Urinary Copper Levels Research Articles

Liver Transplantation and Neurological Manifestations in Wilson Disease

Purpose: The role of liver transplantation (LT) in managing the neurological manifestations of Wilson's Disease (WD) is not yet conclusive. A 26 year-old man with WD with cirrhosis experienced a dramatic improvement in motor function and cognitive testing early after LT, as well as normalization of copper balance. Methods: A 26 y/o Hispanic man presented with progressively increasing abdominal distension, dark urine, clumsiness of gait and cognitive deficits. He did not have any history of emotional disorder/drug or alcohol dependence/suicidal ideation/hallucinations. On physical examination he had a tense, distended abdomen with diffuse tenderness, BS+, liver and spleen could not be palpated. Imaging revealed a large ascites and splenomegaly (9.5 × 18 × 19 cm) without parenchymal lesions. Liver had a nodular contour and coarse echo pattern. CT of the Abdomen/Pelvis revealed massive ascites with a small, shrunken, irregular liver with nodular periphery. Patient was started on lasix, spironolactone and lactulose. EGD showed portal gastropathy and Grade 1 esophageal varices and ophthalmologic evaluation did not show KF rings. Laboratory studies showed Iron Deficiency anemia with normal antibody levels of ANA, AMA, alpha 1 antitrypsin and anti Sm Ab. SAAG>1.1 with 24 Hr urinary copper level of 1835 mcg/l and ceruloplasmin level of 3 mg/dl, liver copper 974 mcg/gm (dry wt) was consistent with Wilsons disease. Patient was started on D-Penicillamine and subsequently put on trientine due to heavy proteinuria and referred for a liver transplant. He finally got a liver transplant (sibling) and currently is in good health without any neurological deficits and marked cognitive improvement. Results: Asonuma et al reported that LRLT from heterozygous carriers of the WD gene could resolve clinical signs and symptoms of WD and correct the parameters of copper metabolism. In this case study, Copper metabolism in the WD recipient was compared before and after transplantation with marked reduction in urinary copper excretion. Long-term follow-up should be continued to evaluate this specific therapy.[figure1]Figure

Wilson Disease in Children: Serum Aminotransferases and Urinary Copper on Triethylene Tetramine Dihydrochloride (Trientine) Treatment

To evaluate the efficacy of and adherence to trientine and/or zinc therapy in children with Wilson disease (WD). We retrospectively reviewed the clinical records of all children with WD in the pediatric liver/liver transplant program at our institution between 1998 and 2006. A total of 22 children with WD were evaluated and treated. Seven with fulminant disease required liver transplantation and 15 were treated with trientine and/or zinc. Ten of those 15 had follow-up for 12 to 60 months and 6 of the latter 10 were followed for 12 to 18 months. All 10 patients were started on a trientine treatment regimen. Mean alanine aminotransferase (ALT) levels decreased from 183 +/- 103 IU at presentation (n = 10) to 80 +/- 46 IU at 12 months (n = 10) and 66 +/- 40 IU at 18 months (n = 7). Mean 24-hour urinary copper levels increased from 156 microg at presentation to 494 microg at 1 to 2 months, then decreased to 71 microg after 21 to 24 months of treatment. Three of 10 patients had normalized ALT levels and 1 patient with cirrhosis continued with normal ALT levels since presentation. Four of 10 patients were documented to be nonadherent, as manifested by increased ALT levels (99 +/- 31 IU); 1 patient had previously normalized ALT levels. In 3 of 10 patients, ALT level decreased but remained at an abnormal level (93 +/- 53 IU). Trientine and/or zinc therapy is effective for children with WD. Nonadherence is a common cause of increased aminotransferase levels in patients with WD.

Serum, urinary and stone zinc, iron, magnesium and copper levels in idiopathic calcium oxalate stone patients

Many theories have been put forward to explain the mechanism of stone formation and growth. The aim of this study was to investigate the urinary, serum and stone levels of zinc, iron, magnesium, and copper in patients with calcium oxalate stones and to investigate urinary and serum element levels in healthy controls and to find a possible connection between the elements and calcium oxalate stone formation. A total of 104 patients with calcium oxalate stones ranging in age from 3 to 79 years (mean 44.0 +/- 18.1) and 77 healthy controls ranging in age from 18 to 77 (mean 44.2 +/- 17.9) were included in this study. The mean urinary iron and copper levels in stone patients were significantly higher than healthy controls (P = 0.000). The mean urinary zinc and magnesium levels in healthy controls were significantly higher than stone patients (P = 0.000). There was no significant difference in the serum levels of magnesium and copper in stone patients and healthy controls. Serum zinc and iron level were significantly high in healthy controls as compared to stone patients. Each stone had all 4 elements. Zn and Mg have inhibitory effect on calcium oxalate stone formation. Fe and Cu could be promotor of the calcium oxalate stone formation.

Significance of copper determination in late onset of Wilson's disease

Background. Wilson's disease is an autosomal recessive disorder of copper metabolism resulting from the dysfunction of a copper transporting P-type ATPase encoded on chromosome 13. When capacity for hepatic storage is exceeded, the excess copper manifests itself in toxic action. In this article, the case of a sudden unexpected death of a 22-year-old woman, as a result of a subclinical course of Wilson's disease, is reported. Methods/Results. A woman with no past medical history of underlying liver disease was hospitalized for nine days before death because of strong hemolytic anemia of unknown origin. Intoxication by lead, mercury, cadmium, thallium, zinc, chromium, manganese, and arsenic compounds was excluded. High levels of copper in blood and urine (AAS method) were found (blood: 3.90 μg/ml, urine: 8.10 μg/ml, 12140 μg/24 h; normal – blood: 0.88 μg/ml, urine: 0.051 μg/ml, < 51 μg/24 h). Symptomatic treatment, aimed at multi-organ failure, was applied immediately. In spite of intensive care, the patient died. Post-mortem findings indicated the presence of anasacra and ascites, hydropericardium, brain edema, orange-like coloration of internal organs, and cirrhotic liver. Histopathological examination of liver slices revealed complete micro- and medionodular cirrhotic changes, focal central necrosis of the hepatocytes and cholestasis. The copper content in liver was 89.8 μg/g (normal: 3.58 ± 1.71 μg/g). Conclusions. Assessment of tissue copper content is essential for the diagnosis of Wilson's disease in the living or after death (in living it can be helpful in proper diagnosis, and after death it enables one to ascertain the cause of a sudden death). The copper level in the liver in Wilson's disease is about 25 times higher than in the healthy liver.

La enfermedad de Wilson: formas de presentación en la infancia

Wilson's disease can manifest with symptoms of liver disease or neuropsychiatric disorders in children and adults. This autosomal recessive disorder is caused by a copper metabolism disorder due to a mutation in the ATP7B transporter. Excessive amounts of copper accumulate in the body due to inhibition of the release of copper into bile. Because effective treatment is available, recognizing this disease in presymptomatic or early stages, when it can be reversed, is highly important. Diagnosis is often easy but the available tests (measurement of ceruloplasmin, and blood, urinary and liver copper levels) can be misleading. There is no single test with 100% sensitivity in screening nor do any of the tests, when used alone, provide 100% specificity. Diagnosis is currently based on the combination of clinical findings and the results of laboratory tests. Genetic study, with a finding of mutations in the two alleles of the ATP7B gene, is still not a rapid and easily available alternative and the absence of these mutations does not rule out the possible presence of other mutations not yet described.

D-Penicillamine improved laparoscopic and histological findings of the liver in a patient with Wilson’s disease: 3-year follow-up after diagnosis of Coombs-negative hemolytic anemia of Wilson’s disease

We report a 13-year-old girl who presented with hepatic failure and hemolytic anemia. Laboratory findings showed a normal serum copper level (104 microg/dl), high urinary copper level (2370 microg/dl), and low serum ceruloplasmin level (14.3 microg/dl). Slit-lamp examination revealed Kayser-Fleischer rings on her cornea, and she was diagnosed with Wilson's disease. Plasma exchange and continuous hemodiafiltration relieved the serious condition, after that laparoscopic examination was performed. Administration of D-penicillamine and restriction of dietary copper (<1 mg/day) were started, leading to a normalized serum alanine amino transferase (ALT) level. After 3 years, she again underwent laparoscopic examination, and the laparoscopic and histological findings of her liver were obviously improved. Management of the copper level can reverse severe liver fibrosis in Wilson's disease.

Living‐related liver transplantation for Wilson's disease

Liver transplantation with liver grafts from deceased donors is the treatment of choice for patients suffering from Wilson's disease (WD) with end-stage liver disease. There are few reports, however, on the use of liver grafts from living-related donors for WD. Five (two pediatric and three adult recipients) underwent living-related liver transplantation (LRLT) for WD at the University of Tokyo. Two patients presented with fulminant hepatic failure with hemolysis, and the other three presented with decompensating cirrhosis, one with an overlapping neurologic WD. All recipients had a low serum ceruloplasmin level (median: 18 mg/dL), high urinary copper level (mean: 1119 microg/d), and presented with Kayser-Fleischer rings before transplantation. Although one patient died from early graft thrombosis unrelated to WD, the other four patients have shown an excellent long-term prognosis. Following successful transplantation, there was a significant reduction in urinary copper excretion (median: 64 microg/d) in all patients. The neurologic symptoms of WD in one patient, however, worsened after 2 months and gradually subsided, but not completely, over the 2-yr follow-up. For advanced liver failure in WD, we consider LRLT a valuable life-saving option. The improvement of neurologic symptoms, however, requires further evaluation.

Wilson Disease—Keeping the Bar for Diagnosis Raised *

We read with interest the article by Ala et al.1 regarding the diagnosis of Wilson's Disease in siblings, both of whom were in their eighth decade of life. We recently diagnosed Wilson's Disease in a 60-year-old woman, underscoring the conclusions reached by Ala et al. This 60-year-old woman was recently referred to us for further evaluation of liver disease. She had no significant past medical history and experienced neither neuro-psychiatric symptoms nor symptoms referable to chronic liver disease. Thus, there was nothing that would warrant further evaluation for Wilson's Disease. An abdominal ultrasound had been obtained to evaluate mild, transient upper abdominal pain and had revealed changes consistent with cirrhosis and portal hypertension. She had essentially normal liver tests, and initial evaluation for causes of chronic liver disease had been negative except for serum ceruloplasmin, which was minimally abnormal. A 24-hour urine copper level was greater that 120 μg/24 hr. She was, therefore, referred to us. Our evaluation confirmed the lack of neurological features, and ophthalmologic examination did not demonstrate Kayser-Fleischer rings. Serum ceruloplasmin and serum-free copper level were normal. The liver biopsy demonstrated steatohepatitic cirrhosis with a negative rhodanine stain. The hepatic copper was quantified at 1,021 μg/g dry weight. To confirm the diagnosis of Wilson's Disease, we performed fluorescent DNA sequence analysis of the ATP7B gene, which demonstrated compound heterozygosity for the H1069Q mutation and the E1064A mutation, an identical genotype to the patients who presented with neurological manifestations recently described by Ala et al. We initiated therapy with trientine. Whereas the H1069Q mutation is the most common mutation found in patients with Wilson's disease, the E1064A mutation has only been described once prior to the report by Ala et al.2 In summary, we diagnosed Wilson's Disease in a woman in her seventh decade of life with no symptoms referable to either liver or neuro-psychiatric disease. This finding underscores the conclusion reached by Ala et al. that the diagnosis of Wilson's Disease should be entertained in patients of all ages who present with evidence of liver disease, neurological disease, or psychiatric symptoms. Roman E. Perri M.D.*, Si Houn Hahn M.D., Ph.D. , Matthew J. Ferber Ph.D. , Patrick S. Kamath M.D.*, * Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, Department of Laboratory and Medical Pathology, Mayo Clinic College of Medicine, Rochester, MN.

Metal contents of liver parenchyma after percutaneous ethanol injection or radiofrequency ablation in patients with hepatocellular carcinoma before and after trientine hydrochloride therapy

We administered trientine hydrochloride, a drug used in the treatment of Wilson's disease, to patients with hepatocellular carcinoma after radical treatment with percutaneous ethanol injection or radiofrequency ablation, and examined its effect on the reduction of liver-tissue copper content. We enrolled 24 patients with 3 or fewer primary lesions of Child class A or B hepatocellular carcinoma with diameters of 3 cm or less who had undergone radical treatment with percutaneous ethanol injection or radiofrequency ablation. Trientine hydrochloride was orally administered in a single daily dose of 250 mg to 12 patients before a meal (at fasting, group 1) or at a total daily dosage of 750 mg, divided into 3 doses, to 12 patients (group 2). This study was a randomized between-groups comparative study of 12 weeks' duration. We used the particle-induced x-ray–emission method to determine liver-tissue mineral content. Urine copper and serum mineral levels were also measured, and transaminase levels were examined. Liver-tissue copper content decreased significantly, to 160.1 μg/g dry weight, after treatment, compared with the pretreatment level of 306.8 μg/g dry weight ( P < .05). We detected no significant difference in iron or zinc content before and after treatment. The copper content was significantly reduced after treatment in both groups ( P < .05). The urine copper level was significantly increased after 1 week of treatment but decreased thereafter. Serum copper levels were significantly reduced after treatment ( P < .01). We detected no significant difference in transaminase level before and after treatment. Iron-deficiency anemia in 1 patient after 12 weeks' treatment was the only adverse reaction, and it was improved by the administration of an iron product. We noted no other overt adverse reactions. In patients with hepatocellular carcinoma, trientine hydrochloride therapy may significantly reduce copper content in liver tissue.

Case 1: The girl who couldn't sit still

A seven-year-old Caucasian girl was referred to the hospital from the community with concerns about abnormal movements of her upper and lower extremities and slurring of speech. Before this, she had a two-week history of low grade fever, difficulty with feeding herself, deterioration in handwriting and trouble concentrating in school. She was seen by her family doctor at the onset and was believed to have had a viral infection. There was no history of a preceding sore throat or any concurrent symptoms such as headache, vomiting or fluctuating level of consciousness. Her past medical history was unremarkable. She was not taking any medications and there was nothing to suggest any intentional or accidental drug or poison ingestion. On examination, she was afebrile with stable vital signs. She was alert and cooperative but would not speak to hospital staff. She displayed facial grimacing, thrusting of the tongue and bilateral writhing nonpurposeful movements of her arms and legs, as well as the ‘milk maid’ sign when asked to squeeze the examiner’s fingers. She had a mild fleeting erythematous macular rash over her forearms. Cardiac auscultation revealed normal heart sounds, with no audible murmur or rub. The remainder of her examination was normal. Laboratory investigations showed a white blood cell count of 11.1×109/L (polymorphs 4.8×109/L, bands 1.1×109/L, lymphocytes 4.0×109/L), hemoglobin of 128 g/L, and platelets of 536×109/L. Her erythrocyte sedimentation rate was elevated at 30 mm/h (normal <10 mm/h). Throat swab, cerebrospinal fluid culture, blood and urine toxicology screens and a head CT scan were normal. Antinuclear antibody, anti-double stranded DNA antibody, and 24 h urine copper level and serum ceruloplasmin were normal. Anticardiolipin antibody and the lupus anticoagulant screen were both negative. A further laboratory test confirmed the diagnosis.

Mineral metabolism in male cyclists during high-intensity endurance training.

This study examined the effects of intense endurance training on basal plasma and 24-hour urinary calcium (Ca), magnesium (Mg), iron (Fe), zinc (Zn), and copper (Cu) levels in 9 male competitive cyclists. The supervised training program followed a baseline period and included a volume phase (6 weeks, averaging 87% of maximal heart rate [HR(max)]), an interval phase (18 days, 100% of HR(max)), and a 10-day unloading taper. The primary training outcome measure was 20-km time-trial cycling performance. Subjects ate unrestricted diets and maintained their weight. Compared to baseline, performance improved significantly (p < .05), while mineral metabolism was not significantly different after the volume phase. However, after the interval phase, renal Ca excretion increased (p < .05) and plasma Ca fell slightly below the clinical norm. As compared to the interval phase, urinary Ca decreased (p <.05), plasma Ca increased (p < .05), and performance further improved (p < .05) after the taper. Whereas Mg, Fe, Zn, and Cu metabolism remained unchanged throughout the study, greater renal Ca excretion was associated with very high intensity interval training.

Effect of desferrioxamine on urinary copper and zinc excretion in ?-thalassemia major patients

Twenty-one β-thalassemia major patients were included to study urinary zinc and copper excretion before and after high dose desferrioxamine (DF). The mean basal zinc excretion (1193.72 ± 1079.64 μg/24 hr) was higher than the mean zinc excretion observed in controls (427.6 ± 74.37 μg/24 hr) (P < 0.001). There was no significant difference between urinary copper levels of patients (185.48 ± 175.45 μg/dl) and the control group (150.0 ± 37 μg/dl) (P > 0.05). No significant difference was observed between the mean basal zinc levels and zinc levels after treatment (1751.06 ± 1462.72 μg/24 hr) (P > 0.05). Although the mean copper excretion was decreased following DF treatment (164.16 ± 117.8 μg/dl), the difference was not significant (P > 0.1). There was a significant interaction for urinary copper and zinc excretion (r = 0.413; P < 0.05). J. Trace Elem. Exp. Med. 13:195–198, 2000. © 2000 Wiley-Liss, Inc.

Zinc and copper in preterm neonates: relationship with breast milk.

The study was conducted to assess copper and zinc levels in neonate's serum, mother's serum, neonate's hair and urine and to ascertain association between them. It is of concern whether zinc and copper deficiency is present at birth and maternal blood and breast milk zinc and copper levels have any effect on this. The study sample included 155 neonates with gestational age 26-41 wks and birth weight 0.550-3.800 kg. Mother's serum, breast milk, neonate's serum, hair, urine samples were analysed for zinc and copper by atomic absorption spectrophotometry. Gestational age was estimated either singly or by combination of date of last normal menses, fetal ultrasonography, and postnatal measures of physical and neurological development by clinical examination and weight by Secca electronic balance. The neonates were classified into term and preterm, small (SGA) and appropriate for gestational age (AGA). Neonates over 37 wks and 2.5 kg served as controls. To assess the dependency, relationship and effectiveness of quantitative predictive variables on the predictions of values, multiple regression analysis was used. Neonates between 26-30 wks gestational age and < 2.5 kg birth weight had significantly low serum zinc and copper. Breast milk zinc was low in mothers delivering preterm and < 2.5 kg neonates. Urinary copper and zinc levels were high in preterm appropriate for gestational age (Pre AGA) than term neonates. Multiple regression analysis revealed that neonate's serum Cu, serum Zn, hair Cu, hair Zn, urine Cu and urine Zn had contribution variability of 49.8%, 51.8%, 49.2%, 16.6%, 52.2% and 68.9%, respectively. The effect of mother's serum, breast milk, and neonate's serum copper and zinc collectively was significant for serum copper (F = 29.59) and hair zinc (F = 32.03). Preterm and low birth weight infants during subsequent growth and development should be supplemented with zinc and copper when on breast feeding.

Metabolism of administered triethylene tetramine dihydrochloride in humans

Triethylene tetramine dihydrochloride (trien 2HC1) has been used for the treatment of Wilson's disease, which is characterized by the accumulation of copper in various organs. We previously developed an HPLC system for analyzing trien, and found a trien metabolite in the urine when trien was orally given to humans. In this study, the metabolite was identified as 1- N-acetyltriethylene tetramine (acetyltrien) by FAB-MS and 1H-NMR spectroscopy. Trien and acetyltrien were capable of combining with copper, iron and zinc. However, the chelating activity of acetyltrien was significantly lower than that of trien. When trien was given to healthy adults, the amount of trien excreted in the urine was about 1% of the administered trien, whereas that of acetyltrien was about 8%. Most of the trien was excreted within the first 6 hours after the administration, while acetyltrien was excreted for over 26 hours. The urinary copper, iron and zinc levels all increased in parallel with the trien excretion.

Regression of Kayser-Fleischer Rings During Oral Zinc Therapy

Fourteen patients presenting with neuropsychiatric manifestations of Wilson's disease were treated with oral tetrathiomolybdate (TM) for 8 weeks followed by oral zinc (Zn) maintenance therapy. The patients were evaluated prospectively at baseline and at yearly intervals for up to 5 years by slit-lamp biomicroscopy and photography, quantitative neurologic and speech pathology examinations, 24-h urine copper collection, and a quantitative scoring of magnetic resonance imaging (MRI) of the brain. Kayser-Fleischer (KF) ring size decreased significantly during the 5-year study period (p < 0.0001). Although results of neurologic examination, speech pathology examination, and 24-h urine copper level analysis in symptomatic Wilson's disease patients improved during the study period, KF ring regression did not correlate with the improvement in these clinical parameters (p > 0.05). However, there was a correlation between MRI scores and KF ring regression (p = 0.02). Anticopper therapy with TM followed by zinc maintenance therapy is a safe and effective treatment for patients with neurologically symptomatic Wilson's disease. This treatment leads to reduction in KF ring size; however, KF ring reduction is not a good predictor of clinical improvement for patients with neuropsychiatric manifestations of Wilson's disease.

Simultaneous determination of urinary zinc, cadmium, lead and copper concentrations in steel production workers by differential-pulse anodic stripping voltammetry.

The determination of toxic metals in urine is an important clinical screening procedure. In this study, differential-pulse anodic stripping voltammetry on a hanging mercury drop electrode was used for the simultaneous determinations of zinc, cadmium, lead and copper in the urine of 23 production and 23 quality control workers in a steel production plant and their matched normal controls. The urine specimens were pre-treated with a mixed acid solution and Analytical Products Group set-point laboratory standards were used to check the analytical accuracy. The results indicated that the urinary zinc, cadmium, lead and copper levels of the production and quality control workers are significantly higher than those of the controls. The possible connection of these elements with the etiology of disease is discussed. The results also show the need for immediate improvements in workplace ventilation and industrial hygiene practices.

Zinc and copper levels in serum and urine: relationship to biological, habitual and environmental factors

Zinc and copper levels were determined in serum and urine of 434 subjects living in an industrial and an agricultural area of Tarragona Province, Spain. Zinc and copper concentrations were related to a range of factors such as sex, age, blood pressure, and drinking and smoking habits. Geometric mean serum zinc and copper concentrations were, respectively, 113.9 and 84 μg dl −1, while the mean values for urine zinc and copper concentrations were 698.7 and 26.6 μg g −1 creatinine. Serum zinc and copper levels and urine copper concentrations in men were significantly lower than in women, while there were no differences in serum or urinary zinc and copper levels with age. The consumption of alcohol significantly reduced the levels of zinc and copper in serum, whereas blood pressure had no influence on these values. The levels of zinc and copper in urine were not affected by the smoking and drinking habits, place of residence, or blood pressure. In general terms, the results of this study agree with previously reported values from different countries.

Failure of Simple Biochemical Indexes to Reliably Differentiate Fulminant Wilson's Disease From Other Causes of Fulminant Liver Failure

Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (< 0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (chi 2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of simple biochemical indexes to reliably differentiate fulminant Wilson's disease from other causes of fulminant liver failure

Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase–to–bilirubin ratio (<0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (χ2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis. Massively elevated hepatic copper stores with normal serum copper concentrations were seen in some patients; in others tissue copper concentration from different regions of the same liver varied up to 7-fold. Treatment with D-penicillamine in five patients had no observable beneficial effect. (HEPATOLOGY 1992;16:1206–1211.)

D-penicillamine prevents the development of hepatitis in Long-Evans Cinnamon rats with abnormal copper metabolism.

The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatocellular carcinoma. Because we found a corresponding gross copper accumulation in the liver of the rats, we examined whether the development of hepatitis in our rat system could be prevented by administration of D-penicillamine. D-Penicillamine is a copper-chelating agent and one of the drugs effective for human Wilson's disease, in which abnormal copper metabolism is also observed. The results show that D-penicillamine treatment inhibited the elevation of serum transaminases, suppressed abnormal histological changes in the liver and completely prevented the onset of hepatitis in the Long-Evans Cinnamon rats. We further found that the copper concentration in the liver and serum copper and ceruloplasmin levels were decreased, whereas the urinary copper level was increased in the D-penicillamine-treated Long-Evans Cinnamon rats. These findings demonstrate that the pathogenesis of hereditary hepatitis in Long-Evans Cinnamon rats is due to abnormal copper accumulation in the liver.