to 20-30mg/kg/day in 2-3 divided doses Thrombocytopenia, bone marrow depression, proteinuria, autoimmune conditions,worsening of neurological symptoms
Zinc 25-30 mg of elemental zinc 3 times a day Abdominal discomfort
Trientene 25mg/kg/day in 3 divided doses Same as penicillamine
Ammonium tetrathiomolybdate 120 mg/kg/day in six divided doses Anemia , thrombocytopenia , bone marrrow depression and hepatotoxicity
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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.

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Prognostic Scores for Wilsons Disease with
fulminant hepatiits
Bilirubin micro mole/l) Aspartate amino transferase (U/l ) Prothrombin time prolongation (second) Prognostic Score
lt100 lt100 4 0
101-150 101-150 4 8 1
151 -200 151 -200 9 -12 2
201 -300 201 -300 13 -20 3
gt300 gt300 gt20 4
Score lt6 Recovery likely with treatment Scoregt7
List for emergency liver transplantation Score 6
or 7 Regular review with list for emergency
liver transplantation
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• 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

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• 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.