OBJECTIVES: To explore the mechanism of Gandou Fumu Decoction (GDFMD) for improving Wilson's disease (WD) in tx-J mice. METHODS: With 6 syngeneic wild-type mice as the control group, 30 tx-J mice were randomized into WD model group, low-, medium- and high-dose GDFMD treatment groups, and Fer-1 treatment group. Saline (in control and model groups) and GDFMD (3.48, 6.96 or 13.92 g/kg) were administered by gavage, and Fer-1 was injected intraperitoneally once daily for 14 days. Oil red and HE staining were used to observe lipid deposition and pathological conditions in the liver tissue; ALT, AST, albumin, AKP levels were determined to assess liver function of the mice. Western blotting and RT-qPCR were used to detect hepatic protein and mRNA expressions of GPX4, ACSL4, ALOX15, FTH1, FLT, TFR1, FAS, SCD1, and ACOX1, and Fe²⁺, MDA, ROS, SOD, GSH and 4-HNE levels were analyzed to assess oxidative stress. RESULTS: The mouse models of WD showed obvious fatty degeneration in the liver tissue significantly increased serum levels of ALT, AST and AKP, decreased albumin level, increased Fe²⁺, MDA, ROS, 4-HNE levels, decreased SOD and GSH levels (P<0.05), lowered protein expressions of ACOX1, GPX4, FTH1, FLT, FAS, and SCD1, and increased protein contents of TFR1, ACSL4 and ALOX15 in the liver. Treatment with GDFMD and Fer-1 improved liver histopathology and liver function of the mouse models, decreased the levels of Fe²⁺, MDA and ROS, increased SOD and GSH levels, and reversed the changes in hepatic protein expressions. CONCLUSIONS GDFMD improves liver steatosis in mouse models of WD possibly by inhibiting hepatocyte ferroptosis through the GPX4/ACSL4/ALOX15 signaling pathway.
Animals ; Ferroptosis/drug effects* ; Mice ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Hepatolenticular Degeneration/drug therapy* ; Hepatocytes/metabolism* ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Fatty Liver/metabolism* ; Arachidonate 15-Lipoxygenase/metabolism* ; Coenzyme A Ligases/metabolism* ; Liver/metabolism* ; Male

Wilson's disease typically presents symptoms associated with liver damage or neuropsychiatric disturbances, while endocrinologic abnormalities are rare. We report an unprecedented case of hypopituitarism in a patient with Wilson's disease. A 40-year-old woman presented with depression, general weakness and anorexia. Laboratory tests and imaging studies were compatible with liver cirrhosis due to Wilson's disease. Basal hormone levels and pituitary function tests indicated secondary hypothyroidism and adrenal insufficiency due to hypopituitarism. Brain MRI showed T2 hyperintense signals in both basal ganglia and midbrain but the pituitary imaging was normal. She is currently receiving chelation therapy along with thyroid hormone and steroid replacement. There may be a relationship between Wilson's disease and hypopituitarism. Copper deposition or secondary neuronal damage in the pituitary may be a possible explanation for this theory.
Adrenal Insufficiency/diagnosis/etiology ; Adult ; Brain/diagnostic imaging ; Depression/etiology ; Female ; Hepatolenticular Degeneration/*complications ; Humans ; Hypopituitarism/complications/*diagnosis/drug therapy ; Hypothyroidism/diagnosis/etiology ; Liver Cirrhosis/complications/diagnostic imaging ; Magnetic Resonance Imaging ; Steroids/therapeutic use ; Thyrotropin-Releasing Hormone/therapeutic use

Wilson's disease typically presents symptoms associated with liver damage or neuropsychiatric disturbances, while endocrinologic abnormalities are rare. We report an unprecedented case of hypopituitarism in a patient with Wilson's disease. A 40-year-old woman presented with depression, general weakness and anorexia. Laboratory tests and imaging studies were compatible with liver cirrhosis due to Wilson's disease. Basal hormone levels and pituitary function tests indicated secondary hypothyroidism and adrenal insufficiency due to hypopituitarism. Brain MRI showed T2 hyperintense signals in both basal ganglia and midbrain but the pituitary imaging was normal. She is currently receiving chelation therapy along with thyroid hormone and steroid replacement. There may be a relationship between Wilson's disease and hypopituitarism. Copper deposition or secondary neuronal damage in the pituitary may be a possible explanation for this theory.
Adrenal Insufficiency/diagnosis/etiology ; Adult ; Brain/diagnostic imaging ; Depression/etiology ; Female ; Hepatolenticular Degeneration/*complications ; Humans ; Hypopituitarism/complications/*diagnosis/drug therapy ; Hypothyroidism/diagnosis/etiology ; Liver Cirrhosis/complications/diagnostic imaging ; Magnetic Resonance Imaging ; Steroids/therapeutic use ; Thyrotropin-Releasing Hormone/therapeutic use

The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy.
Administration, Oral ; Adolescent ; Chelating Agents ; administration & dosage ; adverse effects ; therapeutic use ; Chelation Therapy ; adverse effects ; methods ; Child ; Copper ; urine ; Drug Administration Schedule ; Drug Hypersensitivity ; etiology ; Drug Therapy, Combination ; Hepatolenticular Degeneration ; drug therapy ; Humans ; Injections, Intravenous ; Male ; Neutropenia ; chemically induced ; Partial Thromboplastin Time ; Penicillamine ; administration & dosage ; adverse effects ; therapeutic use ; Prothrombin Time ; Thrombocytopenia ; chemically induced ; Time Factors ; Treatment Outcome ; Unithiol ; administration & dosage ; adverse effects ; therapeutic use

Adolescent ; Child ; Child, Preschool ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Hepatolenticular Degeneration ; diagnosis ; drug therapy ; Humans ; Male ; Penicillamine ; administration & dosage ; adverse effects ; Zinc Sulfate ; administration & dosage ; adverse effects

OBJECTIVE: To investigate the clinical character and therapeutic effect of late-onset Wilson disease,and to provide some evidence for its diagnosis and treatment. METHODS: Clinical character, changes of copper metabolism, and therapeutic effect of 8 patients with late-onset Wilson disease were analyzed. Ceruloplasmin level was measured by nephelometry, and the copper contents in the serum, urine, and liver were measured by flame atomic absorption spectroscopy. The initial treatment was sodium dimercaptosulphonate, followed by D-penicillamine and/or zinc. RESULTS: Patients with late-onset Wilson disease accounted for 7.0% of all patients, Who presented liver disease symptoms such as loss of appetite or nausea at the early stage and were misdiagnosed easily. Their blood routine and aminotransferase levels were normal in most patients with late-onset Wilson disease, and all patients had Kayser-Fleisher rings. There was significant difference between the liver function and copper metabolite test. The average urinary copper content was 4 072 microg/24 h on the first day after administrating sodium dimercaptosulphonate, which was 18.1 times as much as that before the treatment, and 2.5 times as much as that of D-penicillamine. No obvious adverse reactions were observed. The prognosis was usually good. CONCLUSION Enough attention should be paid to late-onset Wilson disease which is not rare and easy to be misdiagnosed. Good response can be expected in patients treated with sodium dimercaptosulphonate in the initial stage.
Adolescent ; Adult ; Ceruloplasmin ; metabolism ; Chelating Agents ; therapeutic use ; Child ; Child, Preschool ; Copper ; metabolism ; Female ; Hepatolenticular Degeneration ; diagnosis ; drug therapy ; Humans ; Male ; Middle Aged ; Penicillamine ; therapeutic use ; Prognosis ; Young Adult

OBJECTIVETo observe the effect of Gandou Decoction IV (GDIV) on serum indexes of hepatic fibrosis and liver function in patients with Wilson's disease (WD).

METHODSSixty-one WD patients were assigned to two groups, 30 patients in the sodium dimercaptosulphonate (DMPS) group and 31 patients in the GD IV group. Both groups received 8 courses of DMPS treatment with 6 days as one course, and the GD IV group was given GD IV additionally. Serum indexes of liver function were examined, serum matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were detected by double antibody sandwish ABC enzyme-linked immunosorbent assay (ELISA), and serum hyaluronic (HA), laminin (LN), procollagen III (PC III) and collagen type IV (C-IV) were determined by radioimmunoassay (RIA).

RESULTSAfter treatment, all indexes of hepatic fibrosis and liver function had no significant change in the DMPS group, while in the GD IV group, the serum TIMP-1 level markedly decreased (P <0.05), the ratio of MMP-1/TIMP-1 significantly increased (P <0.01), and serum indexes of liver function markedly decreased (P < 0.05), but the changes in serum levels of HA, LN and PCIII, as well as in serum MMP-1 and C-IV were insignificant (P> 0.05), though they showed a trend of decreasing or increasing, respectively.

CONCLUSIONShort-term decopper-ing treatment with DMPS alone has no significant effect on hepatic function and serum fibrosis indexes in WD patients, while combined with GD IV, it can improve liver function and display an anti-fibrosis effect through inhibiting the serum TIMP-1 level and increasing the ratio of MMP-1/TIMP-1.

Adolescent ; Adult ; Chelating Agents ; therapeutic use ; Child ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Hepatolenticular Degeneration ; blood ; drug therapy ; Humans ; Liver Cirrhosis ; blood ; prevention & control ; Matrix Metalloproteinase 1 ; blood ; Phytotherapy ; Tissue Inhibitor of Metalloproteinase-1 ; blood ; Unithiol ; pharmacology ; therapeutic use ; Young Adult

Chelating Agents ; therapeutic use ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Hepatolenticular Degeneration ; drug therapy ; Humans ; Integrative Medicine ; methods ; Phytotherapy ; Succimer ; therapeutic use ; Treatment Outcome

Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin (<20 mg/dL), high 24 hour urine copper (>100 microgram), high hepatic copper content (>250 microgram/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.
Adenosine Triphosphatases/*genetics ; Cation Transport Proteins/*genetics ; Copper/*metabolism ; Diagnosis, Differential ; Genetic Screening ; Hepatolenticular Degeneration/*diagnosis/*drug therapy/genetics ; Humans ; Liver/*metabolism ; *Mutation ; Penicillamine/administration & dosage/therapeutic use ; Triethylenetetramine/administration & dosage/therapeutic use ; Zinc/administration & dosage/therapeutic use

OBJECTIVETo observe the clinical manifestation of 155 patients with hepatolenticular degeneration (HLD) complicated with epilepsy and the therapeutic effect of integrative Chinese and Western medicine treatment on them.

METHODSClinical manifestation of patients and its relationship with abnormalities in cranial CT and/or MRI were observed. Patients were treated by combined treatment of copper repellent with sodium dimercaptosulfonate 20 mg/kg per day by intravenous dripping, and modified Gandou Decoction (GDD) by oral intake and antiepileptics as well, after treatment for 8-10 courses, the clinical effect, copper levels in urine and serum were compared between groups.

RESULTSIn the 155 HLD patients, 96 were complicated with petit mal and 59 with grand mal. In the CT and/or MRI conducted in 72 patients, all showed abnormal images, besides such frequently met images as bilateral symmetrical basal ganglia focal lesion in 65 case-episode (90.3%) and brain atrophy of various degrees in 61 case-episode (84.7%), the massive lesions in cerebral white matter as principal, with the cortex involved, were also found in 54 patients (74%), which were mostly bilateral and symmetric or located in 2 adjecent lobes of brain, the sites of damage, in sequence of occurrence, were frontal lobe, parietal lobe, temporal lobe and callosal gyrus. Brain atrophy was found in all the remained patients without above-mentioned lesions. Abnormal EEG was shown in 29 patients (40.2%), which mainly manifested as theta wave of moderate to high potential and/or short paroxysmal spike-slow or sharp-slow complex wave evoked. The urinary copper level in patients after treatment was 34.5 +/- 21.6 micromol/24 hrs, significantly higher than that before treatment, 4.49 +/- 1.93 micromol/24 hrs (P < 0.01). And the serum copper level in patients also lowered significantly (P< 0.01). Epileptic seizure was controlled completely along with the gradually improving of extrapyramidal symptoms.

CONCLUSIONPartial seizure was the most common type of seizure of HLD patient complicated with epilepsy, the next is systemic seizure. Cerebral damage lesion and obvious brain atrophy could be the main etiological factors of HLD complicated with epilepsy, combined copper repellent therapy of integrative Chinese and Western medicine, and antiepileptics produced good clinical effect on the patients.

Adolescent ; Adult ; Anticonvulsants ; therapeutic use ; Chelating Agents ; therapeutic use ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Epilepsy ; complications ; drug therapy ; Female ; Hepatolenticular Degeneration ; complications ; drug therapy ; Humans ; Male ; Phytotherapy ; Unithiol ; therapeutic use