Postscript

Introduction

Wilson disease (WD) is an autosomal recessive disorder of copper excretion resulting in reduced secretion of copper into bile and accumulation of copper in tissues.
WD was first described in 1912 by Kinnear Wilson as “progressive lenticular degeneration”.
Estimated prevalence:
- 1 case per ~30,000 individuals.
- Expected number of 8300–11,000 cases in the United States.
- Carrier frequency of 1 in 90
The disease is caused by homozygous or compound heterozygous mutations in ATP7B, which encodes transmembrane copper-transporting ATPase.
ATP7B mediates the excretion of copper into bile.
In Wilson disease:
- ATP7B deficiency leads to copper overload in hepatocytes, which in turn causes hepatocyte damage.
- Once hepatocytes are saturated with copper, they release copper into the blood, which causes damage in other organs.
If untreated, WD is fatal.
Hemolytic anemia has increasingly been recognized as a presenting clinical syndrome even in the absence of overt central nervous system and hepatic disease.

Copper

Copper essential trace element that serves as a cofactor for many physiological enzymatic reactions in critical metabolic pathways.
Recommended dietary intake of copper is 1.5–3.0 mg per day (for adults).
Copper levels are highest in:
- Legumes
- Potatoes
- Nuts and seeds
- Chocolate
- Beef
- Organ meat
- Shellfish
Copper homeostasis is maintained by a network of proteins including:
- Transmembrane copper transporters
- Cytosolic copper carrier proteins
- Copper storage molecules (metallothioneins)
- Copper-requiring enzymes
The liver:
- Is the central organ that regulates systemic copper homeostasis.
- Has the highest tissue expression of the ATP7B copper transporter
ATP7B in the liver:
- Facilitates the process of biliary copper excretion into the biliary tract.
- Provides copper for incorporation into apoceruloplasmin for the synthesis of functional (holo)ceruloplasmin.

Pathogenesis

WD is caused by biallelic mutations of ATP7B gene on chromosome 13q14.3
- > 500 distinct mutations
- About 216 pathogenic variants
The earliest manifestation of WD is accumulation of copper in the liver, leading in sequence to:
- Hepatic steatosis
- Hepatitis
- Fibrosis
Once copper storage capacity of hepatocytes becomes exhausted, copper spills into the blood and is carried as labile non-ceruloplasmin-bound copper to virtually all tissues, where its toxic effect (possibly from redox activity) is responsible for clinical symptoms.
The most common organs involved are:
- Brain
- Eyes
- Kidneys
- Bones
- Heart

Clinical presentation

Patient typically present between the ages of 5 and 35 years.
Hepatic manifestations:
- The clinical presentation of WD with liver involvement includes a wide spectrum of signs and symptoms, including:
  - Acute self-limited
  - Hepatic steatosis:
    - May be accompanied by abnormal liver function tests.
    - Evident on liver imaging (by ultrasonography) or by liver biopsy.
  - Hepatitis-like illness to severe hepatitis
  - Liver failure (‘fulminant WD’, more common in females):
    - Often associated with:
      - Coombs-negative hemolytic anaemia
      - Severe coagulopathy
      - Encephalopathy
      - Rapidly progressive renal failure (hepatorenal syndrome)
      - Characteristic labs including:
        
        High bilirubin
        
        Moderately increased aminotransferases
        
        Normal or markedly reduced alkaline phosphatase
  - Cirrhosis (more common males), which may be complicated by:
    - Portal hypertension
    - Hepatosplenomegaly
    - Ascites
    - Low serum albumin
    - Coagulopathy
Neuropsychiatric manifestations
- Second most frequent clinical presentation after liver.
- Include:
  - Movement disorders such as:
    - Tremor (in 55% of patients at diagnosis)
    - Dystonia
    - Parkinsonism
  - Dysarthria
  - Dysphagia
  - Psychiatric symptoms
Ophthalmological manifestations:
- Copper accumulation may result in:
  - Kayser-Fleischer ring
    - Occurs in:
      - Almost 100% of patients with neurological WD.
      - 40–50% of patients with hepatic WD.
      - 20–30% of presymptomatic patients with WD.
    - Results from copper accumulation in the Descemet membrane.
    - Diagnosis requires slit-lamp examination by an experienced observer.
  - Sunflower cataract
Hematological manifestations (see section below)

Hepatology Communications. 2023;7:e0150.

HEPATOLOGY, June 2008

Journal of Hepatology 2012 vol. 56 j 671–685

Diagnosis

The AASLD recommends that WD be considered when the patient presents with one or more of the following:
- Liver abnormalities of uncertain cause, regardless of age.
- Unexplained liver disease associated with neurological or psychiatric disorder(s).
- ALF with nonimmune hemolytic anemia, including acute intravascular hemolysis.
- Recurrent self-limited nonimmune hemolysis.
If WD is considered, the AASLD recommends the following work up:
- Detailed personal and family medical history
- A physical examination focused on evidence of liver, neurological, and psychiatric disease
- Lab testes, including:
  - Liver biochemistries
  - Complete blood count and international normalized ratio
  - Serum ceruloplasmin
    - Typically decreased in WD
    - May also decreased in patients with other types of liver disease
    - Thus, low levels have poor positive predictive value.
  - Basal 24 hours urinary copper excretion
  - Slit-lamp or optical tomography examination for KF rings
  - Neurological evaluation
  - Molecular genetic investigation of ATP7B.

Hepatology Communications. 2023;7:e0150.

A gold standard diagnostic test does not exist for WD. A diagnostic score based on all available tests was proposed by the Working Party at the Eighth International Meeting on Wilson Disease, Leipzig 2001167. The score was found to have good diagnostic accuracy and was adopted in the European Association for the Study of the Liver (EASL) Clinical Practice Guidelines for WD

Scoring system developed at the 8th International Meeting on Wilson’s disease, Leipzig 2001. Nat Rev Dis Primers. 2018 Sep 6;4(1):21

Management

All patients with a newly established diagnosis of WD should be initiated on lifelong medical therapy for WD.
Current management options include:
- Pharmacological therapies:
  - Chelators (increase urinary copper excretion):
    - d-penicillamine
    - Trientine
  - Zinc salts that decrease copper absorption from the digestive tract.
- Liver transplantation :
  - According to EASL and AASLD recommendations, liver transplantation in patients with WD is indicated in acute liver failure or decompensated liver cirrhosis, which does not respond to pharmacological treatments of WD.
- Symptomatic therapies
- Plasmapheresis:
  - Has been shown to reduce copper-related hemolysis and to stabilize hepatic function.
  - Typically used as a bridge to liver transplantation.

Category I: Disorders for which apheresis is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of treatment. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice. J Clin Apher. 2019;34:171–354.

Wilson disease and hematology

Red blood cells
- Coombs-negative (non-autoimmune) hemolytic anaemia
  - Marked hemolysis is commonly associated with severe liver disease, but hemolysis may be the presenting manifestation in patients with WD or may antedate symptomatic liver or neurologic disease by months.
  - Severity ranges from compensated hemolysis to fulminant intravascular hemolysis.
  - In one series, hemolysis was a presenting feature in 25 out of 220 cases (12%); in these patients hemolysis occurred either as a single acute episode or recurrently or was low-grade and chronic.
  - Mechanisms are not entirely understood but are believed to relate to copper-mediated oxidation of erythrocytic components:
    - Direct effect on oxidation of hemoglobin
      - Precipitation of denatured hemoglobin may lead to Heinz body formation
    - Direct damage to the membrane phospholipids
      - Results in irregularly contracted cells.
    - Inhibition of glycolytic enzymes

- - Destruction of the red cells occurs both intravascularly and extravascularly.
  - Coombs-negative hemolytic anemia is part of Leipzig scoring system (see figure above).
  - Diagnosis:
    - Anemia
    - Elevated reticulocyte count (though may be suppressed from inflammation or nutritional deficiency)
    - Hemolytic markers (all of which may be confounded by liver failure):
      - Elevated AST
      - Elevated indirect bilirubin
      - Elevated LDH
      - Low haptoglobin
    - Negative Coombs test
    - Peripheral smear may show:¹
      - No specific morphologic
      - Presence of Heinz bodies
  - Treatment:
    - Supportive with red cell transfusions
    - Chelation therapy
    - Plasmapheresis has been shown to reduce copper-related hemolysis.
White blood cells:
- Leukopenia may occur in patients with hypersplenism and portal hypertension.
- White blood cell count is a prognostic marker in Wilson disease:

Journal of Hepatology 2012 vol. 56 j 671–685.

Platelets:
- Thrombocytopenia may occur in patients with hypersplenism and portal hypertension.

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