Kayser-Fleischer Ring

Etiology

Kayser-Fleischer rings are brown or grayish-green rings that appear to encircle the peripheral cornea, overlying the iris. They result from copper deposition in the Descemet membrane of the cornea due to the excess accumulation of copper from cholestasis, liver disease, or errors in copper metabolism.

Epidemiology

Wilson disease is globally prevalent at a rate of 1 case per 30,000 live births. Almost 95% of patients exhibiting neurological manifestations of Wilson disease display Kayser-Fleischer rings. Among those with non-neurological disease, approximately 50% may have the rings, along with 10% to 40% of asymptomatic patients and 63% of children with Wilson disease. Although Kayser-Fleischer rings can possibly occur, they are uncommon in individuals with other underlying conditions to exhibit those rings.

Pathophysiology

Kayser-Fleischer rings are caused by the deposition of excess copper on the inner surface of the cornea's basement membrane or the Descemet membrane, which extends into the trabecular meshwork. Copper infiltrates from the aqueous humor through the endothelial cells into the Descemet membrane due to its affinity for the basement membrane. 

Copper is present throughout the cornea and deposits as a granular complex with sulfur, imparting the ring's characteristic color. As a result of fluid streaming, copper accumulates both superiorly and inferiorly before involving the iris circumferentially. In addition, copper may also be deposited in the anterior and posterior capsule lens, which may lead to sunflower cataracts with radiating centrifugal extensions. Notably, neither Kayser-Fleischer rings nor sunflower cataracts cause visual impairments. The deposition of excess copper in various other organs gives rise to the additional clinical manifestations of Wilson disease. Specifically, deposits in the basal ganglia contribute to the neurological and psychiatric manifestations.[6][7][8][9]

History and Physical

Kayser-Fleischer rings are generally asymptomatic, appearing bilaterally, with the upper portion of the cornea being the first to be affected. Over time, these rings spread circumferentially and appear as golden-brown rings in the peripheral cornea, originating at the Schwalbe line and extending less than 5 mm onto the cornea (see Image. Schwalbe Line). These rings may exhibit various colors, such as greenish-yellow, ruby red, bright green, or ultramarine blue.

Wilson disease should be suspected in individuals who present with the following conditions:

• Kayser-Fleischer rings on a routine eye examination
• A family history, particularly with a sibling or parent diagnosed with Wilson disease
• Unexplained and acquired Coombs-negative hemolytic anemia
• Neurological symptoms of unexplained origin
• Psychiatric disease with signs of hepatic or neurological disease
• Patients aged between 3 and 55 with unexplained serum aminotransferase elevation, chronic hepatitis with steatosis, poorly responsive autoimmune hepatitis, cirrhosis, or acute liver failure

Age alone should not be used as a criterion to disregard a diagnosis of Wilson disease. A few patients older than 55 present with neurological symptoms of Wilson disease, primarily when previous symptoms were unrecognized. 

Evaluation

Kayser-Fleischer rings may not be easily visible on routine examination. In the initial stages, a slit lamp is generally necessary to identify the rings. However, visibility with the naked eye becomes possible as the disease progresses, especially in patients with lightly pigmented irises and severe copper overload. Therefore, a slit-lamp examination is imperative for diagnosis. Gonioscopy, which is considered the gold standard for diagnosing angle-closure glaucoma, uses a special lens for the slit lamp. This lens allows for the visualization of the angle and may also detect early Kayser-Fleischer rings.

The evaluation for Wilson disease includes ocular slit-lamp examination or anterior segment optical tomography, 24-hour urinary copper excretion, serum ceruloplasmin, serum aminotransferase, complete blood count, serum copper concentration, magnetic resonance imaging of the brain in the presence of neurological symptoms, liver biopsy if diagnosis is uncertain, and genetic testing if liver biopsy is necessary and not possible or remains inconclusive.

Treatment / Management

Lifelong oral chelating agents, such as penicillamine and trientine, form the cornerstone of therapy for Wilson disease by binding excess copper and promoting urinary excretion. Zinc acetate is also utilized to prevent the excessive absorption of copper. During pregnancy, individuals may temporarily combine zinc acetate with chelators as maintenance therapy. Furthermore, upon diagnosis, patients should refrain from consuming shellfish, nuts, chocolate, mushrooms, and organ meats. Once treatment has been ongoing and stabilized, patients can gradually reintroduce some of these foods in moderation. Notably, dietary modifications alone are not sufficient for managing Wilson disease. Individuals experiencing acute liver failure will require urgent evaluation for liver transplant, as medical treatment alone is ineffective in such cases.[10][11]

Although Kayser-Fleischer rings typically disappear with treatment, they may reappear with disease progression. Their presence serves as valuable clinical indicators for monitoring treatment compliance. Chelation therapy leads to the disappearance of the rings in around 80% of patients over 3 to 5 years. Notably, liver transplantation represents a curative option for Wilson disease.

Differential Diagnosis

Although Kayser-Fleischer rings are most commonly associated with Wilson disease, they may also occur in various other conditions such as primary biliary cholangitis, multiple myeloma, chronic cholestasis, neonatal cholestasis, autoimmune hepatitis, chronic lymphocytic leukemia, liver failure, and chronic liver disease.

The following conditions are included in the differential diagnosis of Wilson disease:

• Chronic liver disease occurs from various causes, such as viral hepatitis, alcohol use disorder, autoimmune hepatitis, drug-induced liver injury, hereditary hemochromatosis, and alpha-1 antitrypsin deficiency.
• Chronic hypertensive encephalopathy
• Glioma
• Japanese encephalitis
• Primary central nervous system (CNS) lymphoma
• Tuberculosis meningoencephalitis
• West Nile encephalitis
• Primary biliary cholangitis
• Psychiatric illness
• Fleischer ring of keratoconus

Several key factors aid in narrowing the differential diagnosis. Individuals with Wilson disease and acute liver failure are prone to develop nonimmune hemolytic anemia. Individuals with chronic liver disease attributed to Wilson disease typically exhibit low ceruloplasmin levels, and almost all patients with neurological symptoms associated with Wilson disease present Kayser-Fleischer rings. These distinct findings contribute to distinguishing Wilson disease from other potential etiologies. 

Prognosis

Wilson disease can be fatal if left untreated, often progressing to cirrhosis and complications of portal hypertension, such as ascites and variceal bleeding.[12] Neurological symptoms can progress to dystonia, akinesia, and mutism. However, early treatment leads to a favorable prognosis. Initiating treatment before the onset of cirrhosis and maintaining normal copper levels enables a normal life expectancy. Although liver enzyme levels usually normalize within 1 year of treatment, cirrhosis is permanent. Neurological symptoms may show improvement for up to 18 months, with some residual symptoms likely becoming permanent. Psychiatric symptoms typically improve concurrently with neurological symptoms.[13]

Complications

Copper can accumulate in various organs. Although the primary sequelae of Wilson disease predominantly affect the liver, CNS, and peripheral nervous system, other parts of the body can also be involved. Complications arising from excess copper deposition in Wilson disease include cirrhosis, hepatocellular carcinoma secondary to cirrhosis, mood disorders, psychosis, sleep disturbance, cardiomyopathy, Fanconi syndrome, myopathy, arthropathy, hyperparathyroidism, infertility, sexual dysfunction, gigantism, nonimmune hemolytic anemia, ascites, and varices.