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43 Primary Hyperoxalurias 43 Primary Hyperoxalurias Pierre Cochat, Marie-Odile Rolland 43.1 Primary Hyperoxaluria Type 1 – 541 43.1.1 Clinical Presentation – 541 43.1.2 Metabolic Derangement – 542 43.1.3 Genetics – 542 43.1.4 Diagnosis – 542 43.1.5 Treatment and Prognosis – 542 43.2 Primary Hyperoxaluria Type 2 – 545 43.2.1 Clinical Presentation – 545 43.2.2 Metabolic Derangement – 545 43.2.3 Genetics – 545 43.2.4 Diagnosis – 545 43.2.5 Treatment and Prognosis – 545 43.3 Non-Type 1 Non-Type 2 Primary Hyperoxaluria – 545 References – 545 540 Chapter 43 · Primary Hyperoxalurias Oxalate Metabolism Oxalate is a poorly soluble end-product of the metabo- verted into oxalate by lactic acid dehydrogenase (LDH); lism of a number of amino acids, particularly glycine, it can also be converted into glycolate by glyoxylate and of other compounds such as sugars and ascorbic reductase (GR) and into glycine by glutamate: glyo- acid. The immediate precursors of oxalate are glyo- xylate aminotransferase (GGT). Glycolate can also xylate and glycolate (. Fig. 43.1). The main site of syn- be formed from hydroxypyruvate, a catabolite of glu- thesis of glyoxylate and oxalate is the liver peroxisome, cose and fructose. Hydroxypyruvate can be con- which can also detoxify glyoxylate by reconversion into verted into L-glycerate by LDH and into D-glycerate glycine, catalyzed by alanine: glyoxylate aminotrans- by hydroxypyruvate reductase (HPR), which also has ferase (AGT). In the cytosol, glyoxylate can be con - a GR activity. X . Fig. 43.1. Major reactions involved in oxalate, glyoxylate and HPR, hydroxypyruvate reductase; LDH, lactate dehydrogenase; glycolate metabolism in the human hepatocyte. AGT, Alanine: X, metabolic block in primary hyperoxaluria type 1 (PH1), O, meta- glyoxylate aminotransferase; GGT, glutamate: glyoxylate amino- bolic block in primary hyperoxaluria type 2 (PH2) transferase; GO, glycolate oxidase; GR, glyoxylate reductase; . Fig. 43.2. Bone histology in primary hyperoxaluria type 1: calcium oxalate deposition shown by polarized light microscopy 541 43 43.1 · Primary Hyperoxaluria Type 1 Renal Involvement Primary hyperoxalurias (PH) are rare diseases which are PH1 presents with symptoms referable to the urinary tract characterized by overproduction and accumulation of in more than 90% of the cases: loin pain, hematuria, urinary oxalate in tissues. tract infection, passage of stones, nephrocalcinosis, uremia, PH1 caused by deficiency or mistargeting of alanine: metabolic acidosis, growth delay, and anemia. Oxalate ex- glyoxylate aminotransferase (AGT) in liver peroxisomes erts a toxic effect on mitochondrial function of renal epithe- is the most frequent and most severe form. Deposits lial cells and therefore leads to direct tubular damage [2]. of calcium oxalate crystals in the kidney lead to stones, However, the most common presentation is stone disease. nephrocalcinosis and deteriorating kidney function, Calculi – multiple, bilateral and radio-opaque - are made of while bone disease is the most severe extrarenal in- calcium oxalate. Nephrocalcinosis, best demonstrated by volvement. Careful conservative treatment (high fluid ultrasound, is present on plain abdomen x-ray at an ad- intake, calcium-oxalate crystallization inhibitors, and vanced stage. pyridoxine) should be started early as it may prolong The median age at initial symptoms is 5 to 6 years, kidney survival. Liver and kidney transplantation are ranging from birth to the 6th decade. End-stage renal dis- the final current options. Hyperoxaluria and hyper- ease (ESRD) is reached by the age of 25 years in half of glycoluria are indicative of PH1. patients [1]. PH2, caused by glyoxylate-reductase (GR) deficien- The infantile form often presents as a life-threatening cy in the liver and other tissues, is less frequent and less condition because of rapid progression to ESRD due to severe, and treatment less demanding. Hyperoxaluria both early oxalate load and immature glomerular filtration without hyperglycoluria and increased urinary excre- rate (GFR): one-half of the patients experience ESRD at tion of L-glycerate differentiate it from PH1. the time of diagnosis and 80 % develop ESRD by the age of In addition, there are isolated reports of PH with- 3 years [3, 4]. out either AGT or GR deficiency, so that it is likely that there is at least another form of PH (PH3) yet to be Extrarenal Involvement explained. When GFR falls to below 30 to 50 ml/min per 1.73 m2, continued overproduction of oxalate by the liver along with reduced oxalate excretion by the kidneys leads to a critical Primary hyperoxaluria (PH) results from endogenous saturation point for plasma oxalate (Pox >30 to 50 µmol/l) overproduction of oxalic acid and accumulation of oxalate so that oxalate deposition occurs in many organs [5]. within the body. The main target organ is the kidney since Bone is the major compartment of the insoluble oxalate oxalate is excreted in the urine leading to nephrocalcinosis, pool and the bone oxalate content is higher (15 to 910 µmol recurrent urolithiasis and subsequent renal impairment. oxalate/g bony tissue) than among ESRD patients without Primary hyperoxaluria is associated with increased urinary PH1 (2 to 9 µmol/g). Calcium oxalate crystals accumulate excretion of glycolate in PH1, and of L-glycerate in PH2 first in the metaphyseal area and form dense suprametaphy- (. Fig. 43.1). Secondary hyperoxaluria also occurs and is seal bands on x-ray. Later on, oxalate osteopathy (. Fig. attributed to increased intestinal absorption or excessive 43.2) leads to pain, erythropoietin-resistant anemia, and intake of oxalate. spontaneous fractures. Along with the skeleton, systemic involvement includes many organs because of progressive vascular lesions: heart 43.1 Primary Hyperoxaluria Type 1 (cardiomyopathy, arrhythmias, and heart block), nerves (polyradiculoneuropathy), joints (synovitis, chondrocalci- 43.1.1 Clinical Presentation nosis), skin (calcium oxalate nodules, livedo reticularis), soft tissues (peripheral gangrene), retina (flecked retinopa- PH1, is the most common form of PH. Five different pres- thy) and other visceral lesions (e.g. intestinal infarction, entations are described: i) a rare infantile form with early hypothyroidism) [1]. nephrocalcinosis and kidney failure; ii) a late-onset form Systemic involvement – named oxalosis – is responsible with occasional stone passage in late adulthood; iii) the for poor quality of life leading to both disability and severe most common form with recurrent urolithiasis and pro- complications. Indeed PH1 is one of the most life-threaten- gressive renal failure leading to a diagnosis of PH1 in child- ing hereditary renal diseases, mainly in developing coun- hood or adolescence; iv) a rare condition where the diagno- tries where the mortality rate may reach 100% in the absence sis is first made following recurrence in a transplanted kid- of adequate treatment [1]. ney; and v) pre-symptomatic subjects in whom PH1 is discovered from family history [1]. 542 Chapter 43 · Primary Hyperoxalurias 43.1.2 Metabolic Derangement polymorphism which plays an important role in pheno- type determination [13]. DNA analysis among different PH1 is due to a deficiency or to a mistargeting to the mito- ethnic groups has revealed the presence of specific muta- chondria of the liver-specific pyridoxal-phosphate-depen- tions, founder effects and phenotype-genotype correla- dent peroxisomal enzyme AGT [6]. The resulting decreased tions among North-African, Japanese, Turkish and Paki- transamination of glyoxylate into glycine leads to subse- stani populations [18]. quent increase in its oxidation to oxalate, a poorly soluble end-product. In patients with a presumptive diagnosis of PH, 10 to 30% are identified as non-PH1 because AGT ac- 43.1.4 Diagnosis tivity and immunoreactivity are normal [7]. Among PH1 patients, 75% have undetectable enzyme activity (enz-) and The diagnosis of PH1 is still being often delayed for years the majority of these also have no immunoreactive protein following initial symptoms. The combination of both clini- (cross reacting material, crm-). In the rare enz-/crm+ pa- cal and radiological signs is a strong argument for PH1, i.e. tients, a catalytically inactive but immunoreactive AGT is the association of renal calculi, nephrocalcinosis and renal found within the peroxisomes. The remaining PH1 patients impairment; family history may bring additional informa- have AGT activity in the range of 5 to 50% of the mean tion. Crystalluria and infrared spectroscopy are of major normal activity (enz+), and the level of immunoreactive interest for identification and quantitative analysis of crys- protein parallels the level of enzyme activity (crm+). In tals and stones, showing calcium oxalate monohydrate crys- enz+/crm+ patients, the disease is caused by a mistargeting tals (type Ic whewellite) with a crystal number >200/mm3 of AGT: about 90% of the immunoreactive AGT is localized in case of heavy hyperoxaluria [19]. Such crystals can in the mitochondria instead of in the peroxisomes, where also be identified in urine or tissues by polarized light mi- only 10% of the activity is found; almost all patients who are croscopy or infrared spectroscopy. Fundoscopy may show pyridoxine-responsive are in this group [8]. Interestingly, flecked retina. human hepatocyte AGT, which is normally exclusively lo- In patients with normal or significant residual GFR, calized within the peroxisomes, is unable to function when concomitant hyperoxaluria and hyperglycoluria are indica- diverted to the mitochondria. However patients with a tive of PH1, but some patients do not present with hyperg- X primary peroxisomal disorder – e.g. Zellweger syndrome lycoluria. In dialysed patients, plasma oxalate (± glycolate): – do not exhibit hyperoxaluria. creatinine ratio and oxalate (± glycolate) measurement in dialysate may be contributive [20]. A definitive diagnosis of PH1 requires the measurement 43.1.3 Genetics of AGT activity in a liver biopsy. Despite controversial in- formation about the relationship between AGT activity and PH1 is the most common form of PH (1:60,000 to 1:120,000 the severity of the disease [11], liver biopsy assessment is live births per year in Europe) [1, 9].
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