John T. McCall

Selenium Deficiency and Fatal Cardiomyopathy in a Patient on Home Parenteral Nutrition

An adult patient with chronic idiopathic intestinal pseudo-obstruction maintained on home parenteral nutrition for 6 consecutive years died from cardiomyopathy and ventricular fibrillation. Postmortem examination of the heart revealed widespread myocytolysis and replacement fibrosis similar to that seen in the selenium deficient cardiomyopathy in China (Keshan disease) and animal models. Selenium deficiency in this patient was documented with extremely low concentrations of selenium and decreased activity of the selenoprotein, glutathione peroxidase, in blood, heart, liver, and skeletal muscle. Reports of selenium deficient diets causing myocardial damage in humans and animals and the findings in our patient strongly suggest that his fatal cardiomyopathy was caused by selenium deficiency.

Trace Elements in Human Body Fluids and Tissues

Published figures for trace element concentrations in body fluids and tissues of apparently healthy subjects are widely divergent. For a considerable time, the apparent disparities were readily ascribed to biological sources of variation such as age, sex, dietary habits, physiological conditions, environmental exposure, geographical circumstances, or similar influences. Growing evidence, however, suggests that this interpretation may be seriously questioned in numerous instances. First, values obtained in reference materials leave no doubt that some previous studies must have been subject to gross analytical inaccuracies. Second, it has now been thoroughly documented that inadequate sample collection and manipulation may drastically distort the intrinsic trace element content of biological matrices. This review scrutinizes data reported by a number of investigators. In an effort to settle the currently flourishing confusion, critically selected reference values are set forth for trace element levels in human blood plasma or serum, packed blood cells, urine, lung, liver, kidney, and skeletal muscle tissue.

Diagnosis of Wilson's Disease Presenting as Fulminant Hepatic Failure

The clinical course, results of standard laboratory tests, parameters of copper metabolism, and hepatic morphology in 9 cases (3 of our own and 6 from the literature) of Wilsons disease presenting as fulminant hepatic failure were compared with the findings in 5 cases of idiopathic fulminant hepatic failure. Patients with Wilsons disease were usually younger, and 7 of the 9 patients had Kayser-Fleischer rings. Patients with idiopathic fulminant hepatic failure had elevated 24-h urinary copper, decreased ceruloplasmin, and low or normal serum copper. Fulminant hepatic failure with Wilsons disease differed from idiopathic fulminant hepatic failure by the following biochemical findings: (a) higher copper levels in serum, urine and liver; (b) less pronounced elevations of transaminase levels; (c) higher concentrations of total bilirubin; and (d) lower hemoglobin values. Serum copper was the most useful biochemical test in diagnosing Wilsons disease before death. At autopsy, only hepatic copper concentrations clearly separated the two groups. Serial serum copper levels (antemortem) and quantitative analysis of hepatic copper (after recovery or postmortem) in patients with fulminant hepatic failure should help to exclude Wilsons disease.

Pigmented Corneal Rings in Non-Wilsonian Liver Disease

Kayser-Fleischer rings are pigmented corneal rings at the limbus of the cornea in Descemets membrane that have been deemed pathognomonic of Wilsons disease. However, we have observed four exceptions in patients with non-Wilsonian liver disease. Three patients had primary biliary cirrhosis and one patient had chronic aggressive hepatitis with cirrhosis. Pigmented corneal rings were seen only by slit-lamp examination. Hepatic, serum, and urinary copper and serum ceruloplasmin levels were significantly elevated in the patients with primary biliary cirrhosis. Radiocopper (64Cu or 67Cu) studies in patients with primary biliary cirrhosis showed plasma disappearance curves which allowed a clear distinction from Wilsons disease in that all three patients with primary biliary cirrhosis showed a secondary rise in radiocopper that presumably represented copper incorporation into ceruloplasmin. In one patient, in whom 64Cu in ceruloplasmin was studied specifically, incorporation was found to be normal.

Ionic shift in cerebral ischemia.

Electrolyte and water contents were measured in gerbil brain after unilateral cerebral ischemia. Increase of Na+ and water, and decrease of K+ occurred after an ischemic period of 30 minutes. However, these abnormalities disappeared within 3 hours. When the ischemic period was extended to 3 hours, the abnormalities observed after ischemia for 30 minutes were again encountered, but more significant alterations occurred immediately after re-establishment of blood flow. In addition to more pronounced increase of Na+ and decrease of K+, Ca2+ became significantly elevated after recirculation for 15 minutes and progressively increased during recirculation for 3 hours. The steady rise of Ca2+ appears to be related to the irreversibility of cerebral ischemia.

Abnormalities of Chemical Tests for Copper Metabolism in Chronic Active Liver Disease: Differentiation from Wilson's Disease

Because identical clinical findings, alterations of hepatic function, and changes in hepatic morphology can occur in Wilsons disease (WD) and chronic active liver disease (CALD), chemical tests that reflect copper metabolism are important in the differential diagnosis of these conditions. The authors therefore measured 24-hr urinary copper excretion, hepatic copper concentration, and serum ceruloplasmin concentration in 54 patients with CALD. Twenty-four hour urinary copper excretion was increased in about 50% of patients, was significantly higher during active disease compared to remission, and was in the WD range in approximately 10% of patients. Hepatic copper concentration was also increased in the majority of patients, generally during active disease, and it sometimes overlapped with values reported in WD. By contrast, serum ceruloplasmin levels were elevated in nearly one-half the Cald patients and were never below normal. It is concluded that the chemical tests routinely used to assess copper metabolism in WD are frequently abnormal in CALD. Because the serum ceruloplasmin concentration never fell in the WD range and often was elevated, it is the most reliable routine chemical screening test to differentiate between CALD and WD.

Abnormalities in tests of copper metabolism in primary sclerosing cholangitis

Primary sclerosing cholangitis is a chronic, cholestatic syndrome characterized by fibrosing inflammation of the bile ducts that may lead to cirrhosis and death from liver failure. Previous reports have suggested abnormal hepatic copper metabolism in this disease. Therefore, in 70 patients, we prospectively determined the levels of hepatic copper, serum copper, and serum ceruloplasmin, and the rate of urinary copper excretion to assess the diagnostic and prognostic usefulness of these tests. Virtually all patients had at least one abnormal copper test. Hepatic copper levels were elevated in 87% of patients [292 +/- 38 micrograms/g dry wt (mean +/- SE)] and 24-h urinary copper levels in 64% of patients [135 +/- 15 micrograms/24 h (mean +/- SE)] to values comparable to those seen in Wilsons disease or primary biliary cirrhosis. In advanced histologic stages of primary sclerosing cholangitis, progressively higher mean levels of hepatic and urinary copper were found. In the liver, mean copper content (in micrograms per gram dry weight) in disease stages I and II was 147 +/- 36 (mean +/- SE); in stage III (fibrosis), 302 +/- 68; and in stage IV (cirrhosis), 379 +/- 69. In the urine, mean copper excretion (in micrograms per 24 h) in stages I and II was 72 +/- 14 (mean +/- SE); in stage III, 100 +/- 14; and in stage IV, 207 +/- 30. Higher hepatic and urinary copper levels at initial evaluation were associated with decreased survival during a median follow-up period of 2.6 yr: patients with hepatic copper greater than 250 micrograms/g dry wt and urinary copper excretion greater than 200 micrograms/24 h at initial evaluation had an 18-mo survival of less than 60%. We conclude that abnormal copper metabolism is a universal feature of primary sclerosing cholangitis, that hepatic copper accumulates and urinary copper excretion increases as the disease progresses, and that the hepatic copper concentration and the 24-h urinary copper determination are useful prognostic indicators in this disease.

Effect of d-Penicillamine on Copper Retention in Patients with Primary Biliary Cirrhosis

As part of a double blind, randomized trial evaluating D-penicillamine in primary biliary cirrhosis, we monitored urinary copper excretion and hepatic copper concentration during the 1st year of therapy in 46 patients with this disease. The retention of copper in primary biliary cirrhosis was confirmed by finding abnormally high levels of standard copper measurements in almost all patients before treatment. The hepatic copper was elevated in 43 of 45 patients, the urinary copper in 42 of 46, and the ceruloplasmin in 46 of 46. Urinary copper excretion correlated with the hepatic copper concentration (r = 0.68, P less than or equal to 0.001). No significant correlation occurred between hepatic copper and ceruloplasmin. Hepatic copper concentrations greater than 400 microng per g of dry weight were found almost exclusively in patients with advanced histological disease (P less than or equal to 0.01). Therapy with D-penicillamine and a low copper diet sustained increased urinary copper excretion for 1 year in almost all patients (P less than or equal to 0.001). Among patients taking placebo, the median hepatic copper concentration increased 13 microng per g of dry weight after 1 year. In contrast, among the patients taking D-penicillamine, the median hepatic copper concentration decreased 99 microng per g of dry weight (P less than or equal to 0.02). Continued observation of this therapeutic trial may help to clarify the relationship of copper retention and liver injury in primary biliary cirrhosis.

The endoneurial content of lead related to the onset and severity of segmental demyelination

The endoneurial lead and water content was serially evaluated in the nerves of rats fed lead carbonate and related to the onset and severity of segmental demyelination and remyelination. Lead began to accumulate significantly in the endoneurium by 5 days, reached a maximum level (71 μg/g dry weight) by 34 days, and then fell to the perineurial level (28 μg/g dry weight) by 3 months. The water content of endoneurium did not become significantly increased until the 50th day. Extensive teased fiber grading of pathologic abnormalities carried out on the same animals showed that segmental demyelination began between the 20th and 35th days and worsened progressively. This provides the first evidence that high endoneurial lead concentration precedes segmental demyelination and nerve edema. It suggests that the random Schwann cell damage is more likely to be due to a direct toxic effect of lead rather than to a factor associated with edema or increased endoneurial pressure. Contrary to our expectations, lead content does not parallel water content, as would be expected if lead entry into the endoneurium were associated with an abrupt breakdown of the blood-nerve barrier. A further new finding is the decrease in endoneurial lead content at a time when edema and the pathologic lesions are progressing. This may suggest the development of lead removal mechanisms.

Zinc nutrition in Crohn's disease

A prospective evaluation of zinc status was made in 63 randomly selected patients with Crohns disease. In the patients, mean serum and 24-hr urinary zinc values-105 μg/dl and 383 μg/day, respectively—were not different from controls. However, 46% of these patients had less than normal serum zinc and 36% had low urinary zinc excretions. Simultaneous reductions in both serum and urinary zinc were detected in 19% of patients. A direct correlation (P=0.01) was found between serum levels of zinc and the concentration of albumin, the major zinc-binding protein, in outpatients but not in hospitalized patients or patients with Crohns disease as a whole. Intake of zinc was surprisingly good—a mean intake of 13.4±1.4 mg/day. A significant (P=0.006) association was found between urinary zinc and the Crohns disease activity index but not between serum zinc concentration and this index. No association was found between zinc measurements and the presence or absence of fistulas, use of prednisone or sulfasalazine (Azulfidine), large bowel resections, and length of small bowel resected.