Wilson disease pediatrics case presentation

Case presentation on Wilson disease

1. Case Presentation Dr. Zaira Hussain Fcps r 2 Trainee @ cdf hospital Hyderabad

2. Wilson disease ( Hepatolenticuler degeneration)

3. Introduction Wilson disease is an autosomal monogenic recessive that is associated with primarliy liver disease , degenerative changes in brain and KF rings in cornea. The incidence is approximately 1/30000 birth world wide. Specific treatment is availible but this disease is progressive and potentially fatal if untreated

4. Presenting complaint 8years old female patient Hira d/o Abdul Rehman ,resident of Shikarpur ,admitted through ER with complaints of Yellowish discoloration of eyes = 1.5months Abdominal distention =20 days Bleeding from mouth = 3 days

5. Hopc : According to statement of child mother patient was alright 1.5 month back then she developed yellowish discoloration of eyes which was deepening with the passage of time and progressive involving skin it was associate with dark color urine and pale stool.also c/o low grade fever on and off associated with bodyache. 20 days patient developed abdominal distention which was increasing day by day with the passage of time then developed pedal edema, they went to near by physican where oral medication was given and edema reduced to some extent then parents discontinue medication, no further followup was done. 3 days back child developed bleeding from mouth which was fresh in color about 10 to 15 ml, 2 episodes in a day, no clots for these complaint parents admitted child in peads ward where some iv medication were given and bleeding controlled.

6. Systemic inquiry: GIT : hx of jaundice ,bleeding ,abdominal distension and decrease appetite. No hx of oral ulcers ,altered bowel habits,per rectal bleeding. Respiratory: no hx of cough ,chest infection or ear discharge Cardiovascular system; no hx of shortness of breath ,cyanosis and edema . Central nervous system; no hx of alter level of consciousness and fits.or tremors. Genitourinary system; no hx of dysuria ,hematuria or increased frequency. Musculoskeletal; no hx of rashes or arthritis

7. Past history : No history of blood transfusion or admission in hospital

8. Family history: Child is product of consanguineous marriage Having 4 siblings ,3 are healthy and alive His elder brother died at age of 8 years because of upper Gi bleed but no workup was done.

9. Birth history: Antenatal Hx: Booked case at local Hospital, Regular u/s done No drug hx other than iron and multivitamins supplements Vaccinated for tetanus during pregnancy No hx of DM,GDM, fever or rash during pregnancy Natal Hx: Full term via NVD at hospital Uneventful delivery Postnatal Hx: Immediate cry ,no hx of jaundice ,fever fits after birth Breast feed given within 30 mins after birth.

10. Developmental hx: UpTo date

11. Vaccination hx: Complete and BCG scar present.

12. Nutritional Hx: Decrease appetite due to current illness.

13. Personal history: She is student of class IV with normal school performance, appetite decreased, sleep and bowel habits are adequate.

14. Socioeconomic hx; Father is shopkeeper ,lives in own ventilated house ,drinks unboiled water.

15. general physical examination Young girl of thin built pale looking with obvious abdominal distension lying on bed oriented to time and place cannulated on rt hand with following Vitals: H/R: 90b/min R/R: 20br/min B.P:90/50mmHg (50 th centile) Temp: A/f Subvitals : A+, J+ , Cl+ , Cy-, E+, LN- palmer erythema –ve, spider nevi -ve

16. Anthropometric measures: Weight = 27kg (50 th centile) Height=127cm(50 th centile)

17. abdomen examination: on inspection abdomen is distended with slit like centrally placed everted umbilicus abdomen is moving with respiration with no visible pulsation with some visible prominent viens more over left lateral side on palpation abdomen is soft distended non tender and abdominal grith is 42cm ,liver and spleen palpable. on percussion : shifting dullness positive on ausculation gut sounds audible. perineum and genital exam is unremarkable with no pubic hair

18. Respiratory examination Inspection ;normal symmetrical chest ,with no obviuos deformity Palpation: trachea centally placed Percussion: bl resonant note Auscultation: bl equal air entry ,NVB.

19. Cardiovascular examination: Inspection : no chest deformity ,visible venous pulsation or scar or buldging of pericardium Palpation : apex in the 4 th ICS medial to midclavucular line Auscultation : s1+s2 =0

20. Central nervous system: Bulk : Normal Tone : Normal Power: 5/5 Reflexes : GOOD GCS 15/15

21. 8 years old female hira resident of shikarpur ad through Er with compliants of Yellowish discoloration of eyes = 1.5 months Abdominal distension = 20 days Bleeding from mouth = 3days Her elder brother died with same complaint at age of 8 years but no proper investigations done o/e; young girl ,pale looking with obvious abdominal distention lying on bed well oriented to time,person place cannulated on right hand with following vitals HR=90b/min R/R=20br/min BP=90/60mmHg Temp:37F A+,J+.CL+.E+palmer erythema – ve,spider nevi-ve Abdomen is distended with visible prominent veins with abdominal girth is 42cm, Liver and spleen palpable with positive shifting dullness.

22. Differential Diagnosis???

23. Differential diagnosis

24. INVESTIGATION/CBC HB 8.5 TLC 15.6 N 56 L 30 E 00 M 10 PLT 158,000 MCV 96.8 MCH 33.2 MCHC 34.3 HCT 31

25. UCEs and LFTS Urea 32 Creatinine 0.7 Na 130 K 3.5 Cl 99 Ca 10.5 T.Bili 19.5 D.Bili(mg/dl) 10 ALT/SGPT IU/l 780 AST/SGOT IU/l 660 Alp IU/l 140 Albumin g/dl 2.5

26. PT/INR PT (T) 37.7 (C) 11 INR 2.7

27. Viral markers Anti HCV: Negative HBs Ag: Negative

28. Ana profile

29. U/S WHOLE ABDOMEN The liver measure 10.9 cm with in homogeneous texture and irregular margins. Splenomegaly Portal vein appears patent with normal follow pattern and respiratory variation The hepatic vein also appears normal in size and patent with normal follow pattern and respiratory variation IVC appears prominent measures 1.2 cm and patent with normal flow and respiratory variation Moderate to massive abdominopelvic ascites

30. Eye examination K.F ring seen( On slit lamp examination)

31. Serum ceruloplasmin S.ceruloplasmin: 6 mg/dl Reference range: 20 -60

32. 24hrs urinary copper 24 hrs urinary copper 723 microgram /day Normal; less then 60

33. Final diagnosis CLD secondary to Wilson’s disease

34. Wilson disease: Wilson disease (WD or hepatolenticular degeneration ) is an autosomal recessive disorder that can be associated with degenerative changes in the brain, liver and kayser – fleisher rings in cornea. It is progressive and potentially fatal if untreated, specific and effective treatment is available.

35. Wilson disease: The abnormal gene for Wilson disease is localized to long arm of chromosome 13.(13q14.3). The Wilson disease gene encodes a copper transporting p-type adenosine triphosphate ( ATPase ),ATP7B,which is mainly but not exclusively expressed in hepatocytes and is critical for biliary copper excretion and for copper incorporation into ceruloplasmin. Absence or malfunction of ATP7B results in decreased biliary copper excretion and diffuse accumulation of copper in the cystol of hepatocytes . With the time liver become overloaded and copper is redistributed to other tissue ,including brain,kidneys and conea causing toxicity.

36. Wilson disease

37. Clinical Manifestations

38. Stnages in Wilson disease

39. Diagnosis Wilson disease should be considered in children's and teenagers with unexplained acute or chronic liver disease, neurological symptom of unknown cause, acute hemolysis,psychiatric illnes ,behavioral changes, fanconi syndrome unexplained bone fracture ,osteoporosis and muscle disease myopathy or arthralgia. Most patient with Wilson have decreased Ceruloplasmin level <20mg/dl. Serum copper may be elevated in early Wilson >1.6micromol/L.

40. Urinary copper excretion is increased to >100microg/day. KF rings should be diagnosed on slit lamp examination by ophthalmologist may resolve with adequate treatment. Liver biopsy determine the severity and extent of disease. copper content Normally <10micrgram/g dry weight. In Wilson hepatic copper content may exceed >250microgram/g dry weight . Hepatic copper accumulation is hallmark of Wilson disease and measurement of hepatic parenchyma copper concentration is method of choice of diagnosis

41. treatment

42. Chelating agents are a class of drugs whose mechanism of action is promotion of the excretion of excess body copper through the urine, or in the case of tetrathiomolybdate (TTM), into bile. British anti-Lewisite (BAL) or 2,3-dimercaptopropanol was the first chelating agent introduced as an effective treatment for WD in 1951 which was administered through intramuscular injection . D-penicillamine was the first oral chelating agent used for treatment of WD , and this was followed by development of Trientine That is approved for patients intolerant of d- penicillamine.

43. D –Penicillamine :20mg/Kg/Day for children in two to three divided doses b/f meal Side effects:rash ,thrombocytopenia ,leukopenia,protenuria,renal failure , Pemphigus,goodpasture syndrome,myesthenia gravis,hepatitis,pancreatitis

44. Trientine appears to have less side effects and superior tolerability compared with D-penicillamine, and is becoming a preferred first line treatment for WD. The recommended dose is 20 mg/kg initially and later ~15 mg/kg given as divided doses 2–4 times daily. Poor compliance with medication use is often a significant barrier for optimized management of WD .

45. Zinc acetate: Zinc salts as a treatment for WD acts by creating a negative copper balance by decreasing absorption of dietary copper from gut. Zinc salts have gained popularity for treatment of very young children with WD, treatment of asymptomatic WD patients, and treatment of symptomatic patients who experienced adverse effects with chelation therapy. Dose:25mg 3 times a day in children Limitations of zinc treatment include gastrointestinal upset (leading to intolerance in about one third of patients) and decreased adherence due to multiple daily doses administered away from meals.

46. Liver transplantation ;Curative 85-95% Indications: Fulminant liver disease Decompensated Cirhosis Progressive neurological diseases

47. Long term monitoring Perform a physical examination, 24-hour urinary copper excretion assay, complete blood count (CBC), urinalysis, serum free copper measurement, and renal and liver function tests on a weekly basis for the first 4-6 weeks following initiation of chelation therapy. The best way to monitor efficacy is to measure serum nonceruloplasmin-bound copper. This is measured by the following formula: Total serum copper (mcg/dL) - 3[ceruloplasmin (mg/dL)]. The reference range is less than 15 mcg/dL.

48. An adjunctive way to monitor efficacy is to measure urinary copper excretion. Urinary chelator levels usually measure 200-500 mcg/day. Urinary zinc levels usually measure less than 75 mcg/day. Bimonthly evaluations are recommended through the first year, followed by yearly examinations thereafter. In patients with Kayser-Fleischer rings, a yearly slit-lamp examination should document fading or disappearance if patients are being adequately "decoppered.“ Lifelong, uninterrupted chelation therapy is necessary in all patients with Wilson disease. Frequent follow-up with patients is necessary, secondary to patient decompensation due to noncompliance. This is one of the major causes of fulminant liver failure. Patients must avoid most alcohol consumption and potential hepatotoxic drug therapy.

49. Pathogenesis Abnormal genes for wilson disease is found on chromosome 13 (13q14.3) and encode ATP7B , copper tranporting p-type adenosine triphosphate which is mainly expressed over hepatocyte and critical important for biliary copper excretion and incorporation of copper into ceruloplasmin . Absence or malfunction of ATP7B results decrease copper excretion and causes diffuse acummlation of copper within cytosol of liver and liver becomes overloaded with copper and redistributed to other tissues like brain and kidneys.

50. Clinical manifestation Primarily Liver Brain Kidneys Parathyroid Heart Joints Oculer manifestation

51. Liver Forms of wilsonian hepatic disease include Asymptomatic hepatomegally (with or without spleenomegally ) Chronic hepatitis Acute hepatic failure Crptogenic cirhosiss Manifestion of Decompensated liver disease like ascites, variceal bleeding And other defects of hepatic dysfunction like delayed puberty , amenorrhea, cogulation defects

52. Brain Neurological symptoms can develop insidiously with intension tremor , dysarthra , , rigid dystonia , Parkinsonism , choreform movement, lack of motor co ordination , deteroriation in school performance. KF rings are absent in young patient with hepatic wilson disease upto 50 percent of time but are present with 95 percent of patient with neurological symptoms. Psychiatric symtoms include depression, personality changes, anxiety and psycosis .

53. Coumbs negative hemolytic anemia Coumbs negative hemolytic anemia maybe initial manifestation possibly related to large amount of copper from damaged hepatocyte

54. Other symptoms Pancreatitis Kidney stones Kidney failure Hypoparathroidism Reproductive system joi

55. Oculer Manifestation KF Rings Sun flower cataract

56. KF RINGS

57. Sun flower cataract

58. Diagnosis Wilson disease should be considered in patient in children and teenagers with unexplained acute or chronic liver disease Neurologic symtoms of unknown cause Acute hemolysis Psychiatric illness Fanconi syndrome Unexplained bone or muscle disease

59. investigation Serum ceruloplasmin Ceruloplasmin level less than 20 mg/dl

60. Condition falsly elevate serum ceruloplasmin Acute inflammatory state Estrogen level Serum ceruloplasmin maybe low in Autoimmune hepatitis Celiac disease Carrier of ATP7bB mutation Familial aceruloplasmeia S

61. Free serum copper level and urinary copper excretion Serum free copper level maybe elavated in early wilson disease greater than 1.6micromol/l Urinary copper excretion (normally less than 40 microgram/day) is increased to more than 100microgram/day or often more than 1000 microgram or more per day Typical urinary copper excretion is 1.6 micromol /24 hours in untreated patients in adults and more than 0.64 micromol /24 hours in children

62. In equivocal case response of urinary copper output to chelation therapy maybe diagnostic Prior to 24 hour urine collection patients are given 2500mg oral doses of D- pencillamine 12 hours apart affected patient excrete greater than 1600microgram/24hours

63. Demonstration of KF rings Simple Torch examination Slit lamp Examination Gonioscopy

64. Liver Biopsy Liver biopsy can determine extend and severity of liver disease and for measuring hepatic copper (less than 10microgram/dry weight) Only required if clinical signs and non invasive test do not allow final diagnosis Hepatic copper content more than 250 microgram/dry weight of liver is the best biochemical evidence for wilson disease

65. Investigation for monitoring the severity and complication LFT Pt /INR RFT U/S abdomen

66. Treatment Once diagnosis of wilson disease is being made, lifelong treatment should be intiated and focused on limiting the copper uptake and promoting the copper excretion through dietry and pharmacologic measures Normal diet contain 2-3 mg of copper/day For the patient with wilson disease dietry intake should be restricted to less than 1mg/day

67. High copper contain food Liver Shelfish Nuts Choclates If copper content of drinking water exccceds0.1mg/L than it is nececssary to demineralize the water

68. Copper chelating agents Chelating agents leads to rapid excretion of excess deposited copper. Chelation therapy is managed with D pencillamine in dose of 1g /day in 2 dosesbefore meal for adults and 2omg/kg/day for children Triethylene tetramine dihydrochloeide ( trentine ) at dose of 0.5-2 gram/day for adults 20mg/kg/day for children

69. Trientine is preffered alternative and and first line therapy in some patients. Ammonium tetrathiomolybdate is another chelating agent under the investigation of patient with neurologic disease Initial results suggest that fewer patient experienced neurologic deterioration with this drug as compare to D pencillamine Initial dose include 12omg/kg/day

70. Zinc Zinc also has been used as adjuvant therapy, mainataince therapy and primary therapy due to its unique abilty of impairing the gestrointestinal copper absoption Zinc acetate 25 mg 3 times /day in children over 5 years can be given Zinc can be given as first line therapy in atient with neurologic disease

71. Recent Advances Current Advances in diagnosis and management of Wilson disease

72. New modalities of diagnosis Anterior Segment optical coherence tomography for detection and qunatification of KF rings Imaging advances such as positron emission tomography and Maggentic resonace spectrometry also helped in dignosis by improving our understanding of copper metabolism and by potential early detection of neurlogical abnormalites

73. Management The mainstay of current management of Wilson disease is based on inducing negative copper balance through body and decreased copper intake from diet blocking absorption or by decreasing copper excretion

74. Methanobactin Methanobactin is peptide produced by bacterrium named methylosinus trichosporium with potent affinity for copper It prevents mitochondrial dysfunction and therefore liver injury

75. Gene therapy Gene replacement therapy theoretically can provide potential cure for genetic disease. Lentiviral gene transfer that integrades the ATP7B gene into genome has shown to effective for ameliorating disease progresssion in Animal model of wilson disease.

76. Cell therapy Phenotherapy correction of wilson disease through liver transplantation. Transplantation of adequate amount of healthy hepatocyte may restore ATP7B related ATPase activity at a level adequate for normal copper metabolism.

77. Prognosis Untreated patients with Wilson disease can die of hepatic , neurologic,renal or hematologic complication , Medical therapy is rarly effective in those who are presenting with acute liver failure The prognosis for patient recieving prompt and continous pencillamine is variable and depends upon time of initiation and response to chelation Liver transplantation should be considered for acute liver failure or decompensated cirhhosis of wilson disease Liver transplantation is curative with 5 years survival rate in 85- 90 percent

78. Thank you