Wilson's Disease: The Copper Condrum

Wilson's Disease: The Copper Condrum

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Table of Contents

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1. What Is Wilson's disease

5. Progression to Cirrhosis: Mechanisms

6. Clinical Consequences of Cirrhosis

2. Copper Metabolism (Normal vs. Wilson's disease)

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7. Conclusion: Overview

3. Diagnosis of Wilson's Disease

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8. Quiz!

4. Management of Wilson's Disease

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What is Wilson's Disease? 1

• Wilson's disease is a rare autosomal recessive genetic disorder of copper metabolism.
• A result of a mutation in the ATP7B gene present on chromosome 13.
• ATP7B gene is responsible for excreting excess copper into bile and out of the liver.
• mutation leads to the accumulation of copper in the liver and can spill into the blood and then to other organ systems.

Prevalence

Clinial Presentation

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Copper Metabolism: Normal vs. Wilson's Disease

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GI Absorption:

• Absorption: Dietary Cu²⁺ is reduced to Cu⁺ which is absorbed in the duodenum.

• Intracellular transport: Chaperones like ATOX1 bind Cu⁺.

• Export: ATOX1 delivers Cu⁺ to ATP7A which pumps Cu⁺ into portal circulation for transport to the liver.
• Absorption is unaffected in Wilson's Disease leading to gradual Cu⁺ accumulation2.

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Liver Metabolism:

• Uptake: Hepatocytes uptake Cu⁺ from portal blood through Ctr1.

• Distribution and Processing: Chaperones deliver Cu⁺ to ATP7B, which has two roles:
• Incorporates Cu⁺ into Ceruloplasmin for transport to other tissues

• Mediates Cu⁺ excretion in bile.

• Storage: excess Cu⁺ is bound to by Metallothionein (MT)2.

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Wilson's Disease:

• Dysfunctional ATP7B severely impedes:
• Cu⁺ excretion in bile (most important).
• Incorporation of Cu⁺ into Ceruloplasmin.
• Cu⁺ accumulates progressively in hepatocytes leading to cellular stress.
• Eventually, the hepatocytes die triggering an inflammatory reaction and releasing Cu into the blood .

• This free Cu⁺ can deposit in peripheral tissues2.

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Diagnosis of Wilson's Disease

Inital Clinical Suspicions

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Diagnosis of Wilson's Disease

Clinical Testing

Serum ceruloplasmin test

Liver Biopsy

Genetic Testing

24 Hour Copper Urine Test

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Diagnosis of Wilson's Disease

Serum Ceruloplasmin Test

• Ceruloplasmin is a copper-carrying protein made by the body.
• Serum ceruloplasmin levels are lower in WD patients.
• In WD, ATP7B cannot add copper to ceruloplasmin.
• Ceruloplasmin without copper is readily degraded3.

Values below 10 Mg/dL is most likely indicative a heptic disorder3.

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Diagnosis of Wilson's Disease

Copper Urine Test

• Increased urinary copper is a hallmark of WD.
• Hepatocyte death releases cellular copper, which is filtered by the kidneys4.
• Result in increased urinary copper.

Values exceeding 100 microgrms per 24 hours are commonly seen in WD patients5.

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Diagnosis of Wilson's Disease

Liver Biopsy

• Liver biopsy allows for a histological examination of liver damage by looking at:
• Steatosis
• Hetaptitis
• Cirrohis
• Mallory-Denk bodies
• Liver biopsy enables measurement of heptic copper levels5.

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Diagnosis of Wilson's Disease

Genetic Testing

• Genetic testing is the best method to diagnose WD.

• Direclty tests for mutations in the ATP7B gene.
• WD can result from a variety of mutations across the ATP7B gene7.

Common mutations in specific ethnicities. There are over 300 known in the ATP7B gene that cause WD7.

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Management of Wilson's Disease

Coppper Chelating Drugs

Zinc Supplementation

Gene therapry

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Management of Wilson's Disease

Copper Chelating Drugs

• Penicillamine or Trientine
• These drugs bind free copper in circulation to form a water-soluble complex.
• Copper is prevented from interacting with other tissue and excreted through urine.
• These cannot pass through the blood-brain barrier.
• Not effective for treating copper accumulation in the brain.

• Trientine is generally preferred due to fewer side effects8.

Without chelating drugs

With Chelating drugs

Cu+

Cu+

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Management of Wilson's DiseaseZinc Supplementation

• Prevent copper absorption
• Zinc stimulates the production of metallothionein, which has sequesters copper.
• Copper is prevented from passing into circulation and expelled through feces9.

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Management of Wilson's DiseaseGene Therapy

• One option is editing the ATP7B gene to correct mutations.
• Not likely given the range mutations observed in WD.
• Alternatively, a functional copy of the ATP7B gene is delivered in hepatocytes via viral vectors10.
• Currently, there is one company that is developing something like this: Ultragenyx11.

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Progression to Cirrhosis: Mechanisms

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Clinical Consequences of Cirrhosis

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Hepatic Encephalopathy

• Liver dysfunction leads to toxin accumulation, primarily. ammonia (NH3)18.

• Toxin build up in the brain, causing nerological dysfunction including:
• Confusion
• Sleep disturbance
• Personality changes

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Jaundice

• Yellow discoloration of the skin, , & mucous membranes.
• Damaged liver lose the ability to excrete bilirubrin effectively19.
• build up results in jaundice.

sclera

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Liver Complications

Liver Failure

• Metabolic dysfunction
• Toxin accumulation
• Coagulopathy (tendency to bleed)
• Multi-organ dysfunction

Hepatocellular Carcinoma

• Increased risk of liver cancer

Portal Hypertension

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Increased resistance of blood flow

Liver fibrosis & scarring

Increased portal vein pressure

• Fuid redirected from portal vein to abdominal cavity
• Causes fluid accumulation in the abdomen

Ascites

• Bloodflow is diverted away from the liver to the stomach
• Veins are at risk of rupture & causes bleeding

Gastric Varices

• Increased portal vein pressure leads to blood pooling within the spleen
• Causes enlargement

Splenomegaly

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Conclusion

• Wilson's disease leads to excessive copper accumulation, causing liver damage and progression to cirrhosis if untreated.

• Cirrhosis manifests with symptoms like jaundice, ascites, hepatic encephalopathy, and portal hypertension.

• Early diagnosis using biochemical tests, genetic screening, and liver biopsy is crucial.

• Treatment with chelating agents and zinc therapy can reduce copper levels and slow disease progression.

• Lifelong monitoring is essential to manage complications and improve prognosis.

• Timely intervention helps prevent severe liver dysfunction and enhances long-term health outcomes.

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Quiz

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Question 1/5

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Question 4/5

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Question 5/5

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Sources

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Thank you

Liver

Manifests as:

• Jaundice
• Abdominal Pain
• Dark Coloured Urine

Eyes

Manifests as:

• kayser fleischer rings

Nervous System

Manifests as:

• Muscular stiffness
• Tremors
• Lack of coordination

Brain

Manifests as:

• Mood Changes
• Anxiety and Despression
• Fatigue

Healthy Liver

• Chronic copper accumulation/toxicity leads to liver damage:
• Oxidative Stress: Copper catalyzes the formation of reactive oxygen species (ROS), causing oxidative damage to lipids, proteins, and DNA within hepatocytes
• Mitochondrial Dysfunction: Copper accumulates in mitochondria, impairing their function.
• Hepatocyte death occurs through both apoptosis (programmed cell death) and necrosis (uncontrolled cell death). 12

Inflammation

Chronic inflammation, driven by both copper toxicity and the immune response, contributes to fibrosis.14,15

Fibrosis (scarring)

Repeated hepatocyte injury and inflammation lead to:

• Activation of hepatic stellate cells (HSCs).
• HSCs produce excessive extracellular matrix (ECM), primarily collagen. 16

Cirrhosis

• Cirrhosis is the end-stage of chronic liver injury
• Extensive fibrosis,
• results in the formation of nodules of regenerating hepatocytes surrounded by scar tissue
• Disruption of normal liver architecture
• Impair liver function.17

Fatty Liver

Mitochondrial dysfunction triggers inflammation which causes morphological changes in the liver:

• Steatosis (Fatty Liver): accumulation of lipids in hepatocytes
• Glycogenated nuclei: Nuclei containing excessive amounts of glycogen, appearing clear or vacuolated.13