Hepatic iron overload in aceruloplasminaemia

We report the case of a 52 year old male with diabetes mellitus and long standing evidence of hepatic iron excess. Initially considered to have haemochromatosis, this patient was reevaluated when hepatic iron stores were found to be unaffected by a prolonged course of weekly phlebotomy. The development of neurological disease prompted diagnostic consideration of aceruloplasminaemia, which we confirmed by demonstration of a novel frameshift mutation in the ceruloplasmin gene. Our inability to resolve the patient's iron overload by regular phlebotomy is consistent with recent animal studies indicating an essential role for ceruloplasmin in cellular iron efflux. Evaluation of this case underscores the clinical relevance of aceruloplasminaemia in the differential diagnosis of hepatic iron overload and provides insight into the pathogenetic mechanisms of hepatocellular iron storage and efflux.     

Potential of the international scoring system for the diagnosis of Wilson disease to differentiate Japanese patients who need anti‐copper treatment

Aim: Patients with Wilson disease show complex clinical features. Accurate diagnosis at the initial clinical manifestation is important for patients to receive effective treatment with anti‐copper agents. In this study, we assessed whether the international scoring system for the diagnosis of Wilson disease is a reliable tool for screening Japanese patients with primary copper toxicosis requiring anti‐copper treatment. Methods: Twenty‐three Japanese patients suspected of Wilson disease were enrolled in this study. We performed long‐range polymerase chain reaction to detect ATP7B mutations in this series. Finally, we retrospectively assessed the reliability of using a diagnostic score of 4 or more points as the cut‐off for this scoring system. Results: Ten patients were homozygous or compound heterozygous for ATP7B mutations including a novel mutation of 3837 bp deletion including 3 exons. The mutation would have been missed by the traditional analysis. Six patients were heterozygous for ATP7B mutations. Three of these six patients had additional diagnostic points. The other three patients were diagnosed as carriers of a mutant gene based on their low scores. One of the seven patients free from ATP7B mutation was affected by copper toxicosis. Though the score was 3 points based on increased urinary copper and copper‐positive cirrhosis, anti‐copper treatment promptly improved liver failure, which was likely due to idiopathic copper toxicosis. Conclusion: The international scoring system for diagnosis of Wilson disease is a fairly reliable tool for screening Japanese patients who need anti‐copper treatment. Caution is needed for patients with possible idiopathic copper toxicosis because the maximal score is 4 points.     

2型糖尿病患者血清与尿铜蓝蛋白水平的变化

目的：检测2型糖尿病患者血清与尿铜蓝蛋白（Cp）浓度的变化及探讨临床意义。方法：采用放射免疫法与速率散射免疫浊度法检测57份血清Cp，并采用速率散射免疫浊度法检测110例健康对照组，104例2型糖尿病患者血清Cp，尿Cp与肌酐（Cr）比值及尿白蛋白（Alb）与Cr比值。将2型糖尿病患者分为血糖控制良好组与血糖控制不良组，糖尿病肾病组与无糖尿病肾病组进行分析与比较。结果：放射免疫法与速率散射免疫浊度法检测血清Cp相关性与可比性良好；血清Cp的正常参考上限为542 mg/L（110例健康人的97.5%可信区间），尿Cp/Cr的正常参考上限为0.892 ng/mmol（110例健康人的97.5%百分位点）；2型糖尿病患者血清Cp值显著高于健康对照组（P＜0.001），其中血糖控制不良组血清Cp值显著高于血糖控制良好组（P＜0.01），有糖尿病肾病组尿Cp/Cr显著高于无糖尿病肾病组（P＜0.001）；尿Cp/Cr对糖尿病肾病的诊断敏感性为91.4%，特异性为61.4%，符合率为75.0%。结论：检测血清Cp水平对于了解糖尿病的病情有一定参考价值，联合检测尿Cp/Cr与Alb/Cr对于糖尿病肾病的早期诊断有重要的临床意义。     

Aceruloplasminemia,an iron metabolic disorder

Aceruloplasminemia is an inherited disorder of iron metabolism caused by the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of adult‐onset neurologic disease, retinal degeneration and diabetes mellitus. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. Severe iron overload and extensive neuronal loss were observed in the basal ganglia, while iron deposition and neuronal cell loss were trivial in the frontal cortices. The cerebellar cortex showed marked loss of Purkinje cells. Iron deposition was more prominent in the astrocytes than in the neurons. Excess iron functions as a potent catalyst of biologic oxidation. Astrocytic deformity and globular structures are characteristic features in aceruloplasminemia brains. The globular structures in the astrocytes were seen in proportion to the degree of iron deposition and reacted positively to anti‐4‐hydroxynonenal, one of the indicators of lipid peroxidation, and anti‐ubiquitin antibodies, but not to anti‐α‐synuclein antibody. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemia brains through lipid peroxidation. Ceruloplasmin may play an essential role in neuronal survival in the central nervous system.     

Vaccination against meningococcus in complement-deficient individuals

Autoantibodies to CRP were reported previously in patients suffering from toxic oil syndrome. This syndrome resembles autoimmune diseases such as systemic lupus erythematosus (SLE) or systemic scleroderma. We therefore examined the prevalence of antibodies to CRP and other acute-phase proteins in autoimmune diseases, including SLE, subacute cutaneous lupus erythematosus (SCLE), systemic scleroderma (SSc), and primary biliary cirrhosis (PBC), as well as in bone marrow transplantation-induced chronic graft-versus-host disease and eosinophilia–myalgia syndrome. IgG antibodies to CRP were found in 78% of SLE and in 30% of SCLE patients, while 16% of patients with PBC were positive. In up to 45% of patients with SSc predominantly IgG antibodies to ceruloplasmin were detectable. Lack of systemic involvement as in discoid lupus erythematosus and localized scleroderma (morphea) correlated with low or absent antibody formation. However, no correlation was found between anti-acute-phase protein antibodies with liver disease or other organ involvement. Adsorption studies revealed that non-native epitopes on the CRP molecule, termed modified CRP, are the main target of antibodies. Chronic inflammatory tissue injury in systemic autoimmune disease might increase the presentation of cryptic epitopes of CRP to the threshold required for T cell activation.     

Biological functions of ceruloplasmin and their deficiency caused by mutation in genes regulating copper and iron metabolism

Ceruloplasmin, a multicopper ferroxidase, is involved in iron and copper homeostasis and integrates these metabolic pathways. Impaired biosynthesis of ceruloplasmin caused by gene mutations disturbs iron metabolism with iron deposition in different organs, especially in the basal ganglia, and severe neuronal damage. Dysfunction of ATP7B, a copper-transporting ATPase leads to the development of Wilson’s disease,i.e., multiple abnormalities in copper metabolism associated with reduced synthesis of holoceruloplasmin and biliary copper excretion controlled by both proteins. The lowest content of serum ceruloplasmin is observed in the most grave early neurological form of Wilson’s disease (according to N. V. Konovalov’s classification), which confirms the important role of ceruloplasmin in the striatal metabolism of catecholamines. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 124–133, August, 2000     

喉癌病人血清铜蓝蛋白的测定

采用放射免疫法对６０例正常人、２０例喉部良性疾病和３０例喉鳞状细胞癌病人血清铜蓝蛋白（ＣＰ）进行检测。结果表明，喉癌组血清ＣＰ较正常对照组和良性疾病组明显升高，差异有极显著意义（Ｐ＜０．０１）。以大于正常对照组血清ＣＰ值为阳性，喉癌组阳性率为４３．３％，良性疾病组为１５．０％，两者差异有显著性意义（Ｐ＜０．０５）。结果提示血清ＣＰ测定是喉癌辅助诊断的一项参考指标。     

Genetic linkage between copper accumulation and hepatitis/hepatoma development in LEC rats.

The concentration of copper in the livers of Long-Evans rats with cinnamon-like coat color (LEC), in which hepatitis and then hepatomas develop spontaneously, was recently found to be abnormally high. Therefore, we examined the copper concentrations in the livers of LEC F1 backcrosses (LEC F1 x LEC) to determine the linkage of copper accumulation with development of hepatitis. Consistent with a previously reported ratio of rats with hepatitis to rats without hepatitis of about 1:1, hepatitis developed in 14 of 30 F1 backcrosses. The copper concentrations in the livers of all LEC F1 backcrosses with hepatitis were abnormally high and comparable to those of LEC rats. In contrast, the concentrations in all backcrosses without hepatitis were similar to those in normal Long-Evans with agouti coat color or Brown-Norway rats. Copper accumulation was shown to be closely linked with the development of hepatitis in LEC rats and appeared to be a possible cause of hepatitis. The concentrations of copper in the livers of Fischer 344 rats after carbon tetrachloride treatment were in the range for normal liver, indicating that a high copper concentration in the liver is specific to LEC rats and not a specific characteristic of hepatitis. Furthermore, we found that the size and level of ceruloplasmin mRNA in the livers of LEC rats were the same as those in LEA rats and that the size and level of ceruloplasmin polypeptide in their livers and plasma were almost the same as those in LEA rats. Therefore, these results suggest that the copper accumulation is not due to alteration of expression or to gross alteration of the ceruloplasmin gene.