Any condition that causes calcium oxalate kidney stone disease or nephrocalcinosis and is associated with hyperoxaluria should be included in the differential diagnosis of primary hyperoxaluria type 3 (PH3).
Primary Hyperoxalurias
The three known types of primary hyperoxaluria (PH) are PH1 (due to mutation of AGXT), PH2 (mutation of GRHPR), and PH3 (mutation of HOGA1). Each gene encodes an enzyme for different metabolic pathways relevant for the metabolism of glyoxylate [Cochat & Rumsby 2013]. Oxalate accumulates as an end product in all forms of PH; however, the specific pathways that lead to its accumulation in PH3 require further clarification [Monico et al 2011, Riedel et al 2012, Williams et al 2012].
Of the primary hyperoxalurias, approximately 70% are PH1, 10% are PH2, 10% PH3, and 10% do not have an identified genetic cause [Hopp et al 2015]. The clinical manifestations of the three known types of PH overlap considerably.
In some individuals with PH3, significant stone manifestations have been observed in infancy and early childhood; these appear to have abated by later childhood or adolescence [Hoppe 2012, Hopp et al 2015].
Urine oxalate excretion rates tend to be lower in individuals with PH3 than in those with PH1 or PH2 [Monico et al 2011, Hopp et al 2015]. In PH3 urine oxalate excretion appears to be more variable over time. However, because of the overlap of urinary oxalate excretion in all three types, the type of PH (and thus the diagnosis of PH3) cannot be confirmed on this basis alone [Hopp et al 2015].
Hypercalciuria, observed in a subset of individuals with PH3, is not usually observed in PH1 and PH2 [Monico et al 2011, Williams et al 2012].
Hyperoxaluria of the degree observed in individuals with primary hyperoxaluria causes deposition of calcium oxalate crystals in the kidney (nephrocalcinosis) associated with inflammation, kidney damage, and often chronic kidney disease and/or end-stage renal disease (ESRD). ESRD appears to be unusual in PH3, having been reported in just one individual to date [Hopp et al 2015]; however, modest renal impairment has been described in other cohorts [Allard et al 2015].
Systemic calcium oxalate deposition (systemic oxalosis) may develop due to high levels of plasma oxalate in patients with PH who have advanced CKD. Systemic oxalosis results in varying degrees of organ dysfunction including infiltrative cardiomyopathy, arrhythmias due to involvement of the cardiac conduction system, erythropoietin-resistant anemia due to extensive crystal deposition in the bone marrow, pathologic fractures, and/or retinal oxalate deposition [Hoppe et al 2009]. Systemic oxalosis has not yet been reported in any individual with PH3, an observation consistent with the infrequency of end-stage renal disease (ESRD) in PH3.
Differences in urinary metabolites other than oxalate can provide clues regarding the most likely type of PH.
Urine glycerate is increased in most individuals with PH2; however, exceptions (perhaps related to the
sensitivity of the testing process) occur [
Rumsby et al 2001].
See OMIM Primary Hyperoxaluria Phenotypic Series to view genes associated with this phenotype in OMIM.
Idiopathic calcium oxalate stone disease can be associated with mild hyperoxaluria. The hyperoxaluria is typically of a lesser degree (<0.6 mmol/day) than that observed in the primary hyperoxalurias, is variable from one collection to the next, and is frequently associated with mild hypercalciuria.
Secondary Hyperoxalurias
Secondary forms of hyperoxaluria are not uncommon and should be systematically considered.
Dietary or other sources of excessive oxalate or oxalate precursors should be considered in the differential diagnosis. Very high doses of vitamin C are a potential cause. Exposure to toxins such as ethylene glycol can cause marked hyperoxaluria and associated acute renal failure.
Enteric hyperoxaluria results from any cause of fat malabsorption in the small intestine. In the colon, this undigested fat combines with calcium and decreases the amount of calcium available to bind to oxalate. This free oxalate is absorbed. In addition, fatty acids that are not absorbed in the small intestine can damage the colonic mucosa, leading to further increase in oxalate absorption. Thus, any gastrointestinal disease or surgery that impairs fat absorption is a potential cause of enteric hyperoxaluria [Kumar et al 2011]. Hyperoxaluria resulting from short bowel syndrome and following malabsorptive types of gastric bypass surgery can be quite marked, overlapping the range seen in inherited PH of all types.
Medications that interfere with fat absorption from the GI tract (e.g., orlistat) can be associated with hyperoxaluria.
Marked deficiency of dietary calcium, leaving a greater proportion of oxalate free in the intestinal lumen, can result in increased absorption of oxalate resulting in hyperoxaluria.
Nephrocalcinosis of prematurity occurs in a significant proportion of infants born prior to 28 weeks' gestation and is characterized by both nephrocalcinosis and nephrolithiasis [Habbig et al 2011]. Risk factors among premature infants thought to contribute to this disease include urine oxalate that is higher than that observed in infants born at term [Schell-Feith et al 2010] as well as hypercalciuria and hypocitric aciduria. Calcium oxalate crystals have been detected in the renal parenchyma [Schell-Feith et al 2010]. Since individuals with PH3 can develop stones in infancy or during early childhood [Hoppe 2012, Matsumoto & Milliner 2015], there may be confusion with stones or nephrocalcinosis related to prematurity.