2. Wilson disease
Presented by A.H. Hosseini MD

4. COPPER METABOLISM
• Recommended – 0.9 mg/d
• Absorbed from duodenum & prox.SI
• Transported in portal circulation bound protein
to liver
• Liver synthesize Cu bound ceruloplasmin &
excrete copper into bile
• Stored in liver bound with metallathionein

5. HISTORY
• 1912- by Samuel alexander Kinnear Wilson :
“progressive lenticular degeneration”
• In 1921, Hall further characterized hepatic
involvement and introduced the term
hepatolenticular degeneration.
• Using positional cloning techniques in 1993, three
groups independently reported the identification of
the gene responsible for Wilson’s disease,
designated ATP7B

6. EPIDEMIOLOGY
• autosomal recessive inheritance, thus consanguinity is relatively common in
affected families
• a worldwide prevalence of approximately 1 in 30,000 and the heterozygote
carrier state in approximately 1 in 90 persons
• marked differences in organ system involvement and biochemical findings,
suggesting that polygenic or environmental factors may play a role in
expression of the disease
• Forty to 60% of patients: hepatic presentation in the second decade of life
• The remainder of patients come to clinical attention during the third and fourth
decades with a primarily neurologic (34%) or psychiatric (10%) presentation
• All patients have liver involvement, although it may be asymptomatic and well
compensated

7. GENETICS
• Wilson’s disease gene is on the long arm of chromosome 13
• over 250 distinct mutations identified from patients with Wilson’s
disease
• Most of these are small deletions or missense mutations,
• Missense mutations are associated with a predominance of neurologic
symptoms and a later clinical presentation.
• Deletions and other mutations causing premature stop codons are
associated with an earlier clinical presentation predominated by
symptoms of liver disease
• Haplotype analysis (microsatellite markers) may be particularly helpful
in evaluating relatives of a known case

8. PATHOGENESIS
• Mutations in ATP7B
• impaired biliary copper excretion ,
• progressive accumulation of copper in the liver followed by subsequent
deposition in other organs.
• defective hepatocyte incorporation of copper into ceruloplasmin
• failure to clear the high hepatic copper burden
• intestinal absorption of copper was not increased

9. • Serum ceruloplasmin levels are low in Wilson’s disease
because of decreased synthesis of holoceruloplasmin and
rapid clearance of apoceruloplasmin
• Heterozygotes for Wilson’s disease may have low
ceruloplasmin levels yet no pathologic accumulation of
copper in tissues
• The normal ceruloplasmin level results from ceruloplasmin
being an acute phase reactant. In addition, circulating
apoceruloplasmin may be detected by newer immunologic
assays for ceruloplasmin

10. CLINICAL FEATURES OF WILSON’S DISEASE
• clinical manifestations of Wilson’s disease are rarely apparent before age 5
years
• before age 10 years: 83% of patients presented with hepatic
symptoms and 17% with neuropsychiatric manifestations;
• between 10 and 18 years: 52% presented with hepatic and
48% with neuropsychiatric symptoms;
• after age 18 years: 24% presented with hepatic and 74%
with neuropsychiatric symptoms
• all ages: approximately 49% of patients present with hepatic
and 46% with neuropsychiatric symptoms

11. AS A RULE…
A combination of liver dysfunction and other
organ system involvement, at any age, should
suggest Wilson’s disease.

12. KAYSER–FLEISCHERRING RINGS
• After hepatic saturation, copper accumulating in the ocular cornea
• a greenish brown ring at the periphery of the cornea on its posterior surface in
Descemet’s membrane
• Slit lamp examination
• Treatment with copper chelators results in gradual resolution of the rings over
3–5 years
• The K-F ring does not interfere with visual function
• The K-F ring is virtually always present at the time when neurologic or
psychiatric symptoms develop, although there are rare exceptions (5% of
patients with neurologic symptoms)

13. • The K-F ring is not pathognomonic for Wilson’s disease ; prolonged
cholestatic, liver disease, such as chronic hepatitis, chronic intrahepatic and
neonatal cholestasis, cryptogenic cirrhosis, and primary biliary cirrhosis
• Absence of KF rings doesn’t exclude diagnosis even in neurological disease
• grayish brown “sunflower cataract” ; deposits of copper in the
anterior and posterior lens capsule
• they rarely interfere with vision and resolve with therapy
 The other circumstance in which these cataracts may develop is from a copper -
containing foreign body lodged intraocularly (chalcosis)

15. spectrum of disease

16. HEPATIC PRESENTATION
• Clinical symptoms of liver disease virtually never occur before age 3–5
years
• asymptomatic mild elevation of serum amino transferase levels
 All children and adults who have unexplained chronically elevated serum
aminotransferase levels require a serum ceruloplasmin, slit-lamp examination, 24-hour
urine copper excretion, and most likely, a liver biopsy to establish the underlying
diagnosis
• acute hepatitis(Clinical signs of jaundice, anorexia, nausea, malaise, pale stools, and
dark urine mimic infectious hepatitis

17. • fulminant hepatic failure (Symptoms progress to fatigue, hepatic
insufficiency, extreme jaundice (because of the accompanying hemolysis), severe
coagulopathy, ascites, hepatic coma, renal failure, and death if liver transplantation is not
performed )
• In one study of patients in this clinical setting, a ratio of
o appeared to be diagnostic of Wilson’s disease

18. POINT!!!
• A similar, and unfortunate, fulminant presentation has been described
in patients who had been successfully treated for up to 20 years with
copper chelators but who discontinued therapy or became
noncompliant for as little as 8 months’ time
• Similar presentations have occurred after the discontinuation of zinc
therapy

19. • Chronic hepatitis (during adolescence or young adulthood, Malaise, anorexia,
fatigue, abdominal pain, and nausea may precede the onset of jaundice and hepatic
dysfunction )
 polyarthralgias, edema, gynecomastia, ascites, clubbing, or spider angiomata, when
present, indicate the chronic nature and likelihood of hepatic fibrosis or cirrhosis
• cirrhosis (Although cirrhosis and its complications are relatively common
presenting features of Wilson’s disease in childhood, the disease may remain silent
and asymptomatic well into adulthood, when patients present with neurologic,
psychiatric, endocrine, or other symptoms.

20. AS A RULE…..
• all children age 3–4 years or older with
cirrhosis should undergo evaluation for
Wilson’s disease

21. • Cholelithiasis: common in adolescents with Wilson’s disease and
results from ongoing hemolysis in the presence of cirrhosis
• Abdominal pain in a patient with Wilson’s disease should prompt
ultrasonographic evaluation for gallstones.
• Interestingly, the copper content of gallstones removed from Wilson’s
disease patients was significantly lower than that in pigment stones.

22. • intra-abdominal malignancies (primarily hepatomas,
cholangiocarcinomas, and poorly differentiated adenocarcinomas)
• No case of hepatocellular carcinoma has been
reported in an affected child or adolescent.

23. NEUROLOGICAL
• - Neurologic symptomatology is generally limited to motor
manifestations of extrapyramidal or cerebellar dysfunction
• often second-third decade
• Tremor (resting, intention)
• Drooling, hypersalivation
• Dysarthria
• Coordination defects, clumsiness Dystonia
Writing difficulties Choreiform movements
• Ataxic gait
Headache
Seizures

24. BRAIN MRI CORRELATION OF NEUROLOGIC
FINDINGS
• pseudoparkinsonian
• pseudosclerosis
• dyskinesia

26. PSYCHIATRIC
• Organic dementia
• Neuroses, Anxiety,
• depression,
• Obsessive/ compulsive disorder
• Schizophrenia
• Bipolar disorder
• Antisocial behavior
• Alcoholism

27. RENAL
• Nephrolithiasis
• Proximal renal tubular dysfunction.
• Distal renal tubular acidosis is reflected by the inability to
acidify urine to a pH of less than 5.2 in response to an
ammonium chloride load
• increased tendency for formation of renal stones
• end-stage liver disease may develop severe renal
insufficiency requiring temporary dialysis.
• Isosthenuria

28. • severe proteinuria and the nephrotic
syndrome or a Goodpasture- like syndrome
are more likely to occur as a consequence of
penicillamine administration rather than of
copper toxicity

29. HEMATOLOGICAL
• - Coombs neg. hemolytic anemia
- transient jaundice
- acute intra vascular hemolysis
• When associated with the acute fulminant hepatic presentation,
hemolysis is a poor prognostic factor, contributing to renal failure by
excess hemoglobinuria
• circulating hepatic-derived coagulation factor levels may be low,
platelets may have impaired function, and portal hypertension may
cause splenomegaly and resultant thrombocytopenia and leukopenia

30. CARDIAC INVOLVEMENT
• Electrocardiographic, including left ventricular
hypertrophy, ST wave depression, and T wave
inversion.
• Arrhythmias
• orthostatic hypotension (although asymptomatic),
indicating autonomic dysfunction.

31. SKELETAL MANIFESTATIONS
• may even be the first clinical symptoms of the disease
• Bone demineralization is the most common feature possibly caused by the
hypercalciuria and hyperphosphaturia resulting from renal tubular dysfunction
• Other radiologic changes include rickets and osteomalacia,
osteoporosis, spontaneous fractures, bone fragmentation
near joints
• Stiffness of larger joints is a complaint of many patients

32. SKIN MANIFESTATIONS
• Skin pigmentation on the anterior aspect of the
lower legs, because of deposition of melanin
• acanthosis nigricans
• Blue lunulae of the fingernails

33. ENDOCRINE ABNORMALITIES
• Hormonal imbalance secondary to chronic liver disease has
been thought to lead to amenorrhea in women and
gynecomastia in boys
• increased androgen levels and abnormalities in the
hypothalamic–pituitary–testicular axis in males
• Additional infrequent associations with Wilson’s disease include
diabetes mellitus exocrine pancreatic insufficiency &
hypoparathyroidism

34. Laboratory Findings

35. • Patients with Wilson’s disease may present with almost any
combination of abnormalities in liver blood tests, or even no
abnormality at all
• Serum aminotransferase levels are characteristically only mildly to
moderately elevated, with AST > ALT
• Serum alkaline phosphatase is usually in the low range
• Serum phosphate and uric acid may be low because of renal tubular
losses
• Changes on radiologic evaluation of the skeleton may include
osteoporosis, rickets, osteomalacia, localized demineralization,
osteoarthritis, and other lesions

36. DIAGNOSIS
• No single laboratory test result can establish this diagnosis without
confirmatory clinical and laboratory data, with the possible exception of
genetic testing under certain circumstances
• Liver function tests
• Serum ceruloplasmin
• Urinary copper excretion
• Hepatic parenchymal copper concentration
• Liver biopsy
• Neuro radiological imaging
• Genetic studies

37. SERUM OR PLASMA CERULOPLASMIN
• Synthesized in liver-acute phase reactant
• level less than 20 mg/dL suggests the diagnosis of Wilson’s disease
• LOW levels seen in patients with massive protein loss, kwashiorkor,
severe copper deficiency, severe hepatic insufficiency, hereditary
hypoceruloplasminemia, or aceruloplasminemia, or fulminant hepatitis; in
the normal neonate; in those with Menkes’ syndrome; and in 10% of
heterozygotes for Wilson’s disease
• Level < 5 mg/dl: strong evidence of WD
• If the serum ceruloplasmin concentration is greater than 20 but less than 35 mg/dL, the
diagnosis of Wilson’s disease is not excluded

38. • If ceruloplasmin is normal but there is a high index of suspicion, then
① a 24-hour urine copper excretion (best after penicillamine challenge),
② slit-lamp examination, and
③ liver biopsy
should be performed to confirm or exclude the diagnosis.
• If a sibling has Wilson’s disease, then haplotype analysis can
potentially be performed.

39. the diagnosis of Wilson’s disease must be
confirmed by
• an elevated urine 24-hour copper excretion above 100 μg/24 hr (normal,
<40 μg/ 24 hr),
• an elevated urine copper during a penicillamine challenge
• the presence of a K-F ring (and the absence of other cholestatic liver
disorders),
• elevated hepatic copper content (>250 μg/g dry weight) with consistent
liver histology

40. URINARY COPPER
• 24 hr urinary Cu excretion
• Dx & monitoring
• Basal 24 hr urine Cu > 100 μg in symptomatic WD
• But > 40 μg may indicate WD , req. further test
• Pencillamine challenge test
500 mg D-pencillamine orally at beginning and
repeat after 12 hr during 24hr urine collection
> 1600 μg Cu/24 hr urine - positive

41. 24 HOUR URINE
• Urine must be collected in copper-free containers to avoid
contamination
• Additionally, determining if the collection was a full 24-hour
collection should be confirmed by measuring total urinary
creatinine excretion (normal, 10–20 mg/kg/ 24 hr).
• False-positive results of a 24-hour urine copper excretion
(i.e., >100 μg/24 hr) may be seen if the patient is receiving
any type of copper chelation therapy, if the collection is
contaminated by exogenous copper, or if the patient has
chronic active hepatitis, cholestatic cirrhosis, or nephrotic
syndrome

42. SERUM FREE COPPER
• Increased level of serum “free” copper
• Serum free Cu is non-ceruloplasmin bound Cu
• Total S.Cu (mcg/dl)- 3x serum ceruloplasmin
Cu (μg/dl)
• Normal level<15 mcg/dl
• > 25 mcg/dl in untreated WD
• < 5mcg/dl indicates over-treated

43. HEPATIC PARENCHYMAL COPPER
CONCENTRATION
• Normal - <40-50μg/g dry wt. liver
• Critical value- > 250 μg/g dry wt.
• Further evaluation needed if 70- 250μg/g ,if
active liver d/s or symptoms of WD

44. LIVER BIOPSY
• Mild steatosis- earliest
• Auto immune hepatitis histologic findings
• Cirrhotic changes-macronodular
• marked hepatocellular degeneration & parenchymal
collapse
• Cu staining is variable- poor predictive value

45. NEURO-IMAGING
 Brain CT abnormalities:
• 73% with ventricular dilation, 63% cortical atrophy, 55% brainstem
atrophy, 45% hypodense areas in basal ganglia, and 10% posterior
fossa atrophy.
• MR imaging- evaluate neurologic WD & prior to
treatment
• MRI- T2 hyperintensity in basal ganglia,thalami

46. GENETIC STUDIES
• Molecular genetic testing has been available in recent years and is most helpful if the
diagnosis remains in doubt
• DNA mutation analysis can be performed for a defined ATP7B mutation,
• common mutations in the appropriate ethnic population
• haplotype (microsatellite) marker analysis if a first-degree relative has Wilson’s
disease.
• Prenatal diagnosis ???

47.  Tests that appear to be of no value in establishing the diagnosis of
Wilson’s disease
• computed tomography (CT) scanning &
• MRI of the liver,
 because liver copper content cannot currently be detected or
quantitated by these modalities

48. AN ASYMPTOMATIC PATIENT IN WHOM A K-F RING IS FOUND
ON ROUTINE OPHTHALMOLOGIC EXAMINATION
① a serum ceruloplasmin level should be performed.
② If it is low or there is high suspicion and it is normal,
③ a 24-hour urine copper excretion should be performed and
consideration given to a liver biopsy.
④ Elevated urine copper excretion, a low ceruloplasmin, and a K-F ring
establish the diagnosis.
⑤ However, if the liver or spleen is enlarged or liver blood tests are
abnormal, a liver biopsy should be performed.

49. ASYMPTOMATIC SIBLINGS OF WILSON’S DISEASE PATIENTS
① screened for the disease after age 3 or 4 years unless hepatomegaly or
abnormal aminotransferase levels are found earlier.
② A thorough history and physical examination, slit-lamp examination,
and laboratory analysis should be performed
③ If all tests are normal, it is very unlikely that the relative has Wilson’s
disease
④ However, if any of those tests are abnormal, a liver biopsy should be
performed for histology, electron microscopy, and quantitative copper
analysis.

50. ⑤ An alternative, less invasive approach is to evaluate the known
patient, the sibling, and the parents for DNA haplotype (microsatellite
markers) to determine if the sibling in question has inherited the
Wilson’s disease gene.
⑥ Haplotype analysis is informative in over 90–95% of cases
⑦ Another approach is to genotype the affected relative and if ATP7B
mutations are identified, to test the sibling in question for these
mutations.
⑧ Finding two mutations or informative microsatellite markers will
establish the diagnosis of Wilson’s disease and preclude the need for
liver biopsy unless there are signs or symp- toms of chronic liver
disease

51. treatment

52. • Anti –copper drugs-
-D-Pencillamine
- Zinc
- Trientene
- Tetrathiomolybdate(TM)
• Diet
• Drinking water
• Concomitant hepatic,neurological management
• Liver transplantation

53. D-PENICILLAMINE
• a sulfhydryl- containing metabolite of penicillin
• The actual mechanism on how this drug works is not
known
• “decoppering effect,”
• “detoxification effect”
• It is recommended to begin the penicillamine therapy
with one fourth to half of the desired dose and increase
the dose slowly over 1–2 weeks.

54. • The dosage for older children and adults is 1 g of penicillamine
orally per day in four divided doses given ideally at least 30
minutes before or 2 or more hours after meals.
• If an overtly ill patient fails to show clinical improvement, the
dosage can be increased to 1.5–2.0 g/d.
• In young children, a dosage of 20 mg/kg/d rounded to the nearest
multiple of 250 mg is given ideally in three divided doses
• After stabilization, the dose may be divided into two or three
daily doses not to be given with meals
• D-penicillamine may have an antipyridoxine effect, thus all
treated patients should also receive 25–50 mg of pyridoxine daily

55. • During the first month of penicillamine therapy, the patient
should be monitored weekly for fever or rash.
• A complete blood count and platelet count, urinalysis, and
renal and liver blood tests should be obtained every 1–2
weeks
• If the patient responds appropriately with resolution of symptoms and
normalization of liver blood tests, monitoring is performed every 1–3 months
for the first year and every 6–12 months thereafter.
• An annual 24-hour urinary copper excretion is helpful in
mon- itoring chronic penicillamine therapy

56. • In 10–50% of patients, neurologic symptoms worsened shortly after
penicillamine therapy was started
• Continued or altered penicillamine therapy generally resulted in
reversal of this worsening although irreversible neurologic
abnormalities have been reported
• Thus, it is recommended that the penicillamine dosage be reduced to
250 mg/d if neurologic symptoms worsen and gradually increased every
4–7 days by 250 mg/d until urinary copper excretion exceeds 2000 μg/d

57. TRIETHYLENE TETRAMINE DIHYDROCHLORIDE
(TRIENTINE)
• It does not contain sulfhydryl groups; rather it chelates copper by forming a
stable complex with copper through its four nitrogen atoms in a planar ring.
• better safety profile.
• The initial dosage for adolescents and adults is 750–1500 mg daily in two to
three divided doses before meals.
• Maintenance therapy is typically 750 or 1000 mg/d.
• In children, the dose generally used is 20 mg/kg/d rounded off to the nearest
250 mg.
• The toxicity includes bone marrow suppression (a sideroblastic anemia),
nephrotoxicity, and skin and mucosal lesions .
• Female patients may become iron deficient and require iron supplementation

58. AMMONIUM TETRATHIOMOLYBDATE
• an alternative approach to the treatment of Wilson’s disease is based
on whether the patient presents with neurologic or hepatic symptoms
• Because up to 50% of patients in an earlier series who had neurologic
disease showed worsening of their symptoms with penicillamine
therapy, ammonium tetrathiomolybdate, for initial therapy in
neurologically affected patients
• it is absorbed and complexes with copper and albumin in blood,
preventing cellular uptake and resulting in decreased intracellular
copper stores
• After 8 weeks, the drug was stopped and patients were maintained on
oral zinc acetate, 50 mg three times a day

59. - inhibit CU absorption
- bind with copper (chelator)
- used in neurological WD
- S/E- anemia,neutropenia,
hepatotoxicity
- 120 mg/d ie. 20mg x 3 with meal
60mg bed time
- 8 weeks therapy
- weekly neurological examination

60. ZINC THERAPY
• Zinc has been proposed as maintenance or adjunctive therapy for Wilson’s disease.
• Zinc inhibits intestinal absorption of copper
• The dosage of zinc acetate, given between meals, that currently is advocated is 50
mg of elemental zinc three times daily or zinc sulfate, 150– 220 mg three times daily
• Common side effects include headache and gastrointestinal upset, which are
perhaps less common with zinc acetate.
• Because of its slower onset of action, zinc therapy is generally not used as initial
therapy for symptomatic patients.
• Zinc therapy may play a role in presymptomatic patients or siblings
• It should also be stressed that patients have deteriorated and developed fulmi- nant
liver failure after the discontinuation of zinc therapy.

61. ANTIOXIDANT THERAPY
• Vitamin E, 400–1200 IU/d, may be given orally in divided doses
with meals safely.
• Because high-dose vitamin E may interfere with vitamin K–
dependent clotting factor synthesis, the prothrombin time should
be monitored and vitamin K supplementation used if necessary.

62. LIVER TRANSPLANTATION
• acute fulminant hepatic failure,
• those with fulminant hepatic failure after inadvisably discontinuing copper
chelation therapy
• decompensated cirrhosis unresponsive to medical therapy
• To better determine the criteria for referral for liver transplantation, Nazer et
al. developed a prognostic index based on grading from 1–4 points the
serum bilirubin concentration, serum AST, and prolongation of prothrombin
time

63. NAZER PROGNOSTIC INDEX
Lab
measureme
nt
normal
value
Score
0
Score
1
Score
2
Score
3
Score
4
Serum
bilirubin
0.2-1.2 <5.8 5.8-8.8 8.9-11.7 11.8-17.5 >17.5
SGOT 10-35 <100 100-150 151-200 201-300 >300
PT
prolongation
diff.
12-14s <4s 4-8s 9-12 13-20 >20

64. NAZER INDEX
• Mild hepatic failure- score <6 survived with medical therapy
• Moderate hepatic failure- 7-9
• Severe hepatic Failure - >9 fatal courses or required transplantation
• The authors developed a new index based on serum bilirubin, INR, AST,
albumin, and WBC at presentation.
• A score greater than 11 of a possible 20 was predictive for death, with a 93%
sensitivity, 98% specificity, and 88% positive predictive value

65. SPECIAL CIRCUMSTANCES
 PREGNANCY
• During pregnancy, it is advisable to continue penicillamine therapy at a dosage
of 750–1000 mg/d
• Several patients who have discontinued therapy for longer periods during
pregnancy have had episodes of acute hemolysis or worsening of liver disease
including fulminant hepatic failure.
• All children fathered by patients with Wilson’s disease have been normal
• Although infants may be at a small risk for a connective tissue or skin
abnormality during penicillamine therapy, the risk to mother and infant of
discontinuing copper chelation therapy appears to be greater.
• If cesarean section is anticipated, some authorities recommend reducing the
dose of penicillamine to 250 mg/d 6 weeks before delivery to reduce the risk for
impaired wound healing

66.  SURGERY
• Penicillamine has inhibitory effects on collagen cross- linking
• Therefore, to prevent interference with wound healing, it is
recommended that when patients with Wilson’s disease undergo
surgery, the dose of penicillamine be reduced, but not stopped, for 10–
14 days postoperatively

67. DIET
• Avoid liver ,shell fishes,nuts,chocolate,mushroom
• After 6-12 months Rx, one meal + shell fish/ wk
• If enteral feeding,Cu <1.5 mg/d
• Drinking water - < 0.1 ppm Cu

68. ANTI COPPPER DRUGS
Drugs Mode of action Neurological
deterioration
S/E Dosage monitoring
D-pencillamine Chelator
induces
cupuria
1
20-40 % in
initial phase
BM
suppression,ne
phrotic
syndrome,
Hepatotoxicity,f
ever,
250-
500mg/d,incre
mental
250mg4-7d
Max.1-1.5g/d (
2-4 doses)
Maint-750mg-
1g
Pyridoxine-
25mg/d
24hr.U Cu-200-
500μg
Free Cu-
10-15μg/dl
1,3,6,12,18,
24 months
Then
annually

69. DRUGS MODE OF ACTION SIDE EFEECTS DOSAGE MONITOR
Trientine Chelator induces
cupuria
Gastritis,aplastic
anemia rare,
Sideroblastic
anemia
750-1500mg/d
(2-3 doses)
20mg/kg/d(child
Maint-
750-1000mg
24hr U.Cu &
Non-ceruloplas
Bound copper
1,3,6,12,18,24
months-annually
Zinc
Metallothione
inducer,
Inhibits Cu
absoption
Gastritis,pancreatitis
,Zn accumulation
150mg/d in 3
divided doses
75mg/d
(child, <50 kg)
24hr .U.Cu-
50-125μg/d
&
24h.U.Zn
> 2mg/d
3,6 months,6 month
2yr,then yearly

70. SUMMARY
• WD- is an medical enigma with wide spectrum
• Proper clinical examinations
• Integrated diagnostic approach
• Treatment for various clinical profiles
• Zinc as a new paradigm shift in Rx
• Hepatic transplantation
• Monitoring., and prognosis
• Lifelong Rx and normal expectancy
• Fatal if not treated.