brief description of Wilson's Disease

1. Hepatology lectures for
5th Sem;MBBS
Pratap Sagar Tiwari
MBBS,MD (Medicine),DM (Hepatology)

2. WILSON’S DISEASE
INTRODUCTION
1
2
3
PATHOPHYSIOLOGY
4 PROGNOSIS
MANAGEMENT

3. INTRODUCTION
• WD was first described in 1912, by Kinnear Wilson, as a familial
disease characterized by progressive, lethal neurologic dysfunction
with LC and a corneal abnormality, the Kayser-Fleischer (“KF”) ring.
• WD (hepatolenticular degeneration) is due to a genetic
abnormality inherited in an AR manner that leads to impairment of
cellular copper transport.
• It is found worldwide, with a prevalence of approx. 1 case in 30,000
live births.
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4. NORMAL COPPER FLUXES AND POOLS
• The daily requirement for copper is approximately 0.9 mg.
• Dietary copper intake is approx. 2-5 mg per day.
• The body contains 50-150 mg of Cu, predominantly in the muscles, bones, and
connective tissues.
• The Cu pool in the musculoskeletal system is in constant exchange with plasma.
• Plasma contains approximately 1 mcg/mL, of which 60–95% bound to ceruloplasmin.
• Ceruloplasmin is a source of Cu for peripheral organs, where Cu is an essential cofactor
for many enzymes.
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5. COPPER FLUXES AND POOLS
• Dietary copper intake is approx. 2-5 mg
per day.
• Excess copper (60 %) is predominantly
excreted into the bile, where it ends up
as fecal copper. Renal losses account for
only 5-15 % of the daily excretion of
copper.
• Copper (40 %) is absorbed in the
duodenum and proximal small intestine.
, binds mainly to circulating albumin, and
is taken up by various tissues.
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6. COPPER FLUXES AND POOLS
• From this intestinal pool, 75% flows
through the portal system with albumin
or transcuprein and is taken up by the
liver.
• The remaining 25% is bound to albumin
in the circulation.
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7. COPPER FLUXES AND POOLS: liver
• In the liver, 20% of Cu is re-excreted back
into the GIT through bile and 80% is
transported to the periphery, bound to
ceruloplasmin.
• The biliary excretion is approx 2.5 mg/d. Near-similar
amounts are excreted from other secretions (saliva,
gastric, pancreatic, and intestinal fluid).
• These are the endogenous Cu excretions, and a large
proportion (approx 80%) is again reabsorbed by the
intestinal mucosa.
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When copper is deficient in the diet, there is enhanced affinity of metallothioneins in enterocytes for copper, thus
increasing its absorption and vice versa.

8. COPPER FLUXES AND POOLS: fecal/urine
• The daily fecal losses are a combination
of unabsorbed dietary Cu and small
proportion of excreted endogenous Cu
amounting to approx 1.5–4 mg/d.
• Urinary Cu excretion is low (10–
100 μg/d).
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Excess copper (60 %) is predominantly excreted into the bile, where it ends up as fecal copper. Renal losses account
for only 5-15 % of the daily excretion of copper.

9. COPPER FLUXES : Summary
• Ingested copper is absorbed by enterocytes
mainly in the duodenum and proximal small
intestine.
• Absorbed copper is transported in the portal
circulation in association with albumin and the
amino acid histidine and is avidly removed from
the circulation by the liver.
• Hepatocytes utilize copper for metabolic needs,
incorporate copper into nascent ceruloplasmin,
and transport excess copper into bile.
• Most excess copper is excreted via this biliary
pathway into feces; only a minor amount is
excreted via the kidneys.
• Impaired biliary copper excretion can lead to
hepatic copper retention.
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10. PATHOGENESIS
• The gene, ATPase copper transporting beta (ATP7B), is expressed mainly in
hepatocytes.
• The gene product ATP7B facilitates transmembrane transport of copper within
hepatocytes.
• Absent or impaired ATP7B function decreases biliary excretion of copper, resulting in
toxic hepatocellular copper accumulation.
• Eventually exceeding storage capacity, hepatic copper released into the bloodstream
deposits in other organs, notably the brain, kidneys, and cornea.
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Loss of functional ATP7B diminishes hepatocellular incorporation of copper into ceruloplasmin.
This explains the decreased blood level of ceruloplasmin in most patients with WD because apoceruloplasmin has a
shorter circulating half-life than ceruloplasmin

11. CLINICAL MANIFESTATIONS
• There is wide variability in the reported rates of the diff CMs seen at the time of
presentation:
1. Liver disease: 18 to 84 % of pts
2. Neurologic symptoms: 18 to 73 % of pts
3. Psychiatric symptoms: 10 to 100 % of pts
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12. MANIFESTATIONS IN WILSON DISEASE
➢Asymptomatic
➢Acute Hepatitis
➢ALF/ACLF
➢Chronic Hepatitis
➢Cirrhosis
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• Copper deposition begins at birth in pts with WD and gradually produces clinical disease.
The majority of pts are DX between the ages of 5 -45 years, though it has been DX in
younger pts and in pts in their 70s.
• Children may be DX through screening because of an affected sibling.

13. MANIFESTATIONS IN WILSON DISEASE
➢Asymptomatic
• Acute Hepatitis
• ALF/ACLF
• Chronic Hepatitis
• Cirrhosis
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• Asymptomatic WD has been documented in 3–40% pts in various
studies.
• These pts have incidentally detected hepatomegaly, raised
transaminases, or are siblings of the index WD pts detected on
screening.
• A majority of these cases are identified in first decade of life or in
adolescence.

14. MANIFESTATIONS IN WILSON DISEASE
• Asymptomatic
➢Acute Hepatitis
• ALF/ACLF
• Chronic Hepatitis
• Cirrhosis
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• Acute hepatitis (10–25%) mimics acute viral hepatitis,
autoimmune hepatitis, and drug-induced liver injury.
• Jaundice, anorexia, nausea, malaise, fever, pale stools, and pain
in the abdomen are often the predominant symptoms.
• The biochemical investigations show unconjugated
hyperbilirubinemia, raised transaminases.

15. MANIFESTATIONS IN WILSON DISEASE
• Asymptomatic
• Acute Hepatitis
➢ALF/ACLF
• Chronic Hepatitis
• Cirrhosis
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• ALF (8–20%) is predominantly seen in childhood and adolescents.
• It is usually a/with Coombs-negative non immune intravascular
hemolysis.
• The presentation mimics acute hepatitis, but the condition
deteriorates rapidly over days to weeks and is often fatal.
• It results in deep jaundice, hemolysis, coagulopathy, ascites,
encephalopathy, and renal failure.

16. MANIFESTATIONS IN WILSON DISEASE
• Asymptomatic
• Acute Hepatitis
• ALF/ACLF
➢Chronic Hepatitis
• Cirrhosis
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• Chronic hepatitis (10–30%) is seen especially in adolescents and
young adults.
• Nonspecific and constitutional symptoms such as fatigue,
anorexia, nausea, and malaise may present before onset of
jaundice and hepatic dysfunction.
• Associated delayed puberty, amenorrhea, polyarthralgia, may be
present.

17. MANIFESTATIONS IN WILSON DISEASE
• Asymptomatic
• Acute Hepatitis
• ALF/ACLF
• Chronic Hepatitis
➢Cirrhosis
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• Pts may present with complications of cirrhosis (35%–
60%), including ascites (SBP), HE, and AKI (including HRS) or PHTN
(variceal bleeding).

18. CLINICAL MANIFESTATIONS
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19. KAYSER–FLEISCHER RINGS
• These constitute the most important single clinical clue to
the diagnosis and can be seen in 60% of adults with
Wilson’s disease (less often in children but almost always
in neurological Wilson’s disease), albeit sometimes only
by slit-lamp examination.
• Kayser–Fleischer rings are characterised by greenish-
brown discoloration of the corneal margin appearing first
at the upper periphery.
• They disappear with treatment.

20. INVESTIGATION: SERUM CERULOPLASMIN
• Serum Ceruloplasmin : Approx 85-90 % of pts with WD have low serum ceruloplasmin
levels (<20 mg/dL or 200 mg/L).
• A very low serum ceruloplasmin concentration (<5 mg/dL or <50 mg/L) provides strong
evidence for the DX of WD.
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21. CAUSES OF LOW SERUM CERULOPLASMIN
Approx 10-20 % of asymptomatic heterozygous carriers have serum ceruloplasmin
<20 mg/dL (200 mg/L). Other causes of low serum ceruloplasmin include:
• Disorders that cause marked renal or enteric protein loss, such as nephrotic syndrome or
protein-losing gastroenteropathy.
• End-stage liver disease of any cause with associated poor synthetic function for
production of all hepatic proteins.
• Rare diseases such as Menkes disease (an X-linked disorder of copper transport leading to
decreased intestinal copper absorption) and aceruloplasminemia (a rare disorder leading
to the absence of ceruloplasmin and problems in iron metabolism).
• Copper deficiency (eg, due to inadequate copper inclusion in parenteral nutrition,
malabsorption following gastric bypass surgery, excessive zinc administration.
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Ceruloplasmin is an acute phase reactant, so levels may be elevated in the setting of inflammation and tissue injury.

22. TOTAL SERUM COPPER
• Serum copper measures the total serum copper (ceruloplasmin-bound
copper + nonceruloplasmin copper or “free copper”). Ninety percent of the serum
copper is bound to ceruloplasmin.
• Total serum copper does not reflect tissue levels and therefore unreliable in
diagnosis.

23. 24–HOUR URINARY COPPER ASSAY
• Urinary copper excretion is useful for the DXs of WD and for monitoring therapy.
• Values >40 mcg/24-hours (0.64 micromol/24-hours) are suggestive of WD, and individuals
with this finding should undergo further evaluation.
• NOTE: Elevated urinary copper excretion may also be seen in pts with other forms of
chronic active liver disease and in heterozygotes for WD, but most often levels are below
100 mcg per 24 hours. The test should not be used in pts with renal failure.
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Measuring 24-hour urinary copper excretion while giving D-penicillamine is a useful confirmatory test; more than 25
μmol/24 hrs is considered diagnostic of Wilson’s disease.

24. MANAGEMENT OF WD
• Lifetime therapy aimed primarily at treating copper overload is required in pts with WD,
and treatment should be considered in these phases:
1. Removing or detoxifying the tissue copper that has accumulated.
2. Preventing reaccumulation.
3. Treatment of complications of PHTN.
4. Additional treatment of neurologic symptoms.
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25. TREATMANT
The copper-binding agent : D-penicillamine, Trientine, Trientine
• D-penicillamine: 1.5 μg/day (range 1–4 μg). The dose can be reduced once the disease
is in remission but treatment must continue for life, even through pregnancy. Toxic
effects occur in one-third of patients and include rashes, protein-losing nephropathy,
lupus-like syndrome and bone marrow depression.
• If these do arise, trientine dihydrochloride (1.2–2.4 μg/day) and zinc (50 mg 3 times
daily) are potential alternatives.

26. SURVIVAL
• Data are lacking regarding life expectancy among untreated pts with WD.
• One study found that the median survival following the development of neurologic
symptoms was approximately five years.
• Pts who develop ALF due to WD have an acute mortality rate of at least 95 % in the
absence of a LT, with death occurring in days to weeks.
• The prognosis for pts who receive and are adherent to treatment for WD is excellent,
provided advanced liver disease is not already present. In such patients, life expectancy
is normal, though treatment may lead to worsening of neurologic symptoms.
• Liver transplantation is indicated for fulminant liver failure or for advanced cirrhosis
with liver failure. The value of liver transplantation in severe neurological Wilson’s
disease is unclear.
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27. END OF SLIDES