Wilson Disease
September  2016

A 26 year-old man applies for Life insurance. He was diagnosed with Wilson Disease at age 7. Currently he takes Cuprimine 750 mg daily and is without symptoms. Labs done two months prior to application showed a normal CBC, normal lipids and liver function tests. Serum Copper was 38 mcg/dl (72-166) and Alpha-fetoprotein was 3.3 ng/mL (<6.1). Ceruloplasmin was 4.6 mg/dl (16-31).

The remainder of the laboratory tests were within normal ranges. His physical examination was reported as normal. A recent ultrasound of the abdomen showed normal liver size with some increased echogenicity of the liver noted.

What is Wilson disease (WD) and what are the prognostic implications of this chronic condition?
In London in 1912 Samuel Alexander Kinnier Wilson described four patients with lenticular degeneration and hepatic cirrhosis. He also found eight additional cases in the medical literature. The condition has since been known as Wilson Disease (WD). WD is also known as hepatolenticular degeneration due to the accumulation of copper in the liver, the cornea (Kayser-Fleischer rings) and the lens of the eye.

WD is an autosomal recessive disorder, and estimates are that about one in 90 carry a defective copy of the ATP7B gene. It is estimated that WD occurs in one person in 10,000 to 30,000 persons worldwide, although there are some isolated regions (e.g. mountainous Crete) where the prevalence is much higher.

Adults take in about 1.5 mg of dietary copper a day, while our daily requirement is .75 mg. The majority of excess copper is excreted in the bile and feces, and a lesser amount is excreted in the urine. 

The ATP7B gene (on chromosome 13) encodes for the ATP7B protein. This protein is responsible for transporting copper within hepatocytes. Normal hepatocytes incorporate copper to form ceruloplasmin. Ceruloplasmin in the blood stream functions as a ferroxidase vital for iron metabolism.

When ATP7B malfunctions, copper is not efficiently formed into ceruloplasmin nor is it efficiently excreted in the bile, causing copper to accumulate in bodily tissues. Over 300 genetic mutations have been described in the ATP7B gene. And most of those affected have different mutations on each copy of chromosome 13, a condition known as compound heterozygotes.

In WD copper accumulates in hepatocytes causing cell damage and is released into the blood stream as free serum copper. While ceruloplasmin levels may be normal or low due to decreased production, free serum copper is elevated. This leads to gradual accumulation of copper and damage to other organ systems (eye, central nervous system, etc.)

Patients with WD most commonly present with liver disease, neurologic disease or psychiatric symptoms. The age of onset ranges from 5 to 35 years of age. Patients may present with liver disease (steatosis, hepatitis or cirrhosis), which is seen more commonly in children. Those manifesting neurologic disease as a first symptom have mean age of onset between 15 and 21 years.

But even these patients will have some amount of liver damage. Diagnosis of Wilson Disease can be made through screening of relatives of known patients. Common findings are low ceruloplasmin levels, elevated aminotransferases, low platelets and specific genetic mutations if the index mutation is known.

If the family history is not contributory, WD can be a very challenging diagnosis due to the wide variety of clinical presentations. These presentations generally fall into 3 categories: hepatic; neurologic; and psychiatric. See Tables 1 and 2 for manifestations and approximate frequencies in hepatic and neurologic disease.

 

Table 1 – Clinical manifestations of liver disease in WD

​Sign or SymptomFrequency
​Kayser-Fleischer Rings (Figure 1)​50%
​Hepatomegaly and/or splenomegaly​15% - 49%
​Jaundice, anorexia, vomiting​14% - 44%
​Ascites and/or edema​5% - 50%
​Upper GI bleeding (variceal bleeding)​3% - 10%
​Clotting problems​3% - 8%
​Hemolysis​1% - 20%
​Fatty liver​13%
​Asymptomatic​5% - 23%

 

Figure 1 – Copper deposits in Descemet’s membrane in the cornea causes visible golden to reddish rings (arrow)

CopperDeposits.jpg 


Table 2 – Clinical manifestations of neurologic disease in WD

Sign or SymptomFrequency
​Dysarthria​85% - 97%
​Ataxia or gait abnormalities​30% - 75%
​Muscle spasm or rigidity​11% - 69%
​Tremor​22% - 55%
​Parkinson-like symptoms​19% - 62%
​Drooling​48% - 86%


Other less common neurologic findings include: seizures, cognitive impairment/dementia, autonomic dysfunction.

Those patients presenting with primarily psychiatric manifestations can face a long delay in diagnosis due to the common symptoms being depression, personality change, irritability and unusual behavior. These manifestations can go unrecognized as Wilson Disease in children, adolescents and young adults. 

Other than identifying a specific mutation that matches with an affected relative, there is no pathognomonic lab test for WD.  Laboratory tests often performed for diagnosing WD include: Serum ceruloplasmin – The typical value in WD is low (<20 mg/dl), however this is not specific for WD as any liver disease, malabsorption syndromes, and heterozygous carriers often have low levels. Those with WD may also have normal levels as ceruloplasmin rises with estrogens, pregnancy and inflammation.

Serum Copper – The portion that is not bound to ceruloplasmin is called nonceruloplasmin-bound or free serum copper. Typically this will be elevated > 20 to 25 mcg/dl in cases of WD. It also may be elevated in any cause of acute liver failure, chronic cholestasis, or copper intoxication. In treated WD patients levels <5mcg/dl may indicate copper depletion.

Urinary Copper Excretion – Typically 24 hour urinary copper excretion is >100 mcg(>1.6 micromol) in most patients with WD, however elevated values can be seen with other active liver disease and in heterozygotes. Up to 25 % of WD patients will have lower excretion levels > 40-100 mcg/24 hours (.64 – 1.6 micromol).

Penicillamine Challenge or Liver Biopsy – These tests are usually reserved for borderline cases where the diagnosis is equivocal. Penicillamine is thought to increase urinary copper excretion proportionally more in WD than in other forms of liver disease. However, lack of standardization impairs its use in adults. Liver biopsy with staining for copper and quantitation of copper can also aid in the diagnosis. Using a cutoff of 250 mg copper per gm of liver, the sensitivity was 83% and specificity 99% for WD in one study.

The Leipzig Scoring System for Wilson Disease was developed and distributed through a European Association for the Study of the Liver Practice Guideline in 2012. It uses point totals from a combination of clinical findings and test results to establish the diagnosis of WD.

The treatment of Wilson Disease is lifetime therapy with medications. Typically chelators D-penicillamine or Trientine have been used as initial therapy to remove copper from the tissues. Later, chelators can be continued at a reduced dosage, or zinc salts can be used to reduce the absorption of copper. Diet is also altered to avoid foods with high copper content such as mushrooms, cocoa, chocolate, peas, beans, nuts, shellfish, kidney or liver.

The prognosis of Wilson’s disease is related to the amount of damage that was present when it was discovered and treatment was started. Acute liver failure and cirrhosis have the prognosis of those conditions. In one series of patients undergoing liver biopsy, 54% had cirrhosis at the time of diagnosis of WD. The neurologic, hepatic and psychiatric manifestations generally start to improve with treatment.

Long-term survival of WD has been reported from a study of 229 patients in Austria. At 20 years the survival rate of those with WD was 0.92 compared to age & sex matched Austrian population survival of 0.97. However, those WD patients with cirrhosis were almost 7 times more likely to die than those without (Figure 2).

Figure 2 – Kaplan-Meier survival estimates of WD patients with and without cirrhosis


NaR is Number at risk. From Beinhardt S et al. Clinical Gastroenterology and Hepatology 2014;12:683–689


It is not clear if there is an excess risk of developing cancer due to WD in the absence of cirrhosis. There is a known increased risk of hepatocellular carcinoma (HCC) in patients with cirrhosis of any cause. Currently, screening for HCC is recommended only in those patients with WD and cirrhosis.

When decompensated liver disease is present, liver transplant may be required. The transplant cures WD and long-term survival has been reported as good (Figure 3) Characteristics associated with a poorer survival were male gender, pre-transplant renal insufficiency, emergent transplant procedure and a neurological indication for transplant.

Figure 3 – Kaplan-Meier survival estimates from 121 patients with WD and liver transplant in France

Kaplan-Meier survival3-WD.jpg 

A is overall survival. B is survival in adults and children. From Guillaud O, et al. Journal of Hepatology 2014 vol. 60 pp 579–589

Returning to the Case
While we did not have the details of how Wilson Disease was discovered in this applicant, the recent examination tells us that he has no evidence of neurologic or hepatic disease. Therefore, the excess mortality risk would be minimally to slightly increased. 

References

  • Guillaud et al., “Long term results of liver transplantation for Wilson’s disease: Experience in France” J of Hepat 2014;60:579-589.
  • Beinhardt S et al., “Long-term Outcomes of Patients With Wilson Disease in a Large Austrian Cohort” Clin Gastroent and Hepat 2014;12:683-689.
  • Nemeth D et al., “Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson’s Disease” Gastroenterol Research & Practice 2016 1-6.
  • Das S et al., “Wilson’s disease: an update” Nature Clin Prac Neurology 2006;2(9):482-493.
  • Up To Date last accessed 9/1/16
  • “EASL Clinical Practice Guidelines: Wilson’s disease” J of Hepat 2012;56:671-685.