Oxalosis can be hereditary or acquired. Hereditary oxalosis, or primary hyperoxaluria, is a general term for at least three rare autosomal recessive disorders. Types I and II primary hyperoxaluria are alterations of glycoxalate metabolism resulting in the production of excess oxalate ions. Type III primary hyperoxaluria is caused by increased oxalate absorption by the gastrointestinal tract2
. All three types are characterized by chronic renal failure and usually death at a young age. In fact, prior to the advent of hepatorenal transplantation, 80% of patients with primary hyperoxaluria died by age 203
Acquired, or secondary, oxalosis exists in five sub-categories. Exogenous oxalosis is a well established side effect of the ingestion of oxalate, ethylene glycol, xylitol infusion, and methoxyflurane anesthesia. Enteric oxalosis describes the increased absorption of normal dietary oxalate in enteric diseases. Uremic oxalosis is associated with chronic renal insufficiency. Vitamin intake has also been linked to oxalosis. Dietary lack of cofactors such as pyridoxine and thiamine pyrophosphate has been implicated in deficiency oxalosis3
. Additionally, excessive intake of vitamin C has been found to cause oxalosis4
. The system-wide manifestations of the categories of oxalosis described above are similar as they all involve alterations in systemic oxalate metabolism. There is a subcategory to characterize the presence of oxalate deposits in the absence of oxalate metabolism alterations. This so-called dystrophic oxalosis has been associated with acute tissue injury, such as in the eye, or infection by oxalate producing micro-organisms, such as Aspergillus niger3
The involvement of several organs is typical in oxalosis not of the dystrophic type. Due to alterations in oxalate metabolism, deposits of calcium oxalate crystals are found first in the kidney and commonly in myocardium and thyroid follicles. In fact, the kidney, being the primary site of oxalate excretion, is always implicated. The findings described in this report are therefore unique for two reasons. Oxalosis of an atherosclerotic plaque has not previously been described. In addition, the oxalosis we observed, while not confined to a single organ, specifically did not involve the kidney.
All of the four cases described above share at least one rare commonality – the presence of calcium oxalate deposits in coronary atherosclerotic plaques, which, to our knowledge, has not previously been described. In addition, oxalosis in the absence of chronic renal insufficiency is a peculiar finding. All four of these patients suffered from chronic disease, including three with advanced AIDS. Yet, beyond this commonality, there is apparently no clear relationship between all four cases. These findings therefore raise several questions. Why has oxalate deposition in atherosclerotic plaques, seen four times in a single study, never been previously identified? If man’s only outlet for endogenous oxalate is renal excretion3
, why is there no renal involvement in these four cases? How should this type of oxalosis be classified?
Identification of Calcium Oxalate
The identification of oxalate by its optical properties is well established, most famously characterized by polarization microscopy. However, in the absence of polarization and specific chemical testing, randomly oriented and fragmented crystals may be difficult to interpret. The most frequent orientations in histological material have refractive indices very near that of the mounting medium3
. This contributes to poor visibility in ordinary light microscopy, which may account for a failure to identify oxalate when unsuspected. In addition, the von Kossa silver nitrate procedure, a popularly employed technique to identify calcium deposits, in fact stains the phosphate anion rather than the calcium cation. Due to the low solubility of calcium oxalate, it is expected that oxalate would have a lower threshold of positivity in von Kossa staining. Accordingly, the von Kossa procedure inconsistently stained oxalate in our trials (3/5 stains). Furthermore, if stained, the oxalate deposits no longer polarize, rendering them indistinguishable from ordinary phosphate deposits. Other chemical tests for calcium oxalate can be employed, such as Yasue’s silver nitrate-rubeanic acid method, Pizzolato’s mercurous nitrate method, and the napthalhydroxamic acid method3
. As an alternative, we employed an array of stains using alizarin red S. Staining with alizarin red S has distinct advantages beyond its ease and reliability. We employed an algorithm described by Proia et al to distinguish calcium oxalate from other calcium deposits, such as phosphate and carbonate1
. While we have not performed ultrastructural microanalysis, the histologic and histochemical tests utilized in this study have been shown to confidently identify crystalline deposits of calcium oxalate5
Oxalate Deposition and Renal Function
Also of primary interest is the apparent lack of correlation between the oxalosis we observed and renal involvement. The link between renal insufficiency and both renal tubular and myocardial oxalosis is well established6
. Additionally, studies of patients on hemodialysis indicate that the duration of renal failure contributes to the extent of oxalosis7
. Indeed, at the time of death these patients underwent acute system-wide organ failure. However, there was no history of chronic renal disease in any of the four cases. Recent BUN and creatinine levels confirmed this. Autopsy slides indicated no extensive renal disease and, more importantly, no oxalate deposition in renal tubules.
Classification of Oxalosis
The absence of oxalate in the kidneys of our patients is most surprising, given that the primary site of oxalate deposition in virtually all types of systemic oxalosis is the kidney. Kidney involvement is characteristic in cases of exogenous oxalosis, enteric oxalosis, hereditary oxalosis, and oxalosis in vitamin deficiencies. One rare and notable exception exists, so-called dystrophic oxalosis, defined as oxalate deposition without apparent disturbance in systemic oxalate metabolism3
. Dystrophic oxalosis has been reported in AIDS patients in the globe of the eye8
, the eyelids9
, and a renomedullary insterstitial cell tumor10
. Notably, 3 of our 4 cases had AIDS and were being treated with HAART.
An argument can be made that deposition of oxalate crystals in atherosclerotic plaques of coronary arteries is a form of dystrophic oxalosis. However, the oxalosis we observed was not limited to coronary arteries, but was in all cases also seen in the follicles of the thyroid as well as other sites, as described in each case. Therefore, the lesions we observed, not confined to a single organ, do not conform to the definition of dystrophic oxalosis. Since the pattern of involvement we observed has not been reported before, it is tempting to speculate that the oxalosis we observed represents an alternative oxalate metabolic pathway other than those currently described involving the kidney.
Oxalosis of the heart is a well studied phenomenon. Myocardial oxalosis has been linked to heart block11
and restrictive cardiomyopathy in primary hyperoxaluria12
. In secondary uremic oxalosis, Salyer et al reported myocardial lesions with involvement of intramural coronaries in the absence of atherosclerosis. Arterial wall oxalosis has also been described in primary and secondary oxalosis in association with peripheral gangrene13
. Arbus and Sniderman describe the deposits in the middle third of the media of large vessels. None of the above, however, describes intimal involvement or any association to atherosclerosis. What is unique about our findings is the presence of calcium oxalate within atherosclerotic plaques in the coronary arteries. Therefore, we feel that the lesions we observed are a distinct form of cardiovascular involvement in oxalosis - atherosclerotic oxalosis.