Allen C. Alfrey

Does iron affect osteoblast function? Studies in vitro and in patients with chronic liver disease

SummaryIn order to study the role of trace elements as potential osteoblastic toxins, we measured bone aluminum, copper, and iron in 106 ambulant patients with histologically proven liver disease. We used analytical and histochemical methods and we correlated our results with serum biochemistry, forearm and spinal bone density, and dynamic bone histomorphometry. Patients with chronic liver disease had higher iron-stained perimeters than control subjects (P<0.001). However, the mean ironstained perimeter was no greater than 5% of the total mineralized bone perimeter and did not correlate significantly with either the osteoblast perimeters or bone formation rates. The mean concentration of bone iron were 2.5 times (P<0.01) greater in the patients than in the controls although 80% of the patients fell within the normal range. There was a weak negative correlation between bone iron and the osteoblast perimeters (R=−0.18,P=ns) and between bone iron and bone formation (R=−0.30,P<0.05). There were 57 patients (56% of the total) with diminished bone formation, but only 16 had elevated bone iron concentrations. In a regression analysis, age, hypogonadism, and serum albumin concentrations were the most important predictors of osteoblast perimeters and bone formation rates.In vitro experiments using rat osteoblast-like osteosarcoma cells showed that an iron concentration of 400 μmol/liter was required to diminish cellular proliferation and function. Iron concentrations are elevated in the bones of patients with chronic liver disease. However, there is at present insufficient evidence that this metal is responsible for the osteoblast dysfunction seen in these patients. Bone aluminum and bone copper concentrations were within the relevant reference ranges in all patients.

Urinary iron speciation in nephrotic syndrome

In nephrotic syndrome, iron is presented to the tubule fluid in a nonreactive form in association with transferrin as a result of the glomerular protein leak. At an alkaline pH, iron remains bound to transferrin throughout the nephron and is excreted as such in the urine. As urine pH decreases below 6, iron is dissociated from transferrin. In the dissociated form, iron exists in the urine in a soluble, ultrafiltrable, and labile state. It is suggested that iron is maintained in this state by chelation to a relatively small organic compound, such as citrate. This non-transferrin-bound iron is capable of catalyzing bleomycin degradation of DNA, suggesting that this labile form of iron is able to catalyze free radical formation and cause tubule cell injury. Urine from proteinuric states represents one of the few, if not only, biologic fluids containing large amounts of reactive iron species. This may explain the mechanism by which proteinuric states cause tubulointerstitial disease and renal failure.

Trace Metals and Regular Dialysis

Although the emphasis on identifying uremic toxins has centered around organic compounds, it is now apparent that inorganic solutes also may be responsible for some of the symptomatology of the uremic state. The importance of such electrolyte disturbances as the cardiac and neuromuscular effects of hyperkalemia and hypermagnesemia, the extraskeletal calcification caused by hyperphosphatemia and hypertension induced by excess body sodium and water have been studied repeatedly. However, little attention has been directed toward trace element disturbances and their physiological consequences in dialyzed uremic patients.

Systemic toxicity of aluminum in man

Abstract Although systematic aluminum has clearly been shown to be toxic in humans, the evidence for a role in the pathogenesis of Alzheimers disease (AD) is lacking. In fact, given the relatively small concentrations of aluminum found in AD brains, and the clinical and anatomical dissimilarities between AD patients and other maladies with an established aluminum relationship, it seems unlikely that aluminum plays an important role in the pathogenesis of AD. More likely, the increased aluminum reported in AD brains is a result of damage associated with the disease and not a cause.

Phosphate and Prevention of Renal Failure

When a critical level of renal functional deterioration has occurred from a variety of different renal diseases, there is almost invariable progression to total loss of renal function. Ahlmen1 found that the median time for renal impairment to progress to end-stage disease after the plasma creatinine had increased to 5 mg/dl was six months in patients with diabetic nephropathy, ten months in patients with glomerulonephritis, and 14 months in patients with nonobstructive pyelonephritis.

Elemental Analysis in Murine Central Nervous System: Elevation of Rubidium Subsequent to Newcastle Disease Virus Encephalopathy

Abstract: The Cg strain of Newcastle disease virus (NDV) produces neurologic signs and death in mice. This illness is unusual because of the lack of typical features of a viral encephalitis. Specifically, there is a paucity of infectious virus, detectable cellular inflammatory reaction, cytopathic effect, and viral antigen by immunofluorescence. We previously showed an elevation of α‐aminoisobutyric acid in the CNS of moribund NDV‐infected mice, indicating cellular membrane dysfunction. In an attempt to further our understanding of the pathogenesis of the illness, we evaluated CNS concentrations of sodium, potassium, iron, copper, zinc, magnesium, selenium, and rubidium. Elemental analysis revealed no difference between infected and control mice for all elements except for rubidium, which was significantly elevated in infected mice. Elevation in rubidium was detected in infected mice by X‐ray fluorescence and atomic absorption spectrophotometry, whereas rubidium concentrations for control mice were similar by both methods. Neurologic symptoms correlated directly with rising rubidium concentrations. Our data suggest that abnormal trace element levels during viral infection may be one mechanism responsible for the clinical symptoms.