Wilson's disease

Overview

Wilson's illness is a hereditary ailment in which the body accumulates too much copper. Symptoms are usually associated with the brain and liver. Vomiting, weakness, fluid buildup in the belly, swelling of the legs, yellowish skin, and itching are all indications of liver disease. Tremors, muscular stiffness, difficulty speaking, personality changes, anxiety, and psychosis are examples of brain-related symptoms.

Wilson's disease definition

Wilson disease, also known as hepatolenticular degeneration, is an autosomal recessive condition that causes an excess of copper to accumulate in the body. It predominantly affects the liver and the brain's basal ganglia, although it can also impact other organ systems.

Symptoms are mainly associated with the brain and liver. Vomiting, weakness, ascites, leg swelling, yellowish skin, and itching are all indications of liver disease. Tremors, muscular stiffness, difficulty speaking, personality changes, anxiety, and auditory or visual hallucinations are examples of neurological symptoms.

Wilson disease is an autosomal recessive disorder caused by a mutation in the gene coding for the Wilson disease protein (ATP7B). A copy of the gene from each parent must be inherited for a person to be impacted. Blood tests, urine tests, and a liver biopsy, in addition to a clinical examination, are used to make a diagnosis. Genetic testing may be used to screen afflicted people's family members.

The genetic abnormality is located on the long arm of chromosome 13 (13q), and it has been demonstrated that it affects the copper transporting ATP gene in the liver. The majority of Wilson disease patients appear with liver impairment within the first decade of life. Neuropsychiatric symptoms appear in the third/fourth decade of life. Wilson illness is uncommon, yet it is lethal if not diagnosed and treated.

Epidemiology

This illness affects one out of every 30,000 people, with a carrier frequency of one out of every 90. Because of the increasing number of consanguinous marriages, some communities have a greater incidence of Wilson illness. Males and females are both impacted equally. The typical age of onset is four to 40 years old, however this illness has been observed in infants as young as three and individuals as old as 70.

Etiology 

Wilson illness is caused by a mutation in the ATP7B gene on chromosome 13, which regulates the protein transporter responsible for excreting excess copper into bile and out of the body. The protein transporter is found in the liver and brain's trans-Golgi network. The liver is the primary route of copper excretion (95 percent). This extra copper accumulates first in the liver, then in the blood, and finally in other organ systems.

Excess copper induces the formation of free radicals, which cause the oxidation of essential proteins and lipids. The mitochondria, nuclei, and peroxisomes are the sites of the first alterations.

Pathophysiology

A defective copper excretory pathway causes copper to build in the liver and flow into the blood, where it begins to accumulate in various organs and tissues such as the subthalamus, putamen, and cortex of the brain, kidneys, and cornea in Wilson disease. Copper is a transition metal, and high quantities of copper cause the development of a poisonous hydroxyl group and enhance oxidative stress in cells. This oxidative stress causes cell damage, which leads to clinical manifestations such as liver failure, behavioral issues, mobility impairments, and Kayser-Fleischer rings in the cornea.

The body requires copper, mostly as a cofactor for enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine beta-hydroxylase, superoxide dismutase, and tyrosinase. Copper enters the body through the digestive system thanks to copper membrane transporter 1, a transporter protein found in small bowel cells (Ctr1; SLC31A1).

This transporter aids in the transfer of copper into cells, where some of it is linked to metallothionein and some is delivered by ATOX1 to an organelle known as the trans-Golgi network. When copper levels rise, an enzyme called ATP7A releases copper into the portal vein, which leads to the liver. The CMT1 protein and metallothionein are carried by liver cells, and ATOX1 binds to them inside the cell.

Once here, ATP7B binds to ceruloplasmin and releases it into the circulation, where it is removed via secretion into bile. In Wilson illness, both functions of ATP7B are defective. Copper builds up in the liver, and ceruloplasmin is produced in a copper-free form that is swiftly destroyed in the circulation.

When the copper level in the liver exceeds the ability of the proteins that typically bind it, oxidative damage occurs via a process known as Fenton chemistry. Chronic active hepatitis, fibrosis, and cirrhosis arise from this damage. Copper that is not linked to ceruloplasmin is released into the circulation by the liver. This free copper accumulates throughout the body, most notably in the kidneys, eyes, and brain.

Copper is deposited in the basal ganglia, putamen, and globus pallidus (i.e., lenticular nucleus) of the brain; these regions are involved in movement coordination and cognition activities such as promoting mood modulation. Wilson illness is characterized by neuropsychiatric symptoms caused by damage to these tissues.

Clinical presentation 

Patients with Wilson disease may have a favorable family history because it is a heritable condition. Abdominal discomfort, jaundice, weakness, personality changes, depression, migraine headaches, insomnia, seizure, and movement disorder chorea are some of the symptoms that patients may experience. Hemiballismus may have existed in the past.

Neuropsychiatric symptoms, such as asymmetrical tremor, will affect 30-50 percent of individuals. Drooling, ataxia, personality changes, mask-like facies, and clumsiness are all possible signs.

On physical examination, the patient may show signs of hepatosplenomegaly, isolated splenomegaly, or, if the condition has advanced to cirrhosis, the stigmata of chronic liver disease. A slit-lamp examination for Kayser-Fleischer (KF) rings on the cornea and icterus of the sclerae may be revealed by an eye exam (note that the only other disorder with KF rings is Primary biliary cirrhosis). Other symptoms of Wilson illness include movement abnormalities, trouble speaking, mask-like faces, spasticity, muscular stiffness, and lunulae ceruleae skin findings (bluish discoloration at the base of fingernails).

Wilson disease frequently causes skeletal involvement, which mimics early osteoarthritis. Arthropathy often affects the axial bones and spine.

Hemolytic anemia occurs in 10-15% of patients and is caused by red cell lysis caused by the elevated copper content. Wilson disease should be suspected in young patients with reduced liver function, hemolytic anemia, and normal alkaline phosphatase values.

Other organ systems

Medical conditions have been linked with copper accumulation in Wilson's disease:

• Eyes: Kayser–Fleischer rings (KF rings), a pathognomonic sign, can be seen in the cornea of the eyes, either directly or by slit lamp examination, as copper deposits in a ring around the cornea. They are caused by copper accumulation in the membrane of Descemet. These rings are 1 to 3 mm broad and develop near the corneal limbus. They can be dark brown, golden, or reddish-green. They do not present in all Wilson's disease patients. Sunflower cataracts, which are characterized by brown or green pigmentation of the anterior and posterior lens capsules, are also related with Wilson's disease. Neither causes considerable vision impairment. KF rings are seen in around 66% of diagnosed cases.

• Kidneys: Renal tubular acidosis (Type 2) is a disease of bicarbonate handling by the proximal tubules that causes nephrocalcinosis (calcium buildup in the kidneys), bone weakness (due to calcium and phosphate loss), and, in rare cases, aminoaciduria (loss of essential amino acids needed for protein synthesis).
• Heart: Cardiomyopathy (heart muscle weakening) is an uncommon but well-known condition with Wilson's illness; it can lead to heart failure (fluid buildup owing to diminished pump function) and cardiac arrhythmias (episodes of irregular and/or excessively rapid or slow heart beat).
• Hormones: hypoparathyroidism (failure of the parathyroid glands leading to low calcium levels), infertility, and recurrent miscarriage.

Diagnosis

Order a ceruloplasmin level if you have a high suspicion of Wilson illness. It will be less than 20 mg/dL (normal values range from 20 to 40 mg/dL). Urinary copper levels will rise above 100 mcg/dL. These two lab results with Kayser-Fleischer rings are typically sufficient for diagnosis, but if an other diagnosis is possible, request a liver biopsy for liver copper levels; this is the most reliable test for Wilson disease. It should be noted that low levels of ceruloplasmin can be observed in any protein deficient condition.

A copper level more than 250 mcg/g of dry liver tissue is considered positive. An MRI is useful for determining brain involvement. Elevated AST and ALT levels cause liver function tests to be abnormal.

Wilson illness should be suspected if signs of the disease are present or if a family member has the condition. Most exhibited slightly elevated aspartate transaminase, alanine transaminase, and bilirubin levels, as well as mildly abnormal liver function tests. If the liver is severely injured, albumin levels fall due to the inability of damaged liver cells to make this protein; similarly, prothrombin time increases because the liver is not manufacturing clotting components.

In patients with Wilson-related acute liver failure, alkaline phosphatase levels are low. If there are neurological symptoms, an MRI of the brain in the T2 sequence may demonstrate hyperintensities in the basal ganglia. MRI may reveal the distinctive "face of the gigantic panda" pattern.

Liver biopsy

Once additional tests have revealed Wilson's disease, the optimal test is a liver biopsy, which involves the removal of a tiny piece of liver tissue. The degree of steatosis and cirrhosis is examined microscopically, and histochemistry and copper quantification are utilized to determine the severity of the copper buildup.

Wilson's illness is confirmed by a copper level of 250 g per gram of dried liver tissue. Lower amounts of copper are occasionally discovered; in this situation, the combination of the biopsy findings and the other tests might still lead to a formal diagnosis of Wilson's.

In the early stages of the illness, the biopsy often reveals steatosis (fatty material buildup), increased glycogen in the nucleus, and necrosis (cell death). In severe illness, the alterations observed are quite similar to those found in autoimmune hepatitis, such as inflammatory cell infiltration, piecemeal necrosis, and fibrosis 

Finally, cirrhosis is the most common finding in advanced illness. Acute liver failure is characterized by degeneration of liver cells and collapse of the hepatic tissue architecture, usually against a backdrop of cirrhotic alterations. Histochemical techniques for detecting copper are variable and inaccurate, and are considered as insufficient for establishing a diagnosis when used alone.

Genetic testing

Once a mutation is identified, family members can be screened for the disease as part of clinical genetics family counseling. Following the regional distributions of genes linked with Wilson's disease is significant since it can help doctors build suitable screening procedures. Because WD gene mutations differ amongst nations, research and genetic testing in countries with more mixed populations, such as the United States or the United Kingdom, can be problematic.

Management

Copper chelation therapy with penicillamine and trientine is the standard treatment for Wilson disease. Because it has fewer adverse effects, trientine is chosen. Oral zinc may also be administered since it competes with copper for absorption at the metallic ion transporter. It is critical to inform the patient about the negative effects of continuous chelation treatment, which can exacerbate symptoms. D-penicillamine is safe to use throughout pregnancy and poses no harm to the baby.

If the patient develops liver cirrhosis and accompanying complications, a Transjugular intrahepatic portosystemic shunt (TIPS) can be used to treat recurrent variceal hemorrhage. Liver transplantation is a curative procedure.

Baclofen, anticholinergics (trihexyphenidyl), GABA antagonists, and levodopa may be used to treat muscular stiffness, spasticity, and parkinsonian characteristics. In some individuals who were not responding satisfactorily to pharmacological therapy, liver transplantation appeared to be useful in alleviating neurological dysfunction.

A diet low in copper-containing foods is advised, with mushrooms, chocolate, almonds, dried fruit, liver, and shellfish being avoided.

In the neurologic form of the condition, physiotherapy and occupational therapy are useful. The copper-chelating treatment can take up to six months to begin functioning, and these therapies can help people cope with ataxia, dystonia, and tremors, as well as avoid contractures caused by dystonia.

Surgery

The surgery consists mostly of a splenectomy and orthotopic liver transplantation (OLT). The former can be used to treat WD individuals who have significant spleen hyperactivity. OLT is appropriate for decompensated liver disease or "refractory" illness that cannot be relieved alone by medicine. For individuals with WD and fulminant liver disease (FHF) or abdominal issues, OLT is the sole effective therapy.

However, OLT is not appropriate for individuals with just neurological symptoms since transplantation cannot treat long-term neurological impairment. Despite the fact that OLT is a successful therapy, surgery is risky and immunosuppression is uncomfortable. Although OLT resulted in better long-term copper excretion, it is exceedingly expensive.

Cell transplantation

Hepatocyte transplantation and stem cell transplantation are the two most common types of cell transplantation. In recent years, hepatocyte transplantation has been the therapy of choice for aberrant liver metabolism and hereditary diseases. The process of transferring a gene from a donor into the body of a recipient is known as "in vitro" gene therapy. In comparison to "in vivo" gene therapy, "in vitro" gene therapy offers the benefits of low risk and convenience of use. Mature hepatocytes, on the other hand, are highly differentiated somatic cells.

Their ability to proliferate is restricted, and in vitro proliferation is extremely problematic. Immune rejection is also a potential. However, stem cell transplantation may be able to solve this issue. Hepatocytes and bile duct cells can be produced from bone marrow cells in stem cell transplantation. Stem cells can be acquired from donor bone marrow or peripheral blood and have a higher proliferative capacity than hepatocytes.

Furthermore, because stem cells may develop into neurons and other cells, they may be useful in treating the neurological symptoms of WD. An animal study found that both gene therapy and cell transplantation may eventually restore copper homeostasis and cure liver damage, suggesting that cell transplantation is the better alternative.

Hemodialysis

Hemodialysis can lower copper levels in WD patients in a short amount of time while also removing other harmful chemicals. It is appropriate for people with severe or end-stage WD.

Genetic counseling

Genetic counseling is also essential. Although heterozygous carriers of faulty genes are asymptomatic, if they marry someone who has comparable symptoms, they will carry a defective gene to their offspring. Twenty-five percent of heterozygous carriers' offspring are normal, 50% are asymptomatic, and 25% suffer WD.

Symptomatic care and rehabilitative training are also required. A change in symptoms on a daily basis might also allow patients to actively participate in social activities.

Differential Diagnosis

Differential diagnoses include diseases that produce persistent active hepatitis and hemolytic anemias caused by a variety of sources.

To mention a few, neuropsychiatric illnesses that might be misdiagnosed include Parkinsonian syndromes, pantothenate kinase deficiency linked neurodegeneration (iron buildup), neuroacanthocytosis syndromes, and Huntington's disease. Personality changes, stiffness, dystonias, and movement problems can all be symptoms of these illnesses.

Staging

Staging of Wilson Disease:

• Stage 1: Initial accumulation of copper in the liver
• Stage 2: Acute redistribution of copper within the liver, followed by release into the systemic circulation
• Stage 3: Chronic accumulation of copper into extrahepatic tissues including brain
• Stage 4: Use of chelation therapy to restore copper balance

Prognosis

For prognostication, many scoring systems have been proposed. On presentation, some of them include AST, bilirubin, and prothrombin time values, among other things.

Patients with a prognosis score of 7 or above should be considered for a liver transplant. Without treatment, patients with this score usually die within 8 weeks. The prognosis following a liver transplant is favorable. A 15-year survival rate of 87 percent has been recorded.

Complications

The most common complications in patients with untreated Wilson disease are acute liver failure, chronic hepatic dysfunction with either portal hypertension or hepatocellular carcinoma, and the sometimes-relentless progression to cirrhosis, which is characterized by progressive lassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, and ascites.

As the liver fails, bleeding from varices, hepatic encephalopathy, hepatorenal syndrome, and coagulation problems arise. If an urgent liver transplant is not done, death ensues, usually at the age of 30.

Wilson disease, unfortunately, has other systemic implications of copper excess. Cirrhosis is found in the majority of individuals who report with neuropsychiatric symptoms. The reported percentage of patients who have mental symptoms as the presenting clinical characteristic ranges from 10% to 20%. Wilson illness is linked with a wide spectrum of mental abnormalities, ranging from behavioral/mood state changes to movement problems (sometimes choreoathetoid) or parkinsonian symptoms. Chelation treatment might sometimes aggravate these characteristics.

Conclusion 

Wilson illness has no particular therapy and progresses. It is lethal if not treated. An interprofessional team comprised of a gastroenterologist, geneticist, mental health nurse, neurologist, dietician, nurse practitioner, pathologist, radiologist, and internist is ideally suited to handle the illness.

Copper chelation therapy with penicillamine and trientine is the standard treatment for Wilson disease. Some individuals with early illness may be eligible for a liver transplant. The neurological aspects of the condition, on the other hand, are difficult to control. The patient should be informed on the need of eating low-copper meals.

The pharmacist should confirm that the patient is not taking any medications that might damage the liver. Alcohol use should be prohibited. The mental health nurse should evaluate neuropsychiatric symptoms on a regular basis, since they may necessitate extra pharmacological treatments. While liver transplantation is curative, patients must be watched for immunosuppressant medication side effects.

The pharmacist must monitor the chelation therapy since it has a number of side effects that might exacerbate the symptoms. Chelation treatment must sometimes be stopped. A collaborative strategy combining nurses, pharmacists, and clinicians will yield better results.

In the neurologic form of the condition, physiotherapy and occupational therapy are useful. To avoid the transfer of the faulty gene, genetic counseling by a genetics nurse and a clinical geneticist is required. Only by a collaborative effort can the mortality and morbidity of Wilson disease be decreased.