OVERVIEW
A mental disorder caused by a genetic disease that mainly affects the liver and brain.
The main manifestations are affective disorders and behavioral abnormalities, and a few patients may have various hallucinations and delusions.
Genetic defects lead to copper accumulation, causing cirrhosis of the liver and leguminous degeneration in the brain, resulting in mental disorders.
The treatment needs to promote the metabolism of copper through drugs, surgery, etc., and treat the psychiatric symptoms at the same time.
Definition
Hepatomegaly is an autosomal recessive disorder in which the metabolism of copper is impaired, resulting in lesions of the liver, kidneys, bones, joints, eyes, and nervous system.
Psychiatric disorders associated with hepatomegaly are an important type of neurological damage caused by hepatomegaly.
Patients mainly show emotional disorders and behavioral abnormalities, such as apathy, depression, euphoria, excitement and restlessness, childish or bizarre movements, aggressive behavior, and lazy life, etc., and a few of them may have a variety of hallucinations, delusions, and personality changes, etc. [1].
Pathogenesis
The worldwide prevalence of hepatomegaly is 1/2600 to 1/30,000 [1].
Hepatomegaly is associated with psychiatric disorders in 30% to 90% of patients, and 20% to 25% of patients with hepatomegaly have psychiatric disorders as their first symptom [2].
The age of onset of hepatomegaly tends to be between 5 and 35 years, with males being slightly more common than females, and the average age of those who start with hepatic symptoms is 11 years, and the average age of those who start with neurologic symptoms is 19 years [3].
Causes
Causes
Hepatomegaly, also known as Wilson’s disease, is an autosomal recessive disorder of copper metabolism.
The specific pathogenesis of hepatomegaly is still not completely clear, and it may be related to the impaired excretion of copper in the body and excessive copper accumulation in various organs caused by mutations in the patient’s ATP7B gene [4].
The amount of copper obtained from food is far more than the physiological needs of the human body, and the excess copper is normally metabolized and excreted through a substance called copper blue protein synthesized by the liver.
However, in this disease, the ATP7B gene mutation may cause the copper blue protein synthesis obstacle, resulting in the excess copper can not be excreted from the body, and deposited in many places throughout the body, especially in the liver, the brain nucleus of the nerves (the most important is the nucleus pulposus).
The deposited copper will produce a certain degree of tissue toxicity, triggering abnormalities in liver and brain functions, which are typically manifested as abnormal liver function, cirrhosis, involuntary hand and foot movements, making faces, salivation, various psychiatric symptoms, and unsteady walking [5].
High-risk groups
People with family members who have hepatomegaly (family history).
Symptoms
Main Symptoms
Psychiatric disorders
Some patients present with mental disorders as the first manifestation of the disease. However, sometimes it is later than after liver and neurological symptoms.
However, the manifestation of mental disorders varies very much in each individual.
In adolescent patients, mental and behavioral abnormalities may be manifested as decreased learning ability, memory loss, inability to concentrate, personality changes, mood swings, crying and laughing, irritability, and abnormally strong craving and impulses for sexual behavior.
Paranoia, delusions, manifestations similar to schizophrenia and depressive symptoms, and even suicidal behavior can occur in older patients.
Apathy, hallucinations, aphasia, dementia and other symptoms may appear in the late stage.
Other symptoms
In addition to psychiatric disorders, hepatomegaly may present with neurologic symptoms, liver damage, and other systemic impairments.
Neurological symptoms
Extrapyramidal symptoms are predominant, including dystonia, tremor, limb stiffness, and bradykinesia.
Dystonia
Dystonia is often characterized by violent and involuntary twisting and postural abnormalities of the limbs, trunk or even the whole body, and severe contracture of the limbs often occurs in the late stage.
The mouth and face may also be involved, manifesting as slurred speech, difficulty in swallowing and drooling.
There may also be finger movements like playing the piano or milking the cow, frowning, making faces, flipping and twisting of the upper and lower limbs, and other choreographic movements and manifestations of tardive dyskinesia.
Tremor
The most common type of tremor is involuntary shaking of both upper limbs with large amplitude.
In severe cases, there may be “wing-fluttering tremor”, i.e., when the patient extends the upper limbs to both sides, the wrist joints involuntarily flex and straighten abruptly alternately, which looks like the wings of a bird flapping.
Stiffness of limbs and bradykinesia: Stiffness of limbs, slowed or reduced movement, difficulty in writing, and too small writing appear.
Liver damage.
Unexplained yellowing of the skin and sclera (jaundice), poor appetite, nausea, fatigue, depression, abdominal distension, and generalized swelling may occur.
Damage to other systems
Copper ion accumulation in other systems also shows corresponding functional damage, such as kidney damage, osteoarthropathy, myocardial damage, myopathy and so on.
Young female patients may have menstrual disorders, infertility and repeated miscarriages.
Consultation
Department of Medicine
Neurology
When there are symptoms such as tremor, twisting and postural changes of the limbs, accompanied by apathy, depression, euphoria, hallucinations, delusions, personality changes, etc., it is recommended to consult the Department of Neurology in a timely manner.
Pediatrics
Infants, children, and adolescents with onset of symptoms may be referred to the Department of Pediatrics.
Psychiatry
Patients with psychiatric symptoms such as apathy, depression, euphoria, agitation, childish behavior, hallucinations, delusions, personality changes, etc. can consult the psychiatry department.
Hepatobiliary surgery
Patients with clear cause of illness requiring surgical treatment may consult the Department of Hepatobiliary Surgery.
Preparation
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for Consultation
It is recommended to consult the doctor as soon as possible to avoid delay in diagnosis and treatment.
Prepare relevant medical records before the consultation, especially pay attention to collect the patient’s family medical history.
Preparation List
Symptom list
Pay special attention to the time of onset of symptoms, special manifestations, etc.
Is there apathy, depression, euphoria, excitement and restlessness, childish or strange movements?
Is there a decrease in learning ability?
Is there any aggressive behavior, lazy life, etc.?
Are there any hallucinations, delusions, personality changes, etc.?
Are there any paranoid delusions, schizophrenic-like manifestations, depression or even suicide?
Any twisting of the whole body, abnormal posture, slurred speech, difficulty in swallowing?
Is there any tremor of the upper limbs like a bird flapping its wings?
Is there any generalized yellowing of the skin, depression, abdominal distension, poor appetite, nausea, malaise, generalized swelling?
List of medical history
Has a similar patient appeared in the family?
Is there any other history of brain trauma or disease?
Is there a history of hepatitis or cirrhosis?
Is there a history of mental illness?
Checklist
Test results from the last six months, which can be brought to the doctor’s office
Imaging tests: cranial CT, cranial magnetic resonance test
Other tests: blood routine, blood biochemistry (liver and kidney function, blood lipids and glucose, blood electrolytes, cardiac enzymes, etc.), coagulation function, serum copper blue protein, 24-hour urine copper measurement, electrocardiogram.
Medication List
Medication used in the last 3 months, if available in a box or package, carry it with you to the doctor’s office
Drugs to promote copper excretion and reduce copper absorption: D-penicillamine, sodium dimercaptopropanesulfonate, zinc preparations, etc.
Antipsychotic drugs: quetiapine, olanzapine, risperidone and clozapine, etc.
Antidepressants: sertraline, citalopram and fluoxetine, etc.
Antidystonic drugs: amantadine, phenazopyridine, compounded dopa-type preparations, etc.
Other medications: hepatoprotective medications such as silymarin and dicyclomine.
Diagnosis
Diagnosis is based on
Medical history
Family history of the disease.
Symptoms
There are emotional disorders and behavioral abnormalities, such as apathy, depression, euphoria, excitement and restlessness, childish or bizarre movements, aggressive behavior, lazy life, personality changes, hallucinations and other manifestations.
It may also be accompanied by liver injury manifestations such as generalized yellowing of skin, abdominal distension, poor appetite, nausea, malaise, etc.; and neurological injury manifestations such as generalized torsion, abnormal postures, slurred speech, and tremor of both upper limbs.
Physical examination
Examination of mental disorder
The doctor will talk and interact with the patient to observe whether the patient has any emotional disorder and behavioral abnormality, such as indifference, depression, euphoria, excitement and restlessness, childish or strange movements.
The doctor may have the patient complete some psychosomatic scales to further quantify and refine the patient’s mental disorders.
Neurological examination
The doctor will observe the patient for any involuntary twisting or postural abnormalities of the limbs or head and face.
The doctor will ask the patient to move the upper limbs and observe any tremor, or ask the patient to stretch the upper limbs flat to the sides and observe any activity at the wrists like a bird flapping its wings, i.e., fluttering-wing-like tremor.
Let the patient do some movements and observe whether there is any slow and stiff movement, such as writing, and observe whether there is any difficulty in writing or too small writing.
Examination of liver lesions
The doctor will observe the color of the patient’s face, eye sclera and body skin for jaundice.
The doctor may perform a palpation examination of the patient’s abdomen to check for hepatosplenomegaly and cirrhosis.
Examination of the corneal K-F ring
The corneal K-F ring, a ring of yellow-green or yellow-gray pigment located at the edge of the cornea of the eye, is the most important specific sign of hepatomegaly.
The doctor may look at the eye for the presence of the K-F ring under side light exposure with a flashlight.
If a flashlight side light exposure is not seen, an ophthalmic slit lamp examination is needed to clarify the presence of a corneal K-F ring.
The corneal K-F ring is usually not detectable in patients under 7 years of age.
Laboratory tests
These include liver and kidney function, routine blood tests, routine urine tests, serum copper blue protein, and 24-hour urine copper.
The purpose is to find out whether there is liver and kidney function impairment and to clarify the copper metabolism in the body.
During the course of treatment, some of the items may need to be reviewed periodically in order to assess the treatment effect, as well as to monitor the body’s condition and adjust the treatment program.
Magnetic Resonance Imaging (MRI)
Including cranial MRI examination, liver MRI examination.
Cranial MRI may show symmetrical lesions.
Located in the nucleus pulposus, caudate nucleus, thalamus, midbrain, pontine, cerebellar dentate nucleus.
They appear as “woodpecker”, “figure of eight”, “double figure of eight” and “butterfly with wings”.
If the corpus callosum is involved, the mental and neurological symptoms are more serious.
MRI of the liver often shows lipid deposits, irregular nodules and lobar atrophy in the liver.
Note: Patients wearing metal dentures, having heart stents, pacemakers and other metal objects in the body should consult with a doctor before the examination to determine whether the examination can be performed.
Abdominal ultrasound
Abnormal echoes of the patient’s liver can be found, with nodules and enlargement.
Some patients have an enlarged spleen.
Genetic testing
For people with insufficient clinical evidence but high suspicion of hepatomegaly, if an ATP7B gene variant is found, the diagnosis of the disease is confirmed.
The three most common high-frequency pathogenic variants are p.R778L, p.P992L, and p.T935M, which account for 50% to 60% of all pathogenic variants.
Precautions: People with a family history of the disease but without the disease should be tested for themselves and their spouses if they plan to marry or have children.
Liver Puncture Test
Formerly used to measure hepatic copper and to detect pathological manifestations such as hepatic fibrosis.
It is an invasive test and has been replaced by the ATP7B gene test.
Diagnostic Criteria
According to the Chinese Classification and Diagnostic Criteria for Mental Disorders 3 (CCMD-3), the diagnosis of mental disorders due to hepatomegaly needs to meet the following four criteria [6]:.
Meet the diagnostic criteria for mental disorders due to cerebral degenerative diseases.
There are signs and symptoms such as cirrhosis, increased dystonia, tremor, and corneal K-F rings.
There are psychiatric symptoms such as progressive mental retardation, affective disorders, hallucinations, delusions, or personality changes.
Laboratory tests show evidence of impaired copper metabolism.
Differential Diagnosis
Hepatic encephalopathy
Similarities: mental, neurological, and hepatic damage such as mental lethargy, apathy, personality changes, hallucinations, limb tremors, and yellowing of the skin may be present.
Differences
Hepatic encephalopathy usually has no dystonia manifestations such as generalized torsion, postural abnormality, slow movement, etc. It has no manifestations of other parts of the body such as K-F ring, renal damage and osteoarthropathy.
Copper metabolism index lab tests are normal, and there is no ATP7B mutation in genetic testing.
Parkinson’s disease or Parkinson’s syndrome
Similarities: both may manifest as dystonia, motor retardation, cognitive decline, etc.
Differences
In Parkinson’s disease or Parkinson’s syndrome, the tremor is a resting tremor, cognitive impairment occurs in the later stages of the disease, and there is no corneal K-F ring.
There are no abnormalities of copper metabolism on laboratory tests and no mutations in the ATP7B gene.
Huntington’s disease
Similarities: both have a family history of depression, anxiety, agitation, obsessive-compulsive disorder, cognitive decline, and dystonia.
Differences
In Huntington’s disease, the dystonia is characterized by “choreiform” movements, and autonomic dysfunction such as incontinence may be present.
There are no abnormalities in liver function or copper metabolism, and no mutations in the ATP7B gene.
Treatment
Aim of treatment: to correct abnormal copper metabolism, reduce organ damage, improve symptoms, and improve patients’ quality of life and life expectancy.
Treatment principle: early treatment, lifelong treatment, lifelong monitoring. Drug therapy is the mainstay, with surgery, rehabilitation and other methods.
Dietary treatment
Once suspected of having hepatomegaly, a low-copper diet should be started immediately.
Avoid eating the following foods with high copper content:
All kinds of animal offal and blood; shellfish (clams, razor clams, mussels, mussels, oysters); mollusks (squid, squid); snails; shrimps and crabs; bacon, duck, goose.
Nuts (peanuts, walnuts, lotus seeds, chestnuts, sesame seeds); various beans and their products.
Shiitake and other mushrooms; oats, buckwheat, millet; nori, garlic, taro, yam, lily, kiwi.
Foods or beverages such as chocolate, cocoa, coffee, and tea; Chinese herbs such as dragon bones, centipedes, and whole scorpions.
Try to eat less of the following foods that are high in copper:
Beef and lamb; potatoes, brown rice, black rice.
Kelp, bamboo shoots, aloe vera, spinach, eggplant.
Banana, lemon, lychee, cinnamon, etc.
Foods with low copper content suitable for eating:
Olive oil, fish, chicken, lean pork, refined white rice and noodles.
Light-colored vegetables, apples, peaches, pears, ginkgo nuts, scallions, etc.
Suggested diets high in amino acids or protein, such as milk and protein powder.
Medication
The mental disorders associated with hepatomegaly are organic psychiatric disorders, and treatment to improve abnormal copper metabolism is the basic tool, on the basis of which symptomatic treatment is given according to mental and neurological symptoms as well as other lesions.
Blocking copper absorption
Therapeutic purpose: to reduce the copper content in the body by inhibiting the intestinal absorption of copper [8].
Commonly used drugs: zinc sulfate, zinc gluconate, tetramolybdate and so on.
Precautions
To avoid food affecting the absorption of zinc, it is best to take the medicine 1 hour after meals.
Try to eat less food rich in crude fiber and phytic acid, as they can interfere with zinc absorption.
Allow an interval of 2 hours between the administration of zinc preparations and copper-eliminating drugs.
Promoting copper elimination
Therapeutic purpose: to bind copper in the body and form a non-toxic complex to be excreted in the urine.
Commonly used drugs: D-penicillamine, triethyltetramine, sodium dimercaptopropanesulfonate, sodium dimercaptosuccinic acid, etc.
Precautions
D-Penicillamine should be used only if the skin test for penicillin is negative before use.
All copper-excluding drugs should be used from a small dose and gradually increase the dosage, once the neurological symptoms are aggravated, it is necessary to report to the doctor, and if necessary, stop using immediately.
In addition, it is necessary to pay attention to nausea, vomiting, skin rash and other reactions, and regularly recheck the blood routine, liver and kidney function.
Female patients can continue to take zinc preparations during pregnancy, but should not be treated with D-Penicillamine.
Breastfeeding is not recommended for women taking D-Penicillamine.
Symptomatic treatment
Psychiatric symptoms
Excited manic symptoms predominate: quetiapine, olanzapine, risperidone and clozapine may be used.
Apathy and depressive symptoms are predominant: antidepressants such as sertraline, citalopram and fluoxetine are available [9].
Cautions: quetiapine and clozapine are recommended for severe limb tremor and extrapyramidal symptoms; risperidone and olanzapine should be used with caution.
Neurologic symptoms
Dystonia and limb rigidity: drugs such as amantadine, phenazopyridine, medroxyprogesterone, carbidopa (compound dopa-like preparation), piribedil, baclofen, and etoperisone hydrochloride can be used. Localized botulinum toxin type A injections may also be given in severe cases of localized dystonia.
Choreiform movements and tardive dyskinesia: clonazepam, small dose haloperidol can be used.
Limb tremor: Benzodiazepine, Medoxomil, carbidopa (compound dopa-like preparation), clonazepam, etc. can be used.
Treatment of other lesions
Liver injury: drugs such as silymarin and bicyclic alcohol can be used to protect the liver; hemodialysis and plasma exchange can be used to remove copper deposited in the body; liver transplantation should be carried out in time for severe cases.
Leukocyte and platelet reduction: Ricodin, recombinant human granulocyte colony-stimulating factor, recombinant human thrombopoietin and other drugs can be used to raise leukocytes and platelets. Discontinue D-penicillamine if necessary, and perform splenectomy.
Other treatments
Multidisciplinary comprehensive treatment should be carried out for the dysfunction of mood, language and physical activity.
Encourage and help patients to actively participate in various activities and light to moderate physical labor, and school-age children and adolescents should attend school normally [10].
On the basis of medication, with psychological counseling can appropriately relieve the patient’s inner pressure.
Electroconvulsive therapy can temporarily and rapidly severe depression, suicidal tendencies, mainly applicable to a variety of drugs and other treatments are ineffective, generally not as the first choice of treatment.
Prognosis
Cure
Hepatomegaly can be disabling or fatal if untreated, with a case fatality rate of about 5.0% to 6.1% [1].
With active, long-term standardized treatment, especially intervention in the early stages of the disease and before the onset of neurological symptoms, most patients can improve in all aspects of their symptoms and return to normal work and life without affecting normal life expectancy.
Harmfulness
The disease has a long course, and patients who are not treated in time may not be able to live, study and work normally due to mental and neurological symptoms, which brings a great burden to the family and society.
A few patients may commit suicide due to the disease or mental disorder.
Daily
Daily Management
Dietary management
A low-copper diet should be started as soon as hepatomegaly is suspected, as described in the “Dietary management” section above.
Do not use copper eating utensils and appliances.
For patients with dysphagia that severely interferes with eating, a gastric tube should be left in place for nasal feeding.
Water purifiers that are effective in removing copper can be used if available.
Life management
Take medication regularly, do not adjust or stop medication by yourself.
Provide patients with a quiet and safe living environment, equipped with handrails, guardrails and fall prevention equipment.
Stabilized patients can exercise appropriately according to the doctor’s advice, with family members accompanying them when exercising to ensure a safe exercise environment and prevent accidents such as falls and traumatic brain injuries.
Psychological support
Family members should cooperate with doctors to guide patients to correctly understand the disease, accept the disease and establish confidence in the treatment of the disease.
Encourage the patient to participate in some social and family activities and do what he/she can to enhance self-confidence.
When the patient is found to be emotionally unstable and seriously depressed, family members should seek timely help from medical staff for drug intervention and psychological counseling to prevent the patient from suicidal behavior.
Disease monitoring and follow-up
Blood and urine routine, liver and kidney function, coagulation function, and 24-hour urine copper should be checked regularly after starting drug treatment, and reviewed once a month in the first 3 months, and once every 6 months after the condition is stabilized [1].
Liver and spleen ultrasound can be used to assess the progress of the disease and monitor the therapeutic effect of drugs, and it is recommended to be examined once every 3 to 6 months, and once every year if multiple examinations are normal [1].
Cranial MRI can be used to monitor the effect of treatment, and the frequency of review should be based on the doctor’s recommendation.
All patients must be closely monitored for adverse effects of various medications at the same time.
Prevention
Hepatobiliary nuclear degeneration is an autosomal recessive disease, but patients can marry and have children normally after stabilization of symptoms after treatment.
Spouses should be screened for the ATP7B gene before having children.
If the spouse is a carrier, or if the couple has given birth to a patient with hepatomegaly, prenatal genetic diagnostic testing is required when having another child.
Prenatal diagnosis is a procedure in which a doctor obtains chorionic villus or amniotic fluid cells from the uterus during a woman’s pregnancy by chorionic villus puncture (10-12 weeks) or amniocentesis (18-22+6 gestational weeks and weeks) to clarify whether the fetus has the disease.