Epidemiology and Pathophysiology

Epidemiology

• Worldwide prevalence: 1 per 30,000 live births, with many genetic variant mutations with different pathogenicities in the ATP7B gene
• Typical age of onset is 5–35 years (mean age: 13 years)

Pathophysiology

• Normal copper metabolism:
  • Copper is absorbed in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and duodenum → binds to circulating albumin → absorbed by various tissues
  • Excess copper is excreted into the bile → eliminated in feces
• Wilson’s disease is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder caused by mutations in the ATP7B gene found on chromosome 13.
  • Encodes a membrane-bound, copper transporting ATPase
    • Regulates copper transport within hepatocytes
  • ATP7B protein deficiency or dysfunction causes the following:
    • Impaired excretion of copper into bile → hepatic copper accumulation → copper toxicity from oxidant damage to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Decreased incorporation of copper into apoceruloplasmin → copper accumulates in tissues with low circulating levels of ceruloplasmin (circulating copper transport protein)
  • Different/variant mutations in the ATP7B gene help explain some of the different clinical manifestations.
• As the disease progresses, copper accumulates in the following:
  • Liver
  • Brain
  • Cornea
  • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys

Clinical Presentation

Wilson’s disease usually presents in children and young adults. It rarely manifests after 40 years of age. Manifestations are primarily hepatic, neurologic, and psychiatric and may include:

• Liver disease
  • Hepatomegaly +/– splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Ascites
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Jaundice
  • May include hepatitis, acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure, or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
• Kayser-Fleischer rings
  • Copper deposits in Descemet’s membrane of the cornea, manifested as green-brown rings that encircle the iris
  • Present in:
    • > 90% of patients with neurologic or psychiatric presentations
    • 50%–60% of patients with hepatic disease
• Neurologic symptoms: Copper deposits within the brain cause extrapyramidal motor disturbances.
  • In the basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia → wing-flapping tremor and parkinsonism-like symptoms (Note: The term “lenticular degeneration” used in the original description by Wilson, who was a medical student at the time, refers to the lenticular nucleus [putamen + globus pallidus] portion of the basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia.)
  • In the cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum → dysarthria, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, incoordination, and ataxia
  • In the cerebrum → psychosis, dementia, and affective disorder
• Psychiatric symptoms: depression, irritability, or personality changes
• Hemolytic disease: Coombs-negative hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia (HA), often associated with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice at presentation. Hemolytic anemia is commonly seen in acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure due to Wilson’s disease, but it may also be seen without liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure as low-grade and chronic or episodic HA.

Mnemonic

Clinical presentation of Wilson’s disease: ABCD

• A: Asterixis
• B: Basal ganglia degeneration symptoms (parkinsonism)
• C: Cirrhosis
  Corneal deposits (Kayser-Fleischer ring)
• D: Dementia

Diagnosis and Management

Diagnosis

• Testing for Wilson’s disease should be considered in any patient with unexplained liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, neurologic, or psychiatric abnormalities, and first-degree relatives of patients with Wilson’s disease should be screened for the disease. 
• Physical examination: Kayser-Fleischer rings are usually only seen with slit-lamp examination (present only in 50%–60% of those with isolated hepatic involvement, and in > 90% of patients with neurologic involvement).
• Initial work-up:
  • Transaminitis with AST to ALT ratio > 2
  • Decreased serum ceruloplasmin
  • Elevated 24-hour urinary copper excretion
  • CBC
• Imaging: ultrasound may show:
  • Hepatic steatosis
  • Hepatomegaly or splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Findings of cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
• Gold standard tests:
  • Liver biopsy: increased copper detected by quantitative assay (used if initial work-up is indeterminate)
  • Molecular genetic analysis

Management

• Lifestyle:
  • Low-copper diet: Avoid foods rich in copper such as organ meat, shellfish, nuts, and chocolate.
• Medical management (required):
  • Chelation of copper with penicillamine or trientine
  • If poorly tolerated: oral zinc 
• Liver transplant may be required in severe cases such as fulminant liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure.

Prognosis

• Untreated Wilson’s disease is fatal due to the continuous copper accumulation, with patients dying from cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure, or complications due to progressive neurologic disease.
• The life expectancy is unknown but is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables. An approximate 5-year median survival after the appearance of neurologic symptoms was reported in one study. Of the patients who develop acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure due to Wilson’s disease, 95% die within days to weeks without liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver transplantation.
• Survival with treatment is excellent, even in the presence of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver damage (but not if the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease is advanced). Lifelong treatment is required.

Differential Diagnosis

• Huntington’s disease: can also present with neuropsychiatric manifestations in a patient < 40 years old. Symptoms include chorea, athetosis, aggression, depression, and dementia. Huntington’s disease is caused by an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance trinucleotide repeat (CAG) in chromosome 4. Brain imaging shows atrophy of the caudate and putamen. Kayser-Fleischer rings are not seen in Huntington’s disease.
• Parkinson’s disease: can also present with the following neuropsychiatric manifestations: pill-rolling tremor, cogwheel rigidity, bradykinesia, postural instability, and shuffling gait. Parkinson’s disease is associated with the loss of dopaminergic neurons of the substantia nigra. Histology shows deposits of α-synuclein (intracellular eosinophilic inclusions). Kayser-Fleischer rings are not seen in Parkinson’s disease.
• Hepatitis due to other causes (e.g., alcohol, acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen): Neuropsychiatric manifestations of Wilson’s disease help differentiate it from other causes of hepatitis (although hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Hepatic Encephalopathy can be associated with liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure). Clinical history, labs, and imaging can help differentiate causes of hepatitis from Wilson’s disease.