hepatomegaly



OVERVIEW

Definition

Hepatomegaly, also known as Wilson’s disease, is an autosomal recessive disorder in which copper metabolism is impaired due to a mutation in the ATP7B gene, resulting in the deposition of copper ions in multiple tissues and organs, leading to the development of corresponding damage.

Pathogenesis

The worldwide prevalence of hepatomegaly ranges from 1/2600 to 1/30,000, i.e., about 1 in 2,600 to 30,000 people, and the carrier frequency (the rate of carrier of the disease-causing gene, ATP7B, in the population) is about 1.11%, i.e., about 1 in 90 people.

The disease can start at any age, and is most common in children and adolescents, with a high incidence between the ages of 5 and 35.

Causes

Causes

Hepatomegaly is an autosomal recessive disorder, and its main cause is a mutation in the ATP7B gene.

The causative gene, ATP7B, is located on the long arm of chromosome 13 (13q14.3).

Pathogenesis

The ATP7B gene is mainly expressed in the liver, and the expression product, P-type copper-transporting ATPase (ATP7B enzyme), is involved in the transport of copper ions in hepatocytes.

Mutations in the ATP7B gene can cause defects or loss of function of ATP7B enzyme, resulting in impaired biliary excretion of copper ions, and large amounts of copper ions are deposited in tissues and organs such as the liver, brain, kidneys, bones and joints, and the cornea, generating extra-hepatic copper toxicity, leading to damage to multiple organs and tissues and the development of corresponding symptoms.

Symptoms

Main Symptoms

Neuropsychiatric symptoms

Mostly seen in patients aged 10~30 years old, the main manifestations are as follows.

Dystonia

Early dystonia only affects one part of the body, with orofacial dystonia being the most common, often characterized by slurred speech (dysarthria), difficulty in swallowing and involuntary drooling, etc. With the progression of the disease, dystonia may gradually develop into generalized, causing generalized and torsional dystonia.

With the progress of the disease, dystonia can gradually develop into generalized, causing generalized and torsional dystonia, which is manifested by violent and involuntary torsional movements of the trunk and limbs.

Tremor

Tremor occurs when holding a certain position or exercising, with coarse and irregular tremor being the most common, fine tremor with smaller amplitude can also be seen, and static pill-rubbing tremor is less common. The following manifestations are often seen in life.

Involuntary tremor of both upper limbs when the posture of the upper limbs is kept straight.

Involuntary vertical “head nodding” and horizontal “head shaking” movements.

Apparent tremor during daily activities such as pouring water, eating, and tying shoelaces.

Limb stiffness and bradykinesia

Some patients may have stiffness of the limbs, such as the inability to straighten the hand immediately after clenching the fist with force, and need to repeat several times before relaxing.

Delayed or reduced movement and slow walking.

Difficulty in writing, writing too small.

Mental Behavioral Abnormalities

Adolescent patients tend to show decreased learning ability, personality changes, mood swings, irritability and even sexual impulses.

Elderly patients mostly show various hallucinations and delusions, indifference to things and people around them, childish or strange movements, depressive state, and suicidal behavior in severe cases.

Symptoms of liver damage

Mostly seen in infants and children, most of them start at the age of 10~13 years old.

They often show non-specific symptoms of chronic liver disease, such as loss of appetite, nausea, fatigue, abdominal distension, generalized edema, jaundice (yellowing of the skin and the whites of the eyes and deepening of the color of the urine), etc. A small number of children may have sudden onset of acute liver damage.

A small number of children may have sudden acute liver failure, which may be characterized by extreme fatigue, severe gastrointestinal symptoms such as anorexia, abdominal distension, nausea and vomiting, progressive deepening of jaundice, and the appearance of hemorrhagic spots or petechiae all over the body within a short period of time.

Eye symptoms

Under sufficient light conditions, yellow-green or yellow-gray pigment ring can be seen at the edge of the cornea in some patients, which is clinically called “corneal K-F ring”.

A small number of patients may have cataract-related symptoms, such as decreased visual acuity, visual field defects, and decreased dark adaptation.

Other symptoms

In addition to neuropsychiatric symptoms, liver damage symptoms and eye symptoms, copper ion accumulation in other systems can also show corresponding functional abnormalities or damage, common symptoms are as follows.

Most patients have skin pigmentation, especially on the face and the extensor side of both lower legs.

Foamy urine (protein in the urine), low back pain and carnal hematuria and other signs of kidney damage.

Osteoporosis symptoms such as peripheral bone and joint pain, short stature, hunchback, and susceptibility to fracture.

Young female patients may have menstrual disorders, infertility and recurrent miscarriages.

Consultation

Department of Medicine

Neurology

For symptoms such as slurred speech, difficulty in swallowing, involuntary drooling, involuntary tremor of limbs, etc., timely consultation is recommended.

Pediatrics

Children with the above symptoms may also be referred to the Department of Pediatrics.

Preparation

Consultation: registration, preparation of documents, FAQs

Tips for your visit

Children may not be able to describe their symptoms accurately. Parents can help to record the symptoms they have experienced so that they can give the doctor more information.

Preparation List

Symptom list

Pay special attention to the time of onset of symptoms, special manifestations, etc.

Is there any involuntary tremor of the upper limbs?

Is there difficulty in performing activities such as pouring water, eating, or tying shoelaces?

Is there any stiffness in the limbs?

Are there any specific changes in mental behavior, such as irritability, poor learning ability, etc.?

Medical History Checklist

Is there a family history of hepatomegaly?

Checklist

Test results in the last six months, which can be brought to the doctor’s office

Laboratory tests: routine blood test, routine urine test, 24-hour urine copper, serum copper blue protein

Imaging tests: liver and spleen ultrasound, liver magnetic resonance imaging, head magnetic resonance imaging

Medication List

Medications used in the last 3 months, if available in boxes or packages, bring with you to the doctor’s office

Drugs to promote urinary copper excretion: D-penicillamine, sodium dimercaptopropanesulfonate, etc.

Drugs that block copper absorption: zinc sulfate, zinc gluconate, etc.

Diagnosis

Diagnosis is based on

Medical history

Family history of hepatomegaly.

Clinical symptoms

Patients often present with slurred speech, involuntary drooling, stiffness of limbs, bradykinesia, personality changes, loss of appetite, nausea, fatigue, and abdominal distension.

During eye examination, the doctor will use flashlight side light to illuminate, and the corneal K-F ring will be visible to the naked eye; if it is not seen, ophthalmic slit lamp examination will be used for clarification. A few patients may have symptoms such as decreased visual acuity, visual field defects, and decreased dark adaptation.

Laboratory tests

Routine blood and urine tests

Help to determine the initial state of disease progression.

When cirrhosis is accompanied by hypersplenism, blood counts may show a decrease in platelets, leukocytes and/or erythrocytes.

Urine routine may show microscopic hematuria, suggesting renal damage.

Serum copper blue protein

Normal value is 200-500mg/L.

Patients with this disease usually have a serum copper blue protein <200mg/L; if the serum copper blue protein is <120mg/L, it should be taken seriously, and ATP7B gene testing should be performed to make a definite diagnosis.

24-hour urine copper

Under the premise of standardized 24-hour urine collection and normal creatinine clearance, 24-hour urine copper is <100μg in normal subjects and ≥100μg in patients with hepatomegaly.

Children with unexplained elevated liver enzymes, such as 24-hour urine copper ≥40 μg, require ATP7B gene testing for definitive diagnosis.

Special care should be taken to prevent fecal contamination during 24-hour urine specimen collection in children.

Liver and kidney function

Elevated serum aminotransferases, bilirubin and/or decreased albumin suggest impaired hepatic function.

Blood creatinine and urea nitrogen may be elevated in impaired renal function.

Imaging

Ultrasound of liver and spleen

Ultrasound of the liver and spleen often shows thickening of the hepatic parenchyma, increased echogenicity and even nodular changes.

In some patients, splenomegaly can be seen.

MRI

Liver MRI often shows hepatic lipid deposition, irregular nodules and hepatic lobe atrophy.

Cranial MRI mainly shows T1 low signal and T2 high signal in the nucleus accumbens, head of caudate nucleus, thalamus, midbrain, pons, and cerebellum, and in a few cases, T1 high signal or T1 and T2 low signal can be seen.

Genetic Screening

Screening for pathogenic variants in the ATP7B gene is useful in the differential diagnosis of the disease.

It is indicated in patients with insufficient clinical evidence but high suspicion of hepatomegaly.

Diagnostic criteria

Diagnostic Points

Neurologic and/or psychiatric symptoms.

Unexplained liver damage.

Decreased serum copper blue protein and/or elevated 24-hour urine copper.

Positive corneal K-F rings.

Co-segregation of families and analysis of gene variant pathogenicity determined that the patient carries pathogenic variants of the ATP7B gene on both chromosomes.

Diagnostic Criteria

The diagnosis of hepatoblastoid nuclear degeneration is confirmed when (1 or 2) + (3 and 4) or (1 or 2) + (5) above are met.

Pre-symptomatic individuals are diagnosed with hepatomegaly when they meet the above (3 and 4) or 5 but have no obvious clinical symptoms .

If any two of the first three criteria are met, the diagnosis of “probable hepatomegaly” is made and further follow-up is required. ATP7B gene testing is recommended to confirm the diagnosis.

Differential diagnosis

Parkinson’s disease

Similarities: Both have involuntary tremor of the limbs.

Differences: Parkinson’s disease is characterized by resting tremor (tremor that occurs in a quiet state), which is exacerbated by stress or agitation. It may be accompanied by a stony face, a decrease in transient eye movements, and a decrease in the size of the written word.CT, magnetic resonance imaging (MRI), and functional imaging (SPECT/PET) are helpful in differentiating the two.

Cirrhosis

Similarities: Both have symptoms such as loss of appetite, fatigue and jaundice.

Differences: Cirrhosis can be caused by a variety of etiologic factors, such as prolonged and heavy drinking, long-term use of liver-damaging drugs, viral infections, and so on. Patients with cirrhosis are usually not accompanied by neuropsychiatric symptoms and do not have corneal K-F ring.

Treatment

The principle of treatment is early treatment, individualized treatment and lifelong treatment.

The aim of treatment is to prevent and reduce copper accumulation in tissues, and patients should be treated for life. The earlier treatment is started, the better the prognosis. Early treatment can lead to the disappearance of symptoms.

Medication

Medication should be started as soon as the disease is diagnosed, and the doctor will choose the appropriate treatment plan according to the patient’s specific situation.

Drugs to promote urinary copper excretion

D-Penicillamine

D-Penicillamine is the first line of medication for this disease, which can promote the excretion of copper from the urine and also reduce the hepatotoxicity of copper.

Doctors will determine the dosage and duration of the drug based on the patient’s age of onset, clinical symptoms, duration of the disease, and the amount of copper excreted in the urine 24 hours after administration.

Adverse reactions such as fever, rash, muscle weakness, and tremor (temporarily aggravated) may occur in a small number of patients and should be used with caution in patients with severe neurologic symptoms.

Penicillin skin test is required before using this drug, and the result is negative before taking it.

Sodium dimercaptopropanesulfonate

It is mainly used in patients with neuropsychiatric symptoms and acute hepatic failure, as well as in patients who are allergic to penicillamine, or who need rapid copper expulsion due to poor efficacy of D-penicillamine.

Adverse reactions are rare and may include loss of appetite, mild nausea, vomiting, dizziness, headache, and fatigue.

Dimercaptosuccinic acid

Mainly used in patients with varying degrees of liver injury, or neuropsychiatric symptoms, and those with allergy or intolerance to D-penicillamine.

Alternating with D-Penicillamine helps to reduce the adverse effects of long-term D-Penicillamine administration and the attenuating effect of the drug after long-term use.

Adverse effects are rare, with major adverse effects including nausea, vomiting, bloating, loss of appetite, worsening of neurologic symptoms, and fever.

Drugs that block copper absorption

The main application of zinc preparation treatment, can competitively inhibit copper absorption in the intestinal tract, promote fecal copper excretion, but its action is slow, general treatment 1 ~ 3 months to take effect.

Commonly used drugs are zinc sulfate and zinc gluconate.

They are mainly used for the treatment of pre-symptomatic patients, children with manifestations of liver disease or atypical hepatomegaly, pregnant hepatomegaly, those who cannot tolerate D-penicillamine therapy, and maintenance therapy for all types of hepatomegaly.

In asymptomatic infants and children, zinc therapy may be initiated after 2 to 3 years of age.

Adverse effects are mild, with occasional gastrointestinal symptoms such as nausea and vomiting.

Symptomatic drugs

Dystonia and limb stiffness can be treated with amantadine and/or benedryl, and compound levodopa can be used if symptoms are obvious.

Tremor symptoms are often relieved by Benzhexol, clonazepam and other drugs.

For those who are excited and manic, drugs such as quetiapine, olanzapine, risperidone and clozapine can be used.

For those who are apathetic and depressed, antidepressants such as sertraline, citalopram, and fluoxetine are available; sertraline is recommended for pediatric patients.

Those who have liver damage, with or without liver damage need liver protection therapy, can use glucuronolactone, inosine, vitamin C and so on.

Surgical treatment

Splenectomy

It is indicated in patients with severe hypersplenism, long-term significant reduction of white blood cells and platelets, frequent bleeding and/or infections.

For those who cannot apply penicillamine or the effect of penicillamine is not obvious due to the decrease of white blood cells and platelets.

Liver transplantation

In situ or related living donor liver transplantation is often used in patients with fulminant hepatic failure and severe liver disease that is refractory to complexing agents.

Low Copper Diet

A low-copper diet may delay the onset of symptoms and control the progression of the disease, but it is not recommended as the sole treatment and may lead to nutrient malabsorption if the diet is too restrictive.

It is recommended that patients avoid foods high in copper, such as animal offal, beans, shellfish, nuts, chocolate, and duck and goose, in the early stages of treatment.

Copper eating utensils should be avoided during meals.

Prognosis

Cure

Patients who are diagnosed early and receive standardized treatment as early as possible generally have less impact on their quality of life and survival, and most of them can live and work normally.

Harmfulness

If untreated, the prognosis is usually poor, with a case fatality rate of 5.0% to 6.1%, mainly from severe liver disease or severe neurologic symptoms, and a few patients commit suicide due to disease burden or depression.

Associated tremor and dystonia symptoms can affect social activities and ability to lead a life; the greater the tremor, the greater the impact.

Daily

Daily management

Dietary management

Adhere to a low-keto diet under doctor’s supervision, and avoid or eat less food with high copper content.

Foods to avoid

All kinds of animal offal and blood.

Shellfish, such as clams, razor clams, mussels, oysters, snails, shrimps and crabs.

Nuts, such as peanuts, walnuts, lotus seeds, chestnuts, sesame seeds.

Various kinds of beans and their products.

Shiitake mushrooms and other mushrooms.

Bacon, duck and goose.

Oats, buckwheat, millet, nori, garlic, taro, yam, lily, kiwi.

Chocolate, cocoa, coffee, tea.

Foods to minimize

Beef and lamb, potatoes, brown rice, black rice.

Kelp, bamboo shoots, aloe vera, spinach, eggplant.

Banana, lemon, lychee, cinnamon.

Recommended Foods

Foods with low copper content such as olive oil, fish, chicken, lean pork, refined white rice and noodles, apples, peaches, pears, silver fungus and green onions can be eaten in moderation.

A diet high in amino acids or protein is recommended, and milk can be consumed in moderation.

Other dietary precautions

Diet should be light, drink plenty of water and give easily digestible food.

For patients who have difficulty in chewing or swallowing, soft food or semi-fluid food should be provided, and eat small and frequent meals. Avoid intake of dry, hard and rough food.

If there is difficulty in swallowing or choking on water, food should not be forced to avoid choking or aspiration pneumonia.

For patients with severe tremor, wearable devices such as anti-shaking spoons can be used to help patients eat.

Do not urge or disturb the patient to eat.

If well water or water transported through copper pipes is used for daily drinking, its copper content should be checked. If the water has high copper content, a water purification system is recommended.

Exercise management

Moderate aerobic exercise under doctor’s supervision to reduce the symptoms of tremor.

Encourage and help patients to actively participate in various social activities and light to moderate physical labor. School-age children and adolescents should attend school regularly and resume normal life as much as possible.

Safety management

Avoid patients serving hot water, hot soup, etc. to prevent burns.

Tableware should be made of unbreakable materials, avoiding glass and ceramic products, etc.

Keep items with safety hazards, e.g. knives, scissors, etc., away from the patient.

Life management

Pay attention to rest, avoid exertion and keep a happy mood.

Wear soft, loose cotton clothes.

Choose clothes that are easy to put on and take off, and try to wear shoes that do not need to be tied.

Psychological support

Pay attention to the patient’s mental health, release pressure in time, avoid anxiety, depression, excessive tension and other bad emotions.

Family members should pay attention to the patient’s mental state, listen patiently and interact with the patient.

Follow-up and review

After starting drug treatment, regular checkup of blood and urine routine, liver and kidney function, 24-hour urine copper, etc. should be performed as prescribed by the doctor. Generally, 1~2 times per month in the first 3 months, 1 time every 1~3 months after the condition improves, and 2~3 times per year during the period of maintenance treatment.

Liver and spleen ultrasound is recommended to be checked once in 6 months.

If symptoms worsen during treatment or new symptoms appear, consult the doctor promptly.

Prevention

Hepatomegaly cannot be prevented at present, but for those with a family history of hepatomegaly, genetic screening and regular physical examinations can be performed to detect abnormalities early and treat them promptly.