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HYPEROXALURIA
BN APTE, S BHINGARDE
Genetic Department, MRC of Bombay Hospital,Mumbai 400 020.
INTRODUCTION
Hyperoxaluria is a disorder characterised by excessive excretion of calcium - oxalate in urine. Hyperoxaluria has been divided broadly into two classes. a) Primary hyperoxaluria and b) Secondary hyperoxaluria.[1,6]
Primary hyperoxaluria is a rare inherited disorder which results due to a block in the glyoxylate metabolism as shown in Fig. 1. The primary hyperoxaluria is subdivided into two types - primary hyperoxaluria type I and type II.[5,6] Type I hyperoxaluria is also known as glycolic aciduria as a large quantity of glycolic acid is excreted in urine together with oxalic acid. The patients with glycolic aciduria suffer from an inherited defect of the soluble enzyme alpha - ketoglutorate : glyoxylate carboligase which leads to an accumulation of glyoxylate and secondarily to increased biosynthesis of oxalate and glycolate. Patients with type II hyperoxaluria, excrete large amounts of D-glyceric acid in the urine, a compound not detectable in normal urine or in that of patients with type I hyperoxaluria. In type II hyperoxaluria there is a defect in the interconversion of D-glycerate and beta-hydroxypyruvate. D-glyceric acid dehydrogenase is the enzyme involved in the interconversion of D-glycerate to beta-hydroxypyruvate. It is suggested that D-glyceric acid dehydrogenase and glyoxylate reductase (enzyme involved in the conversion of glyoxylate to glycolate) are the same enzymes and that a block in the pathway from glyoxylate to glycolate produced by enzymatic defect leads to hyperoxaluria with reduced glycolic acid excretion. D-glyceric acid could also act as an inhibitor of glyoxylate reduc tase and lead to the same chemical consequences.[7,8]
Secondary or acquired hyperoxaluria, on the contrary, is due to abnormal nutritional state. This may result, from a) increased ingestion of oxalate or b) increased intake of oxalate precursors or c) pyridoxin deficiency or d) hyperabsorption of oxalate.
Nephrolithiasis and oxalosis may become manifest during the first year of life. Most patients experience initial symptoms of renal colic or haematuria between two and ten years of age and succumb because of uraemia before the age of 20 years. In patients with a delayed onset of symptoms, survival to age 50 or 60 has been reported. The symptoms of renal colic and uraemia which these patients develop are identical to those noted in patients with other kinds of calculi and renal disease. X-rays reveal radio-opaque calculi and nephrocalcinosis, but these findings are nonspecific.[9,10]
MATERIAL AND METHODS
The diagnosis of primary hyperoxaluria is based largely on the measurement of urinary oxalate excretion. However, we have used several approaches for the differential diagnosis of hyperoxaluria, into type I and type II.
Microscopy : Fasting urine and urine sample, three hours postmeal were collected for microscopy. The urine samples were centrifuged at 3000 rpm for 10 minutes. The precipitate was used for microscopic examination, which showed a large number of rhombus shaped calcium - oxalate crystals along with some intact and lysed RBCs.
Benzidine Test[11] : A saturated solution of benzidine in acetic acid was prepared. One ml of this reagent was added to two ml of urine sample mixed and one ml of 3% hydrogen peroxide was added. A bluish green colour indicated the presence of blood.
Fig1. Glyoxylate metabolism and sites of metabolic defects in hyperoxaluria type I and type II.
Thin Layer Chromatography[12-15] : The differential diagnosis of primary hyperoxaluria between type I and type II was done by performing thin layer chromatographic (TLC) analysis of urine samples for organic acids. In type I, primary hyperoxaluric patients, a fluorescent band of glycolic acid was seen on TLC, corresponding to the standard glycolic acid, when visualised under UV at 365 nm.
Quantitative estimation [16-17]: Excess excretion of oxalic acid was confirmed by quantitative estimation of oxalic acid in urine using titrimetric method. All patients showed oxalic acid concentration above the normal limits. The results are shown in Table 1.
Case Reports
We present here three cases of hyperoxaluria of typeI. These cases have been diagnosed and are being managed and followed by us for the past three years.
Case 1
AK, an 8 year old boy with short stature was presented to us with the complain of haematuria especially in the evening after vigorous exercise. The urine would be literally red in colour. The patient used to complain of pain in calf and abdomen and also had a lot of itching on his back.
Otherwise the boy was normal, good at school but rather hyperactive. There was no family history of the disease on either side.
Case 2
This is a rather unique and rare case. TM, a 5 year old girl was admitted to our hospital with a history of several episodes of generalised convulsions. She was thinly built and low in weight for her age. About a month before here admission to the hospital, just after going to sleep, she had woken up with a funny sensation in her throat, followed by unresponsiveness to oral commands. Her neck and left side had become stiff. The episode lasted for 30 minutes. There was no history of Koch’s or Koch’s contact. The episodes were preceded a few times with vomits.
Case 3
This is a case of primary hyperoxaluria type I with late on- set. PP, a 45 years old male came to use with a history of microscopic haematuria for several years. He had a lot of psoriasis like skin manifestations all over his body since 5 years of age. IVP was negative with no detectable calculus. CT had revealed a simple renal cortical cyst in the right kidney, which had not changed in size when compared to the previous years record. Left kidney was normal. Patient was non-diabetic.
RESULTS
All patients showed a large number of calcium oxalate crystals in urine. A positive benzidine test confirmed haematuria in all of them. Thin layer chromatographic analysis of urine samples of all the patients showed a strong fluorescent band of glycolic acid. The presence of glycolic acid in these patients, therefore, puts them in hyperoxaluria type I.
Quantitative estimation of oxalic acid was done by titrimetric method. The results of the analysis are shown in Table 1.
These patients are being managed on the following regimen. The adult patient is being given 250 mg BD of Pyridoxin and 5 mg BD of folic acid.
The two children are being given 100 mg BD of pyridoxin and 5 mg OD of folic acid. All of them are on low protein diet. All three patients have responded extremely well to our management procedure and are free of all the clinical manifestations of hyperoxaluria.
TABLE 1
Quantitative estimation of oxalic acid in urineSr. No Patient Oxalic acid mg% 1. AK 18 2. TM 12 3. PP 8 Normal range : 2.5 mg%
The haematuria in all these patients has disappeared. Occasionally oxalate crystals can be seen in a few of their concentrated urine samples. Psoriasis like skin manifestations in PP have practically disappeared. TM has had no episodes of vomiting or convulsions ever since. TM and AK have put on weight are doing very well in school, both physically and scholastically.
DISCUSSION
Oxalate is the major constituent of 65-75% of all kidney stones. A small fraction of patients with Ca-oxalate stones, however, have primary hyperoxaluria. Family studies indicate that both types of primary hyperoxaluria. Type I and type II, are inherited as autosomal recessive traits.[18-20] Although an autosomal recessive mode of inheritance seems most likely in this disorder, dominant inheritance has been suggested by some studies.[18-20]
Given the extensive damage and pain by hyperoxaluria and the relative lack of treatment option, less expensive alternatives must be exploited. A number of recent studies have supported a correlation between the absence of Oxalobacter formigenes in the gastrointestinal tract and the occurrence of hyperoxaluria. Given the possible existence of symbiotic relationship between Oxalobacter formigenes and its mammalian host, it is possible that a novel therapeutic and prophylactic approach to oxalate related illness might involve the introduction of oxalate reducing enzyme in human GI tract. The efforts are on, in this direction.[21]
Alanine-glyoxylate amino transferase deficient mouse has been developed.[21] This provides us a good model system for gene therapy of hyperoxaluria. With these and several other landmark advances in medicines we should have a complete solution to the problem of hyperoxaluria in the near future.
REFERENCES
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3. Hockaday TDR, Clayton JE, Frederick EW, Smith IH, Jr. Primary hyperoxaluria. Medicine 1964; 43 : 315.
4. Williams HE, Smith LH Jr. Disorders of oxalate metabolism. Am J Med 1968; 45 : 715.
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6.Donne MA. Tableau de differents depots de matieres salines et de substance organises qui se font les urines, presentant les caracteres propre a les dintinguer entre eux et a reconnaitre leure nature. CR Acad Sci (D) (Paris) 1938; 6 : 419.
7.Williams HE, IH Jt. Hyperoxaluria (L-glyceric aciduria). In Nyhan WI, ed, Amino Acid metabolism and Genetic Variation McGraw Hill, New York. 1967; 249-54.
8.Williams HE, Smith LH Jr. L-Glyceric aciduria. A new genetic variant of primary hyperoxaluria. New Eng J Med 1968; 278 : 233-39.
9.Williams HE, Smith LH Jr. Primary hyperoxaluria. In Stanbury JB, Wyngaarden JB, and Fredrickson DS, eds. The Metabolic Basis of Inherited Disease, 3rd edition, McGraw Hill, New York. 1972; 196-197.
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12.Bobbit JM. Reinhold publishing corporation/Chapman and Hall, New York and London, Thin Layer Chromatography. 1963.
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21.Hyperoxaluria. Website on Yahoo.com.
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