Prepared by : Dr. Abhishek GargM.D Resident 3rd year

Edited by : Dr. Arun kumar sharma

CASE OF THE MONTH

PARTICULARS OF PATIENT

Miss PRAGYA DHITAL,10 Years old girlFrom Gorkha , NepalAdmitted on 7/4/062 at KCH / BED NO- 321IP 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 progressive pallor without any major bleeds.

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 – 12 years/female healthyo 2nd – 10 years/female patiento 3rd – 8 years/male healthy o 4th – 6 years/male 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• Lymphadenopathy

- absent• 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

childrenMost 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 kala-azar 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:-62-140)

• 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

• 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

Treatment

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.

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.

Demography

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 WDKayser-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.

DiagnosisNo single test is diagnostic by itself, and a group of tests

needs to be doneLaboratory 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 long-standing 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.

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

Medical careOnce 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 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

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.

Bilirubinmicro mole/l)

Aspartate aminotransferase

(U/l )

Prothrombin timeprolongation

(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

Prognostic Scores for Wilson’s Disease with fulminant hepatiits

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.