Hepatolenticular degeneration

　　Hepatolenticular degeneration, also known as Wilson's disease (WD), is a disease caused by copper metabolism disorder related to heredity, which is an autosomal recessive inheritance with a familial tendency. The disease is more common in children and young adults. Due to mutations in the WD gene (located at 13q14.3), which encodes the protein (ATP7B enzyme), there is insufficient synthesis of ceruloplasmin in the serum and obstruction of copper excretion in the bile ducts, leading to an increase in free copper in the serum and its deposition in the liver, brain, kidneys, and other organs, resulting in corresponding clinical symptoms and signs. The lesions mainly damage the basal ganglia of the brain and the liver, causing lenticular degeneration and liver cirrhosis.

　　Patients with hepatolenticular degeneration have a partial decrease in immune function, which can lead to infections in various systems, and most die due to liver failure or concurrent infections. Some patients may have symptoms of pseudo-bulbar palsy, such as swallowing difficulties and water going back up while drinking, especially for patients who have been lying in bed for a long time, who are more prone to develop bedsores, urinary tract infections, and pneumonia. Patients with extrapyramidal symptoms may have difficulty walking, be prone to falls, and develop fractures. Patients with hepatolenticular degeneration in the decompensated phase of liver cirrhosis with portal hypertension and esophageal varices are prone to acute upper gastrointestinal bleeding, even hemorrhagic shock; a few patients may have reduced detoxification ability of the liver, leading to hepatic encephalopathy, hepatorenal syndrome, and other conditions; some patients may also have epilepsy due to brain damage. These various complications often worsen the condition, seriously affect the treatment effect, prolong the hospital stay of patients, and if not treated promptly and accurately, the prognosis of some patients may be worse than those without complications.

　　The clinical manifestations of hepatolenticular degeneration mainly include neurological and psychiatric symptoms and liver symptoms.

　　1. Neurological and psychiatric symptoms

　　(1) Tremors: Early tremors are often limited to the upper limbs and gradually extend to the whole body. They are usually rapid, rhythmic, and resemble wing-like tremors, and may be accompanied by intention tremors that worsen during movement.

　　(2) Speech disorders and swallowing difficulties: Common in children with early onset of HLD, they may speak slowly as if reciting poetry or have a monotone voice like reciting scriptures, and may also have unclear, explosive, or tremulous speech. Swallowing difficulties often occur in late-stage patients.

　　(3) Changes in muscle tone: Most patients have a gear-like or lead pipe-like increase in muscle tone, often leading to slow movements, reduced facial expressions, difficulty in writing, and walking disorders. A few patients with chorea may have reduced muscle tone.

　　(4) Epileptic seizures are less common.

　　(5) Psychiatric symptoms: Early patients often show no significant changes in intelligence, but children with acute onset may experience a decline in intelligence earlier; most patients with hepatolenticular degeneration have personality changes, such as reduced self-control, unstable emotions, and irritability; severe cases may present with depression, mania, hallucinations, delusions, impulsiveness, and may lead to self-harm or harm to others. A few patients may have psychiatric symptoms as the initial manifestation, and are prone to be misdiagnosed with schizophrenia.

　　2. Liver Symptoms

　　(1) It usually occurs between 5 to 10 years of age. Due to the copper ion deposition in the liver reaching supersaturation, it causes acute liver failure, that is, abdominal hepatolenticular degeneration. The clinical manifestations include general malaise, drowsiness, anorexia, nausea and vomiting, abdominal distension, and severe jaundice. The condition deteriorates rapidly, and the patient usually dies within 1 week to 1 month. Often, it is only considered as a possible disease when the history is reviewed after the diagnosis of hepatolenticular degeneration in the同胞.

　　(2) Half of the patients may experience transient jaundice, short-term increase in alanine aminotransferase or/and mild ascites within 5 to 10 years, which will recover quickly. Several years later, when neurological symptoms appear, the liver may be slightly enlarged or not palpable, and the liver function may be slightly impaired or within the normal range, but the B-ultrasound examination has shown varying degrees of damage.

　　(3) During the pediatric period, there is a slow progression of anorexia, mild jaundice, hepatomegaly, and ascites, resembling the manifestations of liver cirrhosis. After several months to several years, the gastrointestinal symptoms may persist or worsen, and gradually, neurological symptoms such as tremors and muscular rigidity may appear. Once neurological symptoms appear, the liver symptoms rapidly deteriorate, and the patient may fall into hepatic coma within a few weeks to 2-3 months. Therefore, liver cirrhosis in children of unknown cause should be excluded from this disease.

　　(4) Some adolescents may present with a slow progression of splenomegaly, leading to symptoms of splenic hyperfunction such as anemia, leukopenia, or (and) thrombocytopenia. The neurological symptoms usually appear soon after splenectomy or/and portosystemic shunt surgery and rapidly deteriorate, often resulting in death within a short period of time; a few patients may rapidly develop neurological symptoms due to esophageal variceal bleeding.

　　3, Corneal pigmented ring

　　Brown K-F rings can be seen around the periphery of the corneal posterior elastic layer with the naked eye or slit lamp.

　　In order to control and reduce the occurrence of genetic diseases, it is necessary to take prevention as the main priority. Although there is still controversy about the higher incidence of hepatolenticular degeneration in close relatives, it is also necessary to strongly advocate avoiding marriage between close relatives. Implementing the law of eugenic protection, all those who may or may not or are very likely to cause congenital diseases in offspring should avoid childbirth. Currently, China is drafting the law of eugenic protection, which prohibits marriage between close relatives. 'Marriage between close relatives' will increase the incidence of some genetic diseases, and the Marriage Law of China has clearly prohibited marriage between close relatives. For those who have been diagnosed, in addition to receiving the above treatment, they should actively treat various chronic somatic diseases and prevent various infectious diseases, and continuously improve their health level. At the same time, due to the risk of the disease among the offspring of the family, it is easy to receive early genetic counseling services.

　　Additionally, a large number of clinical practices have shown that after regular treatment with chelating therapy and symptomatic treatment, the clinical symptoms and signs of many patients with hepatolenticular degeneration have been significantly improved. However, after discharge, some patients believe that their symptoms have disappeared and do not take medication or take less than the prescribed dose, and do not pay attention to avoiding high-copper foods, resulting in the deterioration of the disease and the need to be admitted to the hospital again, even leading to death. Some patients or their families may also be obsessed with certain qigong and discontinue the chelating drugs unilaterally, resulting in the aggravation of the disease and even the loss of the patient's life, regretting it too late! Patients and their families with good compliance with treatment often have long-term relief of the disease and a better quality of life, even achieving excellent achievements in their studies and careers.

　　Patients with hepatolenticular degeneration commonly have anxiety and depression. Due to symptoms such as unclear speech, clumsy movements, and impaired liver function, they may feel disappointed about their future prospects. They may also feel guilty for the economic, human, and material burdens they impose on their families, leading to low mood and a reluctance to cooperate with treatment, even refusing treatment. Some patients may resent their parents due to the genetic nature of the disease and become irritable. In such cases, psychological counseling and treatment are of great importance. Through appropriate psychological therapy adapted to the patient's psychological abnormalities, correcting their psychological biases or abnormal psychology can improve their compliance with the treatment process and is beneficial to improve their prognosis. The level of support from society also significantly affects the efficacy of treatment. Support and encouragement from family members, relatives, friends, etc., in terms of economic, material, and spiritual aspects, can often enhance the patients' confidence in overcoming the disease. Care and nursing for the patient's daily life can often enhance the effectiveness of treatment. Support from schools, units, medical insurance, and administrative departments, even charitable organizations, can help solve some of their difficulties, reduce or eliminate their concerns, and also help patients achieve a good prognosis.

　　Extrapyramidal symptoms, corneal pigmented rings, and decreased absorbance of serum copper oxidase are important diagnostic criteria for hepatolenticular degeneration. In addition, a history of liver disease or liver signs, increased urinary copper levels (>50μg), also have diagnostic significance; while brain CT and MRI scans can be used for auxiliary diagnosis.

　　1. Serum copper

　　Serum copper levels are low, while urinary copper and liver copper content are increased. The absorbance of serum copper oxidase is lower than the normal value in 90% of patients, which is the main biochemical abnormality of hepatolenticular degeneration. The normal range for serum ceruloplasmin levels is 200-400mg/L (or 0.25-0.49O.D); children usually have levels below 200mg/L; the 24-hour urinary copper excretion amount is significantly increased in children, often reaching 100-1000ug/24h; the copper content in cells is measured: in normal adults it is about 20ug/g (dry weight), while in children it can be as high as 200-3000ug/g.

　　2. Liver function tests

　　Liver function tests show increased alanine aminotransferase (SGPT) and thiocyanate turbidity test (ZnTTT).

　　3. Blood count

　　Patients with very low blood counts are an adverse factor for metal chelating agent copper removal therapy. If not treated in a timely manner, it often makes it difficult to persist with copper removal treatment. Patients with severely damaged liver and kidney function should also avoid using drugs that damage liver and kidney function. Liver fibrosis indicators can understand the severity of liver cirrhosis in patients and provide objective observation indicators for anti-liver fibrosis treatment.

　　4. Electroencephalogram (EEG) examination

　　Electroencephalogram (EEG) examination shows about 30％～50％ abnormalities, mostly mild to moderate, but without specificity.

　　5. Brainstem auditory evoked potential

　　The abnormal rate of brainstem auditory evoked potential is relatively high, up to 90％; mainly manifested as prolongation of III-VIPL, decrease in amplitude, which may be due to the diffuse deposition of copper in the brainstem, causing degeneration and demyelination of neurons in the brainstem auditory system.

　　6. Brain CT scan

　　Brain CT scan shows that 30％～40％ of patients have symmetrical hypodense lesions in the bilateral basal ganglia, atrophy of the cerebral cortex and brainstem can also be seen, as well as enlargement of the ventricles and widening of the lateral fissure, etc. Magnetic resonance imaging (MRI) is clearer, showing a wider range of lesions than brain CT scan, not only ventricle enlargement, but also visible abnormal signals in the thalamus area and the brainstem (T1W low signal, T2W high signal).

　　Abnormal changes in electroencephalogram (EEG) and electromyogram (EMG) suggest the damage to the brain and peripheral nerves, muscles. The brainstem evoked potential before and after the course of treatment can be used to assist in judging the severity of brain damage and the efficacy of the patient. Ultrasound examination can understand the imaging classification of the patient's liver, the degree of splenic enlargement, renal cortical damage, and whether there are concurrent gallstones, etc., which is helpful for estimating the prognosis. Cranial CT or MRI scan, in addition to special lesions in the basal ganglia, can help diagnose this disease, and if there is cortical atrophy of the brain, and the formation of softening foci in the frontal and temporal lobes, the patient often has intellectual impairment and poor academic performance, and corresponding brain recovery treatment should be given. Therefore, auxiliary examinations are of great reference value for judging the treatment and prognosis of the patient.

　　For patients with hepatolenticular degeneration, attention should be paid to a low-sodium and low-fat diet in food, and more fresh vegetables and fruits should be eaten, avoiding excessive protein intake and avoiding smoking and drinking.

　　① Avoid eating food with high copper content: millet, buckwheat flour, brown rice, beans, nuts, tubers, spinach, eggplant, pumpkin, mushrooms, fungi, algae, dried vegetables, dried fruits, mollusks, shellfish, snails, shrimp and crab, the liver and blood of animals, chocolate, cocoa. Certain traditional Chinese medicine (Dragon bone, oyster, centipede, scorpion) and so on.

　　② Appropriate low copper food: white rice, white flour, fresh vegetables, apples, peaches, pears, fish, pork and beef, chicken, duck, and goose meat, milk, etc.

　　③ High amino acid or high protein diet.

　　Hepatolenticular degeneration is treatable, and the earlier the treatment starts, the better the prognosis. Therefore, it is emphasized that early detection, timely diagnosis, and treatment should be carried out to strive for a better prognosis. The treatment principle is to reduce copper intake and increase copper excretion.

　　1. Copper removal therapy

　　Apply chelating compounds for copper removal as soon as possible to promote the excretion of copper in the body.

　　(1) D-penicillamine: It is the most commonly used drug, which should be taken for a long time, at a dose of 20～30mg/(kg·d), divided into 3～4 doses and taken orally half an hour before meals. A penicillin allergy test should be conducted before use. Side effects may include fever, rash, joint pain, leukopenia and thrombocytopenia, proteinuria, optic neuritis, etc. Long-term treatment may also trigger autoimmune diseases, such as immune complex nephritis, lupus erythematosus, etc. Vitamin B6 20mg should be taken concurrently, 3 times a day.

　　(2) Trenatin (trienetetramine): 0.2-0.4g, 3 times a day, if there are adverse reactions to penicillamine, this drug can be taken instead. Long-term use can lead to iron deficiency.

　　(3) Dimercaprol (BAL): 2.5-5mg/kg, intramuscular injection, 1-2 times a day, 10 days as a course. Side effects include fever, rash, nausea, vomiting, mucosal burning sensation, hard nodules at the injection site, etc., and should not be used for a long time. Dimercaprol sodium can also be used, 2.5-5mg/kg, administered intramuscularly with a 5% solution, 1-2 times a day, 10 times as a course; or dimercaptoethane disodium, 1-2g (adults) each time, diluted into a 5% concentration solution and administered slowly intravenously, 10 times as a course. The effects of the latter two drugs are similar to those of BAL, with stronger de-copper effects and fewer side effects. The three drugs can be used intermittently and alternately.

　　(4) Zinc: Orally, it can promote the secretion of metallothionein by intestinal mucosal cells, reduce intestinal copper absorption after binding with copper ions. The commonly used one is zinc sulfate, which has low toxicity and can be taken for a long time. Take 200mg half an hour before meals, 3 times a day, and adjust according to the plasma zinc concentration not exceeding 30.6μmol/L. When taken with penicillamine, both should be taken at least 2 hours apart to prevent the chelation of zinc ions in the intestine by penicillamine.

　　2, Psychotropic Drugs

　　At the same time as the de-copper treatment, anti精神病 drugs with fewer extrapyramidal side effects can be selected according to the mental symptoms, such as methyldopa, risperidone, etc., the dose should not be too large, the time should not be too long, and the effect should stop as soon as it is effective.

　　3, Diet Therapy

　　The amount of copper in daily food should not exceed 1mg, and high-copper foods such as green beans, broad beans, corn, mushrooms or fungi, fish and shrimp seafood, shellfish, crustaceans or snails, animal liver and blood, chocolate, and nuts should not be eaten.

　　4, Surgical Treatment

　　Although liver transplantation has been adopted recently with initial hope, it is limited to a very few patients and is still in the exploratory stage.

　　5, Other

　　(1) Liver protection therapy: various vitamins, energy preparations, etc.

　　(2) For extrapyramidal symptoms, you can choose phenytoin 2mg, 3 times a day or scopolamine, 0.2mg, 3 times a day, taken orally.

　　(3) If there is a hemolytic attack, adrenal cortical hormones or plasma substitution therapy can be used.