How does Wilson's disease lead to Fanconi syndrome?

From the Guidelines

Wilson disease leads to Fanconi syndrome through copper accumulation in the proximal tubules of the kidneys, causing damage to mitochondrial function and disrupting energy production, which impairs the tubular cells' ability to reabsorb filtered substances. In Wilson disease, mutations in the ATP7B gene impair copper transport and excretion, causing excessive copper to build up in various organs, including the liver and kidneys 1. When copper accumulates in the proximal tubular cells of the kidneys, it damages mitochondrial function and disrupts energy production. This energy deficit impairs the tubular cells' ability to reabsorb filtered substances like glucose, amino acids, phosphate, bicarbonate, and other electrolytes. The resulting generalized proximal tubular dysfunction manifests as Fanconi syndrome, characterized by inappropriate urinary losses of these substances.

Some key points to consider in the diagnosis and management of Wilson disease and its associated Fanconi syndrome include:

• Patients with Wilson disease may present with renal abnormalities, including aminoaciduria and nephrolithiasis 1
• The diagnosis of Wilson disease should involve molecular testing to confirm homozygosity for one mutation or define two mutations constituting compound heterozygosity 1
• Treatment of Wilson disease involves copper chelation therapy with agents like penicillamine, trientine, or zinc, which can improve or resolve the tubular dysfunction by reducing copper burden
• Early diagnosis and treatment are essential to prevent permanent kidney damage and other systemic complications of Wilson disease

It's worth noting that while the provided evidence includes a study on tyrosinemia type I, which also involves a Fanconi-syndrome-type tubular disorder, the most relevant information for Wilson disease comes from the 2008 study in Hepatology 1. The 2017 study in Genetics in Medicine provides additional context on the diagnosis and treatment of renal disease in tyrosinemia type I, but it is not directly applicable to Wilson disease 1.

From the Research

Wilson Disease and Fanconi Syndrome

• Wilson disease (WD) is a rare inherited disease caused by the mutation of the ATP7B gene, leading to impaired hepatic copper excretion and its accumulation in various organs, including the kidneys 2.
• The accumulation of copper in the kidneys can cause direct toxicity to renal tubular cells, resulting in various degrees of tubular dysfunction, including Fanconi syndrome 2.
• Fanconi syndrome is a disorder of the proximal renal tubules, characterized by impaired reabsorption of glucose, amino acids, and phosphate, leading to their excessive excretion in the urine 2.
• The development of Fanconi syndrome in WD patients is attributed to the excessive accumulation of copper in the renal tubular cells, which can cause damage to the cells and disrupt their function 2.
• Other renal complications associated with WD include proximal and distal renal tubular acidosis, nephrolithiasis, nephrocalcinosis, and bone metabolism abnormalities 2.

Pathophysiology of Wilson Disease

• The pathophysiology of WD involves the accumulation of copper in various organs, including the liver, brain, and kidneys, due to the impaired excretion of copper by the liver 3.
• The accumulation of copper in the kidneys can cause damage to the renal tubular cells, leading to their dysfunction and the development of Fanconi syndrome 2.
• The exact mechanisms of copper toxicity in the kidneys are not fully understood, but it is believed that copper can cause oxidative stress, inflammation, and damage to the renal tubular cells 2.

Diagnosis and Treatment of Wilson Disease

• The diagnosis of WD is based on a combination of clinical, biochemical, and genetic tests, including serum ceruloplasmin and 24-hour urinary copper excretion 3.
• The treatment of WD involves the use of chelating agents, such as penicillamine and trientine, which can increase urinary copper excretion and reduce copper accumulation in the tissues 4, 5.
• Zinc supplementation is also used to inhibit copper absorption in the digestive tract and reduce copper accumulation in the tissues 4, 5.
• The treatment of WD should be tailored to the individual patient's needs and should be monitored regularly to prevent renal and bone complications 2, 6.