| disease | Wilson's Disease |
| alias | Wilson's Disease, Metabolic Cirrhosis, Hepatolenticular Degeneration |
Hepatolenticular degeneration is a hereditary disease primarily affecting adolescents, caused by copper metabolism disorder. It is characterized by liver cirrhosis, softening and degeneration of the basal ganglia in the brain, Kayser-Fleischer rings in the cornea, accompanied by a deficiency of ceruloplasmin and aminoaciduria. Also known as Wilson's disease.
bubble_chart Etiology
The fundamental cause of this disease is the excessive deposition of copper in various tissues of the body, particularly in the liver, brain, kidneys, and cornea, leading to tissue damage and pathological changes.
Regarding the pathogenesis of hepatolenticular degeneration (Wilson's disease), there are several theories: ① A defect in the normal copper-binding substances in the bile of these patients, possibly due to impaired conjugation of chenodeoxycholic acid with taurine, leading to dysfunctional copper secretion in the bile. Evidence against this theory includes the absence of qualitative changes in copper-binding proteins in the bile of these patients and no indication of abnormal bile acid metabolism. ② Abnormal synthesis of hepatic copper-binding proteins, resulting in increased affinity for copper. Supporting evidence includes the observation that the copper-binding constant of hepatic copper-binding proteins in Wilson's disease patients is four times higher than that in patients with primary biliary cirrhosis. However, the methodology of data analysis has been questioned, so whether the high affinity of abnormal proteins for copper is the mechanism underlying Wilson's disease requires further clarification. ③ The most plausible theory is that hepatic lysosomes are involved in copper metabolism. Experimental observations show that the lysosomal copper content in hepatocytes of Wilson's disease patients is 40 times higher than in controls. It is proposed that defective lysosomes in Wilson's disease patients interfere with the process of copper secretion from lysosomes into the bile, leading to excessive copper accumulation in the liver.
In summary, Wilson's disease is not caused by increased intestinal copper absorption but rather by congenital impairment of biliary copper secretion. Due to genetic defects, affected individuals fail to transition from a positive copper balance to normal metabolism by three months after birth, resulting in persistent positive copper balance and subsequent systemic copper accumulation.
bubble_chart Pathological Changes1. Liver
The earliest histological change is glycogen degeneration in the nuclei of hepatocytes in the periportal zone under light microscopy. Intranuclear glycogen appears as clumps or vacuoles, accompanied by moderate fatty infiltration. The fat droplets consist of triglycerides, and their number increases over time, merging and enlarging. The steatosis morphologically resembles alcoholic steatosis. The organelles affected concurrently with or prior to steatosis are mitochondria, which exhibit swelling, membrane separation, cristae dilation, crystalline arrangement, vacuolation, and markedly granular matrix. Mitochondrial changes may be pathogenetically related to steatosis. With D-penicillamine treatment, mitochondrial alterations can diminish or even disappear, indicating these changes are caused by copper toxicity.
The progression from fatty infiltration to cirrhosis varies significantly among individuals. Some patients may develop chronic active hepatitis, characterized by mononuclear cell infiltration (mostly lymphocytes and plasma cells), piecemeal necrosis extending beyond the limiting plate, parenchymal collapse, bridging necrosis, and fibrosis, which must be differentiated from typical chronic active hepatitis. Liver lesions may resolve spontaneously, progress to macronodular cirrhosis, or rapidly develop into fulminant hepatitis, the latter having a poor prognosis.
During cirrhosis formation, there may be inflammatory cell infiltration or parenchymal necrosis, eventually leading to macronodular or mixed macronodular-micronodular cirrhosis. Fibrous septa can vary in width, with bile duct proliferation, and may retain early Wilson's disease pathological features such as ribosomal degeneration and steatosis.
2. Brain
The entire nervous system can be affected, with the lenticular nucleus, thalamus, caudate nucleus, insula, and cingulate gyrus being most severely involved, particularly the putamen within the lenticular nucleus. Macroscopically, cerebral hemispheres show varying degrees of atrophy, with lenticular nucleus shrinkage, softening, and small cavity formation. Histology reveals neuronal degeneration and necrosis, along with astrocyte hypertrophy, hyperplasia, and degeneration.
Copper deposition occurs in the proximal tubules, manifesting as fatty degeneration and hydropic degeneration.
4. Cornea
Copper deposition around Descemet's membrane forms a brown-green pigmentation known as the Kayser-Fleischer ring.
bubble_chart Clinical Manifestations
Although copper accumulation in the liver begins during infancy, liver disease symptoms rarely occur before the age of 6. By age 15, 50% of patients develop symptoms, with occasional cases presenting as late as 60 years old. Initial symptoms manifest as liver disease in 42% of cases, neurological symptoms in 34%, psychiatric symptoms in 10%, endocrine or hematologic symptoms secondary to liver disease in 12%, and renal impairment in 1%. Approximately 25% of patients exhibit involvement of two or more systems simultaneously.
I. Liver
Patients presenting initially with liver disease tend to be younger. Clinical manifestations vary widely, ranging from acute or chronic hepatitis to fulminant hepatic failure or cirrhosis. Thus, liver-related symptoms in Wilson's disease are nonspecific. During the asymptomatic phase or early cirrhosis, liver function may be normal or show only mildly elevated transaminases. Onset is often insidious, following a chronic course. Initial symptoms include lack of strength, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, and hypersplenism, eventually progressing to portal hypertension, ascites, variceal bleeding, and hepatic failure.
In Wilson's disease, the liver is often shrunken or normal in size, with features of post-necrotic cirrhosis. Some patients may present initially with ascites or esophageal variceal bleeding. Additionally, many cases clinically resemble chronic active hepatitis in terms of presentation, laboratory findings, and histology. Some patients are diagnosed only after incidental detection of Kayser-Fleischer rings or the onset of neuropsychiatric symptoms. Therefore, chronic liver disease patients under 35 years old who are HBsAg-negative should be evaluated for Wilson's disease through laboratory testing.
II. Nervous System
Neurological symptoms typically appear in patients aged 12–30 and are almost always accompanied by K-F rings. Initial symptoms are mild but progress rapidly without treatment. Early signs include wrist tremor, grimacing, stuttering, and difficulty writing, along with rigid gait, dysphagia, fluctuating limb rigidity, expressionless facies, and persistent drooling, while intelligence remains intact. EEG shows nonspecific slow waves, which are not diagnostically helpful. CT scans and brain evoked potentials also lack specificity at this stage. MRI is more sensitive than CT for detecting lesions in the cerebrum, cerebellum, or brainstem, though results are often normal in asymptomatic individuals. Liver function tests are usually normal.
These may manifest as behavioral abnormalities, manic-depressive or schizophrenic psychosis, or dementia. At least four types of psychiatric disturbances occur: affective disorders, behavioral abnormalities, schizophrenia-like psychosis, and cognitive impairment. Treatment often provides only partial relief for these symptoms.
IV. Eyes
K-F rings appear as brown, green, or golden-brown pigmentation in the Descemet's membrane at the corneal periphery, up to 2 mm wide, visible with oblique lighting or the naked eye. The rings result from copper particle deposition in density and size. K-F rings nearly always accompany neurological symptoms but may be absent in asymptomatic children or those with liver involvement, particularly chronic active hepatitis. While K-F rings aid diagnosis, they are not pathognomonic for Wilson's disease. Other conditions like prolonged intrahepatic cholestasis in childhood, chronic active hepatitis with cirrhosis, or cryptogenic cirrhosis can also cause copper accumulation in the cornea and other organs due to impaired biliary copper excretion.
Sunflower cataracts are another rare ocular finding in Wilson's disease, often coexisting with K-F rings. This feature typically resolves faster than K-F rings during D-penicillamine therapy.
V. Hematologic System
Acute intravascular hemolysis often occurs during the course of Wilson's disease, with at least 15% of patients exhibiting significant hemolysis. The hemolysis is usually transient and self-limiting, often preceding the manifestation of liver disease by several years, and typically occurs without the presence of Kayser-Fleischer rings. Therefore, for hemolysis patients under 20 years old, other causes of hemolysis should be excluded through generation and transformation tests. In Wilson's disease patients with hemolysis, the blood Coombs test is negative, and the condition is classified as non-spherocytic hemolysis. Occasionally, acute hemolysis may coincide with acute liver failure, indicating a severe prognosis, often leading to death from liver or kidney failure within weeks.
The cause of hemolysis is unclear. Some believe it is due to the liver releasing a large amount of copper into the blood in a short period, leading to excessive uptake of copper by red blood cells, resulting in oxidative injury to the cell membrane and hemoglobin. Others suggest that the toxic effect of copper is due to its oxidative action on the phospholipids of the cell membrane.
Additionally, in patients with liver injury as the primary manifestation, acute liver failure, severe decompensated cirrhosis, reduced synthesis of clotting factors, poor platelet quality, and splenomegaly can lead to thrombocytopenia and leukopenia. These factors contribute to a bleeding tendency in Wilson's disease patients.
VI. Kidneys
The extent of kidney damage in Wilson's disease varies, including reduced glomerular filtration rate, decreased renal blood flow, and tubular lesions. Proximal tubule involvement may manifest as aminoaciduria, glycosuria, elevated uric acid (with low serum uric acid), hyperphosphaturia, hypercalciuria, and proteinuria, the latter including low-molecular-weight globulins and hydroxyproline peptides from collagen breakdown. Distal tubule involvement may lower the pH below 5.2, which is also a cause of kidney stone formation. Penicillamine can significantly improve renal function, but occasionally it may cause severe side effects such as nephrotic syndrome and Goodpasture-like syndrome.
VII. Skeletal System
Manifestations may include decalcification, osteomalacia, rickets, spontaneous fractures, subchondral cysts, bone arthralgia, osteochondritis dissecans, and chondrocalcinosis. Clinical symptoms are often subtle, with patients possibly experiencing knee or other large joint pain and stiffness.
VIII. Others
Cardiac manifestations may include arrhythmias, cardiomyopathy, and autonomic dysfunction. Endocrine changes secondary to liver disease may lead to amenorrhea in young women and delayed development or gynecomastia in males. Pancreatic damage may result in pancreatic insufficiency and diabetes. The nails may show blue lunulae, indicating increased copper content.
Regarding the natural course of the disease, it is theoretically divided into four stages: Stage I: Initial accumulation of copper in hepatocytes until saturation is reached, with no clinical symptoms. Stage II: Copper moves from the cytoplasm into lysosomes, with partial release into the blood. In most patients (60%), this redistribution occurs gradually without obvious clinical manifestations. However, if the process is rapid, a sudden rise in blood copper may cause hemolysis, and rapid intrahepatic redistribution may lead to liver necrosis or chronic active hepatitis, potentially resulting in liver failure. Stage III: Copper accumulates in extrahepatic tissues, leading to cirrhosis, neurological, corneal, and renal damage. Clinical symptoms correspond to these changes, and hemolysis may occur. Patients may die from liver failure or enter remission again. This stage is highly variable: if cirrhosis progresses slowly and extrahepatic copper accumulation is gradual, patients may remain asymptomatic for years, but rapid progression can lead to a severe clinical course. Stage IV: The stage of remission after long-term chelation therapy.
bubble_chart Auxiliary Examination
1. Serum ceruloplasmin
can be measured by enzymatic or immunochemical methods, with a normal range of 1.3–2.6 μmol/L (20–40 mg/dL). In patients presenting only with liver injury, 85% have levels below 1.3 μmol/L, but low ceruloplasmin alone is not a diagnostic criterion for Wilson's disease. Heterozygotes may have low serum ceruloplasmin levels, 25% of patients with chronic active hepatitis exhibit low ceruloplasmin, and 15% of Wilson's disease patients with severe chronic active liver disease may have normal ceruloplasmin levels.
2. Non-ceruloplasmin serum copper
In healthy individuals, copper bound to albumin and amino acids ranges from 15–20 μg/L. Untreated Wilson's disease patients may have levels as high as 500 μg/L, but this can also be elevated in other liver and biliary disorders, limiting its diagnostic value.
3. Urinary copper
Normal levels are <40 μg/24h. In Wilson's disease after Stage I or in symptomatic cases, levels may exceed 100 μg/24h, with some Stage II patients occasionally exceeding 1000 μg/24h. However, other conditions such as cirrhosis, chronic active hepatitis, or cholestasis (including primary biliary cirrhosis) can also elevate urinary copper, reducing its diagnostic specificity. Nonetheless, it can serve as a monitoring indicator for D-penicillamine treatment efficacy.
4. Hepatic copper
Normal content is 15–55 μg/g dry weight. Untreated Wilson's disease patients typically have levels of 250–3000 μg/g dry weight, and levels <250 μg/g dry weight exclude Wilson's disease. However, primary biliary cirrhosis, primary sclerosing cholangitis, extrahepatic bile duct obstruction, biliary atresia, intrahepatic cholestasis, or other biliary disorders can also increase hepatic copper, diminishing its standalone diagnostic value for Wilson's disease.
5. Radiolabeled copper incorporation test
This test is useful in diagnostically challenging cases, such as Wilson's disease with normal ceruloplasmin, heterozygous carriers with genetic defects, or other conditions with Kayser-Fleischer rings and elevated hepatic/urinary copper when liver biopsy is contraindicated. After oral administration of ²⁶Cu (2 mg), serum isotope activity is measured at 1, 2, 4, 24, and 48 hours. In healthy individuals, a peak occurs at 1–2 hours, followed by a decline, then a gradual rise over 48 hours as ⁶⁴Cu is incorporated into ceruloplasmin and released into the blood. In Wilson's disease, an initial peak occurs at 1–2 hours, but afterward, ⁶⁴Cu shows minimal or no incorporation into ceruloplasmin, preventing further serum radioactivity increase. 64 64
For children and young patients with chronic active hepatitis, fulminant hepatitis, or cirrhosis, it is necessary to consider ruling out this disease. K-F rings, serum ceruloplasmin, and urinary copper measurements are essential diagnostic steps. Liver biopsy serves two purposes: observing tissue changes and measuring copper content, thus often having definitive diagnostic value. If necessary, perform the 64Cu binding test. Additionally, the use of DNA restriction fragment length polymorphism linkage analysis is helpful for studying and detecting heterozygotes, as well as diagnosing Wilson's disease.
Exclude other causes of cirrhosis, chronic hepatitis, and fulminant hepatitis.
bubble_chart Treatment Measures
1. Penicillamine
is the drug of choice, and the key to success lies in early diagnosis and early treatment. The initial dose is 1-2g per day, divided into 4 doses taken before meals, which can reverse or alleviate liver, neurological, and psychiatric lesions. The speed of lesion remission varies greatly among individuals, with some recovering rapidly within weeks, while others may show no improvement for years, and sometimes neurological symptoms may even worsen. In the latter case, the dosage of Penicillamine can be increased to 4g per day. After several years, when symptoms significantly improve and the condition stabilizes, the dose can be reduced to 1g per day for lifelong administration. Side effects include allergic reactions, leukopenia and thrombocytopenia, aplastic anemia, proteinuria, and lupus-like syndrome. If allergic reactions occur, desensitization can be attempted before resuming use.
2. Low-copper diet
Foods high in copper, such as shellfish, animal liver, nuts, cocoa, and chocolate, should be restricted to keep daily copper intake below 1.5mg. Drinking water should be softened.
3. Zinc preparations
can inhibit copper absorption in the intestines. Zinc promotes the production of copper-binding proteins in the gut, isolating copper from the intestinal mucosa. Take zinc sulfate or zinc acetate preparations, 50mg each time, three times a day, between meals.
4. Liver transplantation
For patients with significant cirrhosis or liver failure, orthotopic liver transplantation can prolong survival.
5. Other treatments
For those with bone demineralization, supplement with vitamin D and calcium. Treatments for upper gastrointestinal bleeding, esophageal and gastric varices, ascites, etc., are the same as for similar conditions caused by other reasons.
