Wilson's Disease Case Study

A young couple walks into the prenatal ward of the hospital after their second miscarriage in two years [1]. The wife, Topaz, looks fatigued [2], and lacked enthusiasm and an appetite [2]. The husband became worried after Topaz became depressed [3] and appeared to look yellow [3] in complexion. Their doctor, Dr. Haus, called them in at this point and asked Topaz to step into the general examination room.

Dr. Haus began by asking Topaz for a urine sample and a blood test. As they went over the results, Dr. Haus said, “Topaz, your blood has a copper level of 260 μg/dL, which is extremely high. Most normal levels range from 70–155 μg/dL [1]. I believe that you may have Wilson’s disease, which is an inherited genetic disorder that affects your liver’s ability to excrete copper into bile

and causes a buildup, which can then get into your bloodstream and travel to other parts of the body. We are afraid that if we don’t act now, these copper deposits may reach your brain and affect neurological activity even more than it has.” Dr. Haus began an eye exam and scheduled her for a liver biopsy [2]. As Dr. Haus began the eye exam, he recognized the characteristic golden-brown copper deposit around Topaz’s iris, called a Kayser-Fleischer ring (figure 2)[2]. Dr. Haus additionally confirmed his hypothesis by completing a genetic screening test. Wilson’s disease is an autosomal recessive disorder, which explains why her medical history showed nothing abnormal [1].
The genetic test results showed a mutation at position 1069 that causes a substitution for glutamine instead of histamine [7]. The mutation affects the expression of the “ATPase, Cu++ transporting, beta polypeptide” gene (ATP7B) found predominantly in hepatocyte cells that are essential in the copper metabolism pathway (Figure 1) [9]. The gene encodes for a protein in the P-type, ATPase family, found in the golgi apparatus, that specializes in moving copper out of the cell [7][18]. When copper levels rise, ATP7B leaves the golgi and assists in the removal of Copper into bile. Mutation in the allele for this gene leads to absence or diminished function, resulting in decreased copper excretion. As the copper accumulates in the liver, it causes liver disease and damage.
Once the capacity of the liver is exceeded by the buildup, copper diffuses into the bloodstream and deposits into other organs, causing damage specifically to the brain, eyes, and kidneys. This can affect areas in the brain responsible for sleep, making Topaz extremely fatigued [10]. Dr. Haus explains, “Topaz, your jaundice was caused by a build-up of bilirubin (an orange-yellow pigment formed in the liver by the breakdown of hemoglobin) in the bloodstream and body tissue, which often occurs following liver damage (Figure 5) [11].” Additionally, Dr. Haus added, “yellowing of the skin can cause similar symptoms to a common flu, including loss of appetite, which was the third symptom you were having.” [12].
Dr. Haus reviewed Topaz’s bloodwork to determine how the copper buildup in the liver was affecting her blood sugar levels. An Oral Glucose Tolerance Test (OGTT) was administered to monitor the way Topaz’s body processed glucose [14]. Dr. Haus found that Topaz’s blood sugar levels were far below normal at 100 mg/dl [14]. “Well,” Dr. Haus said, “Your results show that you are hypoglycemic. Because you weren’t eating well, your blood sugar levels dropped dramatically and the liver was not able to release stored glucose to your body [4].” Dr. Haus continued, “hepatic cells in the liver convert excess glucose into glycogen through a process called glycogenolysis for the body to use in a period of low intake of food [5]. With this copper buildup, fulminant liver failure (FLF) is possible [15].” The hepatic cells of Topaz’s liver showed increased expression of CD95 and CD95L in her mRNA, which accounts for a tumor necrotic factor (TNF) that triggers apoptosis of cells in the liver (as seen in Figure 4) [15] [16]. “The death of your liver cells accounts for the low blood sugar levels and the inhibition of stored glucose secretion.”
Dr. Haus began explaining the plan of action they would take: to start her on a CD95-antibody and Penicillamine, which binds to copper ions in the body to create complexes that are easier for the body to pass through the urine [6][15]. Dr. Haus told Topaz that her past miscarriages were most likely due to her lack of treatment. He stated, “abnormal copper metabolism is often related to intrauterine fetal growth restriction and preeclampsia, which could have led to your unsuccessful pregnancies” [1]. Dr. Haus continued, “also, recent studies have found that the protein, ATP7B, which is mutated in your genome, plays a substantial role in transporting copper from the placenta to the mother’s body. Because of the mutation, the copper was not transported out of the fetus, and created a buildup which had a profound effect.” Topaz took a deep breath and said, “will I ever be able to have children?” Without hesitation, Dr. Haus responded, “with proper treatment, it is extremely possible for you to conceive a healthy child!” [1]
Figures:

Figure 1 (left) : represents the pathway of copper metabolism in the hepatocyte. The protein, ATP7B, is seen here as “Wilson’s Disease Protein.” Ceruloplasmin is a protein that binds to copper and assists in its removal from the liver. A mutation in the ATP7B protein, as seen in Wilson’s disease, affects the hepatocyte’s ability to remove the copper, resulting in a buildup which leads to liver damage.

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Figure 2 (right): Closeup summary of lysosomal role in copper metabolism. ATP7B enables lysosomes to undergo exocytosis through the interaction with p62 subunit of dynactin that allows lysosome translocation toward the canalicular pole of hepatocytes. [9]

Figure 3: The patient’s eye, who presents a distinguished sign of Wilson’s Disease, a Kayser-Fleischer ring, which consists of a deposit of copper around the Iris that can be seen with a microscope and a bright light source. [8]

Figure 4: The multilevel regulation of the CD95 signaling. The CD95 ligands (otherwise known as FAS) trigger the expression in the proteins in mRNA resulting in tumor necrotic factors triggering the apoptosis of hepatic cells in the liver. The copper buildup results in an exponential signal in the this pathway [13].

Figure 5: The process of how the substance, bilirubin is broken down in the liver to carry out certain metabolic processes. When the bilirubin is not broken down properly, this build-up can cause conditions such as jaundice which accounts for the yellowing of the skin that the patient was experiencing as one of the symptoms [17].

References:
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