Penicillamine-induced degenerative dermopathy in a patient with Wilson's disease.

Penicillamine is a chelator that has been used in Wilson's disease, cystinuria, rheumatoid arthritis and heavy metal intoxication. We report a case of a 31-year-old man presented with skin atrophy, purpura and milia on the hips and shoulders after taking penicillamine for 1.5 years. According to literature review, this type of penicillamine-associated cutaneous adverse effect belongs to degenerative dermopathy, which mostly occurs on bony prominences and points of pressure in patients with Wilson's disease or cystinuria. Withdrawal or reduction of drug dose can improve the features of degenerative dermopathy.

Multicentre, retrospective study to assess long-term outcomes of chelator based treatment with trientine in Wilson disease patients withdrawn from therapy with d -penicillamine.

OBJECTIVES: Trientine dihydrochloride (TETA-2HCl) has been used for the treatment of Wilson disease for over 30 years. The current study was designed to systematically evaluate existing data to further define the long-term outcome of the efficacy and tolerability of TETA-2HCl in Wilson disease patients. METHODS: Medical records of 77 Wilson disease patients were reviewed to collect data on hepatic and neurologic symptoms, copper (Cu) homeostasis and adverse events. Data were collected for 48 months after initiation of TETA-2HCl after withdrawal of D-penicillamine treatment. RESULTS: Mean duration of TETA-2HCl treatment was 8 years (range 5 months-32.5 years). Over the course of TETA-2HCl treatment, 35% of patients had no hepatic symptoms whereas in 49.4% of patients, hepatic symptoms improved. They remained unchanged in 10.4% of patients and worsened in 5.2% of patients. No patients progressed to acute hepatic failure or necessity of a liver transplant. During TETA-2HCl treatment, 46.7% of patients had no neurologic symptoms; in 14.3% of patients, neurologic symptoms improved whereas in 36.4% of patients, they remained stable and worsened in 2.6% of patients. During the evaluation period, 12 patients discontinued TETA-2HCl treatment due to: anemia ( N = 1), inadequate hepatic response ( N = 2), switch to zinc treatment ( N = 8) and patient's decision to withdraw from treatment ( N = 1). Treatment-emergent adverse events were reported by 24.7% of the patients of which gastrointestinal disorders (9.1%) and nervous system disorders (5.2%) were most reported. CONCLUSIONS: TETA-2HCl is well-tolerated and effective in Wilson disease patients following the withdrawal of treatment with D-penicillamine. ClinicalTrials.govIdentifier : NCT02426905.

Pregnancy Outcomes in Wilson's Disease Women: Single-Center Case Series.

OBJECTIVES: To evaluate and compare pregnancy outcomes in women with Wilson's disease (WD) undergoing different therapies during pregnancy. MATERIAL AND METHODS: Retrospective review of medication in WD patients during pregnancy and the outcomes. RESULTS: Of 26 pregnancies, zinc was used in 14 (53.8%), D-penicillamine in 4 (15.4%) patients, and 8 (30.8%) were untreated. Spontaneous abortion was observed in 8 (30.8%) pregnancies - untreated patients (4/8 pregnancies), zinc (2/14 pregnancies) and D-penicillamine (2/4 pregnancies) -, healthy outcome in 12 (46.1%) and birth defects in 6 (23.1%). All cases of birth defects occurred in patients using zinc therapy (6/14 pregnancies). CONCLUSIONS: A remarkably high frequency of fetal complications shed lights on the potentially harmful effect of WD drugs during childbearing age. Zinc's safety profile may have to be better evaluated during pregnancy, as all of birth defects occurred with zinc therapy.

Proteinuria masiva por nefropatía por cambios mínimos secundaria a tratamiento con D-penicilamina en un paciente con enfermedad de Wilson hepática. A propósito de un caso / Massive proteinuria for minimal change nephropathy secondary to treatment with D-penicilamine in a patient with Wilson's disease. Case report

No disponible

Acute Liver Failure due to Wilson Disease: Eight Years of the National Liver Transplant Program in Uruguay.

INTRODUCTION AND AIM: Wilson's disease (WD) is an uncommon cause of acute liver failure (ALF). Our aim was to describe clinical features, diagnostic findings, treatments, and outcomes of patients with ALF due to WD. MATERIAL AND METHODS: Retrospective medical record reviews of all patients with ALF due to WD in eight years in Uruguay. RESULTS: WD was the cause of six (15%) of thirty-nine ALF cases. All patients were females, with a mean age of 18 years. Four patients presented with hyperacute liver failure and two with acute failure. Jaundice was the main complaint of all patients. Mean total bilirubin (TB), alkaline phosphatase (AP), AST, and ALT were 27.5 mg/dL, 45.5 lU/l, 156 IU/L, and 51 IU/L, respectively. Ceruloplasmin levels were low in four patients, urinary cooper was high in four, and two had Kayser-Fleischer rings. All patients had Coombs-negative hemolytic anemia, acute kidney injury, histochemical identifiable copper, and advanced fibrosis on liver histology. The average MELD score was 36. All patients were treated with d-penicillamine and listed for urgent liver transplantation (LT). Prometheus® was performed in one patient. Three patients died: two without LT and one after LT. Three patients survived: one without LT (New Wilson Index<11) and two with LT. The referral time to the program and the total time (referral plus waiting list time) were longer for non-survivors than for survivors (14 vs. 3 days and 23 vs. 8 respectively). CONCLUSION: All cases had typical clinical, analytical and histopathology characteristics. Early referral was determinant of prognosis.

Metabolic profiling of copper-laden hepatolenticular degeneration model rats and the interventional effects of Gandou decoction using UPLC-Q-TOF/MS.

The direct cause of hepatolenticular degeneration (HLD) is copper metabolic disorder caused by autosomal recessive inheritance. Gandou decoction (GDD), a classical traditional Chinese medicine formula, exhibits unambiguous therapeutic effect on HLD in China for decades. However, the mechanism of effect on HLD is not clear. With this purpose, the effects of copper content and histopathology inspection on the HLD rat model were investigated. Then, metabolomics study based on ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MSE) analysis and multivariate statistical analysis was adopted to further reveal the mechanism of action of GDD against HLD. The results showed that the characteristics of liver tissues after GDD treatment were significantly reversed, close to the control group, suggesting that GDD has a therapeutic effect on HLD. Furthermore, HLD interferes with 2 metabolites of the metabolic pathway in rats. Among them, up-regulation of Lactic acid, Tryptophan, Phenylalanine, Triacylglycerol and down-regulation of Linoleic acid, Alpha Linolenic acid, Phosphatidylcholine, Taurine is particularly significant. Analysis of metabolic pathways by a unique pathway analysis revealed significant changes in several pathways including lipid metabolism, amino metabolism and glucose metabolism in HLD. This study showed that GDD could provide satisfactory therapeutic effects on HLD and metabolomics study can be utilized to further understand the molecular mechanisms.

The early history of manganese and the recognition of its neurotoxicity, 1837-1936.

The history of the biomedical recognition manganese-caused neurotoxicity mirrors changing technologies as much as it does the ontology of parkinsonism. The initial 1837 report of manganese-induced neurologic injury was made by John Couper, a university-based physician in Scotland. He made clear that the outbreak occurred among workers at the Charles Tennant bleach manufactory in the environs of Glasgow. The relatively new technology of chlorine generation using manganese accounted for the novel exposure involved. At the time, this factory was the largest hypochlorite bleaching powder producer in the world. As the 19th century progressed, technological change in steel fabrication requiring higher manganese content greatly increased demand for the metal. Nonetheless, more than six decades elapsed before the next reports of manganese neurotoxicity emerged. Two unrelated outbreaks (both on Continental Europe) were reported within weeks of each other in 1901, one by von Jaksch and the other by Embden. All the cases were heavily exposed to manganese-containing dust. By the eve of the First World War, a total of 9 patients with manganese-caused neurologic illness had been reported in five separate Continental European publications. Meanwhile, new technology led to another exposure source. Magnetic separation techniques allowed the extraction of zinc from mixed ore also containing iron and manganese, leading to exploitation of a unique source of high manganese-content ore found in New Jersey. Not long after that technology's introduction, in 1912 Casamajor reported the first U.S. cases of manganism, detailing classic findings. Additional cases from the same cohort were reported a few years later, with continued exposure driven by First World War-driven demand for manganese to be used in armaments. The nosology of chronic manganese neurotoxicity remained in flux, with considerable emphasis on shared attributes with Wilson's disease, a syndrome only then recently described. A landmark 1924 primate study by Mella showed manganese-induced basal ganglion damage; human autopsy study data in the years following further supported the view that manganese toxicity represented a parkinsonian syndrome. As the 1937 centenary of Couper's first report approached, newer technologies (electric arc welding and battery making) were being linked to manganese-caused disease, even as mineral extraction was expanding as a global source of exposure.

Copper Inhibits the AlkB Family DNA Repair Enzymes under Wilson's Disease Condition.

Disturbed metabolism of copper ions can cause diseases such as Wilson's disease (WD). In this work, we investigated the inhibitory effect of Cu(II) ion in vitro on the AlkB family DNA repair enzymes, which are members of the Fe(II)/alpha-ketoglutarate-dependent dioxygenase and include human ALKBH2, ALKBH3, and E. coli AlkB proteins. None of the three proteins was significantly inhibited under normal cellular copper concentrations. However, under WD related condition, we observed that the activities of all three enzymes were strongly suppressed (from 95.2 to 100.0%). We also noted the repair efficiency under ds-DNA condition was less susceptible than ss-DNA to the inhibition.

Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease.

The outcome of consecutive hepatocyte transplants was explored in a rat model of Wilson's disease before the onset of fulminant hepatitis without preconditioning regimens. Rats received a high-copper diet in order to induce a rapid induction of liver failure. Sham-operated rats (15/15) developed jaundice and fulminant hepatitis, and they died within 4 weeks of first transplantation. Despite the continuation of a high dietary copper challenge, long-term survival was observed for a notable proportion of the transplanted animals (7/18). All survivors displayed normalized levels of hepatitis-associated serum markers and ceruloplasmin oxidase activity by posttransplant days 50 and 98, respectively. The liver copper concentrations, the liver histology, and the expression of marker genes were significantly restored within 4 months of transplantation in comparison with the control group. The high expression of a copper transporter gene (ATPase Cu++ transporting beta polypeptide) in the livers of the survivors indicated a high rate of repopulation by donor hepatocytes. Our data suggest that repeated cell transplantation can overcome the limitations of a single therapy session in rats with severe hepatic disease by functionally restoring the host liver without preconditioning.

The risks of free copper in the body and the development of useful anticopper drugs.

PURPOSE OF REVIEW: To review the toxicity and risks of free copper in Wilson's disease, Alzheimer's disease, other disease of neurodegeneration, and cognitive loss in the general population. We will also review the anticopper drugs and how lowering free copper levels with an anticopper drug inhibits fibrosis, inflammation, and autoimmunity. RECENT FINDINGS: Some exciting recent work indicates that free copper levels are increased in Alzheimer's disease, and copper may be involved in disease pathogenesis, opening the way to possible therapy of Alzheimer's disease with anticopper drugs. Copper may also be involved in other diseases of neurodegeneration. A very exciting recent study indicts high intake of copper, mostly from copper supplements, in conjunction with a high-fat diet in more rapid cognitive decline in the general population. Other data indicate that even low levels of copper in drinking water, perhaps similar to copper supplements, bypasses the liver, enters the circulation, increases the blood-brain penetration of copper, and may cause damage. SUMMARY: Some of the implications are that Alzheimer's disease and other diseases of neurodegeneration and fibrotic, inflammatory, and autoimmune diseases may be treatable by lowering the availability of free copper. People in the general population may wish to take steps to lower their free copper levels and, in particular, to abstain from taking copper supplements and ingesting significant amounts of copper in drinking water.

Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation.

AIM: To observe the therapeutic effect of intrasplenic transplantation with embryonic hepatocytes on amelioration of hereditary copper accumulation in toxic milk (TX) mouse modeling Wilson disease. METHODS: Donor hepatocytes were harvested from 14-d fetal liver of a pregnant homogeneous DL mouse. These cells were successively cultured, labeled with fluorescein dye Hoechst 33342 for 24 h, and sequentially infused into the spleen parenchyma of the recipient TX mice. No host immunosuppression measures were taken. Two and four weeks after transplantation, the recipients were killed for routine histologic investigation and immunohistochemistry study up to 4 wk after transplantation. The serum copper and ceruloplasmin concentrations of the recipient mice were determined by graphite furnace atomic absorption spectroscopy. RESULTS: In the following 2nd and 4th wk after transplantation, the donor hepatocytes could be visualized in the livers of 47.3% recipients. The serum ceruloplasmin and copper concentrations increased by 1.6-fold after 2 wk and 2.0-fold times after 4 wk respectively, which ultimately rose from about 30% of the normal level to nearly 60% (P<0.01). The hepatic copper concentration decreased 7.2%, 4 wk after transplantation. Pathologic examination showed that there were many actively proliferative hepatocyte precursor cells with specific embryonic hepatocyte marker AFP migrated into hepatic sinusoids of the recipients. A large number of cells carrying hepatocytes marker and albumin were observed in the recipient spleen tissues. CONCLUSION: Embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo. After transplantation, the hereditary abnormalities of copper metabolism in TX mice could be corrected partially by intrasplenic transplantation of homogeneous embryonic hepatocytes.

Neuropsychiatric aspects of trace elements.

Our knowledge of trace element metabolism has increased dramatically in the last decade. It now seems likely that many trace elements are of significance either as causative or therapeutic factors in a wide range of illnesses. Several of the most topical elements are discussed here in relation to neurological and psychiatric disorders.

Drug-induced arthritis and arthralgia.

In the differential diagnosis of arthritis and arthralgia, one must consider the possibility of adverse drug reactions being responsible. The distinction between primary cause and secondary aggravation of a pre-existing condition is often difficult and sometimes impossible to make; for instance, oral contraceptives may seem on occasion to precipitate pre-existing rheumatoid arthritis and systemic lupus erythematosus and also to cause temporary symptoms resembling these disorders in previously normal subjects. In addition, serum sickness type reactions, myopathies, electrolyte and fluid disturbances, pseudosclerodermas, bone lesions and local reactions to intra-articular injections have been described. One should therefore be aware of the possibility of drug-induced syndromes resembling rheumatoid arthritis, systemic lupus erythematosus, periarthritis of the shoulders, progressive systemic sclerosis, and other rheumatic and arthritic disorders. Though rarely severe or incapacitating, they may cause considerable diagnostic confusion.