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Hepatolenticular degeneration, also known as Wilson's disease, is an autosomal recessive inherited copper metabolism defect. Its incidence is about 1/(500,000 to 1 million). It is clinically characterized by varying degrees of liver cell damage, brain degeneration. and copper salt deposition rings at the corneal edge.

[Pathogenesis]

The pathogenesis has not yet been clarified. The basic metabolic defect is known to be the liver's inability to normally synthesize ceruloplasmin and reduced copper excretion from bile.

Copper is one of the essential trace elements for the human body. Copper ions are involved in the synthesis of many important enzymes, such as cytochrome oxidase, peroxide dismutase, tyrosinase, dopamine β-hydroxylase, lysyl oxidase and ceruloplasmin. However, when there is too much copper in the body, high concentrations of copper can cause cell damage and necrosis, leading to damage to organ function. Its cytotoxicity may be due to its excessive binding to proteins and nucleic acids, oxidation of lipids in various membranes, or the production of excessive oxygen free radicals. Therefore, copper deficiency or excessive storage can cause serious disease.

The stability of copper in the human body is maintained by the dynamic balance between intestinal absorption and bile excretion. About 40%-60% of the copper in the diet is absorbed in the upper small intestine. Copper ions must form low-molecular-weight complexes with amino acids or oligopeptides before passing through the intestinal mucosa, and then enter the liver through the portal vein for the synthesis of ceruloplasmin by hepatocytes. About 0.5 - 1mg of copper is synthesized into ceruloplasmin every day. The results of isotope studies show that 60% to 90% of the copper ingested into the blood circulation is absorbed by the liver within a few hours; 8 hours after ingestion, the ceruloplasmin synthesized by the liver gradually returns to the blood circulation.

Ceruloplasmin is a glycoprotein composed of 1046 amino acids. Its coding gene is located in 3q23-q25. Its molecular weight is about I32ku. Each molecule contains 6-7 copper atoms. It is an oxygenase that oxidizes ferrous iron to trivalent iron and promotes transferrin synthesis. It also catalyzes the oxidation of biogenic amines such as epinephrine, serotonin and dopa glue. In normal human plasma, 90% to 95% of copper is bound in ceruloplasmin, and only a small amount is bound to albumin or amino acids, the latter being the main form of copper transport between blood and tissues.

The liver is the main organ for copper metabolism. 8% of the total copper content in the human body (about 100mg) is stored in the liver, and its concentration ranks first among all organs, followed by brain, heart, kidney and other tissues. About 80% of normal adult liver copper is combined with metallothionein (a small molecule protein whose coding gene is located on chromosome 16) and stored in the cytoplasm, while the rest is combined with various liver enzymes. Liver cells rely on their lysosomes to synthesize ceruloplasmin and secrete human bile. The human body excretes 12-17mg of copper through bile every day, and the amount excreted in urine is only about 0.07 mg. When this mechanism is defective, copper is excreted sharply from bile, but because the patient's intestines absorb copper normally, a large amount of copper is stored in liver cells and ultimately leads to abnormal liver function and liver cirrhosis. At the same time, the amount of non-ceruloplasmin silver in the blood increases, resulting in increased excretion from urine and large deposition in tissues such as the brain, kidney, muscles and eyes, and corresponding symptoms of various systems being involved appear clinically.

[Pathology]

Liver cells initially showed fatty infiltration, most notably around the portal area. Under electron microscopy: changes such as mitochondria have different shapes and sizes, increased matrix density, separation of inner and outer membranes and widening of cristal spacing, and vacuolar or crystalline inclusion bodies can be seen in the matrix; lysosomes contain lipid particles; Peroxisomes have different shapes, and their matrix is granular or flocculent. As the disease progressed, fibrosis and cirrhosis occurred in the liver tissue. In some patients, liver damage changes are not easily distinguishable from chronic active hepatitis.

[Clinical manifestations]

Copper storage in children's liver begins in infancy, but clinical symptoms rarely appear before the age of 6, and their age of onset and clinical symptoms vary greatly. The entire course of the disease can be roughly divided into three stages.

The first is the asymptomatic period starting after birth. During this period, except for a slight increase in urine copper, the child is normal and is rarely found.

After the age of 6 to 8, as the amount of copper deposition in liver cells increases, symptoms of liver damage gradually appear, and the onset of the disease is invisible. At first, the symptoms are mild and are easily ignored, or fatigue, loss of appetite, vomiting, jaundice, edema or ascites may occur repeatedly. Some of these cases may be complicated by viral hepatitis, most of which are difficult to distinguish from chronic active hepatitis, and a few cases have rapid progression to acute liver failure. About 15% of children with this disease can develop hemolytic anemia before symptoms of liver disease appear. This hemolysis process is often transient. Since children often do not have K-F rings at this time, all children with non-spheroidal hemolytic anemia and negative Coombs test should be paid attention to the possibility of excluding the disease. During this stage, children's urine copper increased significantly, serum ceruloplasmin content was low, and generally there was no K-F ring.

Subsequently, copper began to accumulate more and more seriously in extrahepatic tissues such as brain, eyes, kidneys and bones. Urine copper was higher and serum ceruloplasmin was significantly lower. After the age of 12, children gradually develop symptoms of impaired other organ functions: early symptoms of the nervous system are mainly difficulty in language construction (eating slowly), clumsy or involuntary movements, stiff expression, difficulty swallowing, changes in muscle tone, etc., and develop into later stages. Mental symptoms are more obvious, and behavioral abnormalities and mental disorders are common; kidney symptoms include kidney stones and proteinuria. Manifestations of diabetes, amino acid urine and renal tubular acidosis; corneal pigment rings often appear with nervous system symptoms. At the beginning, copper deposits mainly above and below the corneal periphery, gradually forming a ring shape and brownish-yellow. Slit lamp examination is needed at the beginning; About 20% of children develop symptoms of back or joint pain. X-ray examination often includes osteoporosis, narrowing of joint space or osteophytes.

A small number of patients with this disease can also be complicated by hypoparathyroidism, glucose intolerance, insufficient trypsin secretion, and low humoral or cellular rabbit epidemic function.

[Diagnosis]

The disease is treatable. The earlier treatment starts, the better the prognosis. However, because the early symptoms of the disease are often hidden, diagnosis can easily be delayed. Therefore, for children with a family history of the disease, liver disease of unknown cause, hemolytic anemia, kidney disease or neurologic symptoms, the possibility of the disease should be considered and necessary laboratory examinations should be taken.

[Treatment]

The principle of treatment is to reduce copper intake and increase copper excretion to improve its symptoms.

(1) The daily copper content in food in a low-copper diet should not be more than 1mg, and it is not advisable to eat foods with high copper content such as animal viscera, fish, shrimp, seafood and nuts.

(2) The copper complexing agent D-Penicillamine is currently the most commonly used drug. It can complex with copper ions, promote urinary copper excretion, and promote cell synthesis of metallothioneins. The dose is 20mg/kg per day, taken orally in divided doses. Urinary copper should be monitored during treatment, and daily urinary copper excretion>2mg is usually required within the first year of treatment. Neurological symptoms generally improve after several weeks of medication, while liver function improves often requires 3-4 months of treatment. The side effects of this drug are drug rash, thrombocytopenia, nephropathy, arthritis, etc., but the incidence is not high. If necessary, glucocorticoid treatment can be combined for a short period of time. If you really cannot continue taking it, consider triethylene-tetramine hydrochloride at a dose of 0.5 - 2 g per day. In recent years, another highly efficient copper complexing agent, ammonium tetrathiomolybdate (TTM), has been used, which can complex with copper to form Cu (MoS4) 2 and be excreted in the urine, which can improve symptoms in a short period of time.

(3) Zinc preparations Oral zinc preparations can promote the secretion of metallothiones by intestinal mucosal cells and reduce the absorption of intestinal copper after combining with copper ions. Commonly used is zinc sulfate or zinc acetate. The latter has less gastrointestinal reactions, and the daily oral dose is equivalent to 50mg of zinc. Take it in 2 to 3 doses between meals.

(4) Other supportive treatments can provide albumin infusion for liver function impairment and hypercopperemia; levodopa can be used to improve nervous system symptoms.

(5) Liver transplantation For children with acute liver failure or decompensated liver cirrhosis caused by this disease who fail to respond to the above-mentioned treatments, liver transplantation may be considered.