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home - Liver - Metabolic Conditions - Wilsons Disease Written by Dr Sebastian Zeki
Knowledge


Recognises and appropriately investigates patients with auto-immune
liver diseases

Aware of management and complications of autoimmune liver
disease including extra-hepatic manifestations and associations
including malignant complications in PSC

Skills
Appreciates and understands that this range of liver disease is
frequently under-diagnosed and may have been inappropriately
managed

Selects appropriate immunomodulatory therapy has awareness of
side effects and may well require specialist care

Behaviours
Responds urgently to the management challenge of these severe and
often acute diseases and involves more specialist services where
required
Skills
Maintains diagnostic vigilance as uncommon metabolic liver diseases
may go unrecognised and so retains awareness of them as
diagnostic possibilities

Behaviours
Recognises the potential need to screen relatives and keeps up to
date with contemporary developments of screening protocols



Liaises with clinical genetic unit where appropriate

Manages patients with steatohepatitis clearly and always
sympathetically

Wilsons Disease

Wilsons Disease Cu Cu Cu Cu Cu Cu Caeruloplasmin= 132kd proteinSecreted from hepatocytesUnbound- apoceruloplasminBound= holocaeruloplasmin Cu CaeruloplasminNormal range 20-35 mg/dL [Ceruloplasmin] < 20 mg/dL withKayser-Fleischer rings is diagnostic.[Ceruloplasmin] < 5 mg/dL less specific finding is suspicious.85% of Wilson’s have low caeruloplasminFalse +ves include-Disorders that cause marked renal or enteric protein loss -Any severe end-stage liver disease.-Heterozygote carriers have serum ceruloplasmin levels<20 mg/dL. -Menkes disease (X-linked copper transport disorder), aceruloplas-minemia (genetic- cause no synthesis of caeruloplasmin), and copper deficiency Inadequate copper with parenteral nutrition.-The method used for measuring ceruloplasmin may also influence the results- immunologic and the immunodiffusion assaysmay cause over-estimation as dont distinguish between apoceruloplasmin and holoceruloplasmin Portal fibrosisFatty infiltration within hepatocytesGlycogen inclusions within nuclei IV. Progressive neurological diseaseNeuropsychiatric disease —35% prevalenceSigns include a Parkinsonian-like tremor, rigidity, clumsiness of gait, slurring of speech, inappropri-ate and uncontrollable grinning (risus sardoni-cus), and drooling. 10% have psych problemsIII. Copper accumulates in brainII. Systemic diseaseI. Copper accumulates in liverSerum aminotransferases — Mild elevationThe AST >ALT. Kayser-Fleischer rings 50-60 % if hepatic involvement only of patients who present with isolated hepatic involvement compared with more than 90% with neurological involvementAlso seen in other chornic cholestasis conditionsSunflower cataracts Hepatic copper concentration Diagnostic for Wilson's disease = > 250 mcg of copper per gram of dry weight (Normal range <50mcg/ gm dry body weight)15% of confirmed Wilsons fall below thisPenicillamine challenge — This increases copper excretion more in Wilson’s than normals.Give 500 mg twice over 12 hours during a 24 hour urine collection.Urinary copper excretion >1600 mcg/24 hours (>25 micromol) is much more likely in Wilson's.Genetic testing — di- and trinucleotide repeats around ATP7B.Screening- FDR’s should be screened including genotyping studies based upon the proband if d) Copper stain on liver biopsy (not very sensitive)Liver histologySimilar to those of autoimmune hepatitis and nonalcoholic steatohepatitis (NASH). a) Increased serum Cu (colouring on picture)Not a great testCan be elevated in ALF and chronic cholestasis, or decreased in zinc overusageMostly used for monitoringb) Increased urine excretion CuNormal range=30 to 40 mcg/day (450 to 600 nanomol/day)A value >40 mcg/day (>600 nanomol/day) warrants further investigation. 24-hour urinary copper excretion of 100 mcg (>1.6 micromol) in Wilson’s,- can also be seen in other causes of CLDCollected in acidified distilled water to prevent Copper hydroxide precipitation (therefore low estimations)c) Caeruloplasmin decrease By 15 years about 50% will have clinical manifestationsAlso: kidneys/joints/haemolytic anaemiaAge — 5-40H1069Q mutation most frequent (10-40%) . Most are compound heterozygotes. Pathogenesis Investigations Phases Copper membrane transporter 1 Cu Cu Metallothionein Bound Carried by ATOX1 Trans Golgi network Enzyme ATP7A releases copper into portal vein In liver release into blood done by ATP7B linking Cu to caerulo-plasmin and secreting XS Cu In Wilsons, this is imparied and caeruloplasmin is released but copper isntEventually hepatocyte damage allows copper to leak out Written by Dr Sebastian Zeki

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