Primary hyperoxaluria

Primary hyperoxaluria is a rare condition (autosomal recessive), resulting in increased excretion of oxalate (up to 600mg a day from normal 50mg a day), with oxalate stones being common.

Primary hyperoxaluria
SpecialtyObstetrics and gynaecology, urology, medical genetics, endocrinology 

Pathophysiology

The buildup of oxalate in the body causes increased renal excretion of oxalate (hyperoxaluria), which in turn results in renal and bladder stones. Stones cause urinary obstruction (often with severe and acute pain), secondary infection of urine and eventually kidney damage.

Oxalate stones in primary hyperoxaluria tend to be severe, resulting in relatively early kidney damage (say teenage, early adulthood), which impairs the excretion of oxalate leading to a further acceleration in accumulation of oxalate in the body.

After the development of kidney failure patients may get deposits of oxalate in the bones, joints and bone marrow. Severe cases may develop haematological problems such as anaemia and thrombocytopaenia. The deposition of oxalate in the body is sometimes called "oxalosis" to be distinguished from "oxaluria" which refers to oxalate in the urine.

Kidney failure is a serious complication requiring treatment in its own right. Dialysis can control kidney failure but tends to be inadequate to dispose of excess oxalate. Renal transplant is more effective and this is the primary treatment of severe hyperoxaluria. Liver transplantation (often in addition to renal transplant) may be able to control the disease by correcting the metabolic defect.

In a proportion of patients with primary hyperoxaluria type 1 (about 5%), pyridoxine treatment (vitamin B6) may decrease oxalate excretion and prevent kidney stone formation.

Primary hyperoxaluria is an autosomal recessive disease, meaning both copies of the gene contain the mutation. Both parents must have one copy of this mutated gene to pass it on to their child, but they do not typically show signs or symptoms of the disease.

Diagnosis

Classification

There are three main types of primary hyperoxaluria, each associated with specific metabolic defects. Type 1 is the most common and rapidly progressing form, accounting for about 80% of all cases. Type 2 and 3 account for about approximately 10% each of the population.

Type OMIM Gene
PH1 259900 AGXT
PH2 260000 GRHPR
PH3 613616 HOGA1[1]

Mutations in genes causing PH1 and PH2 result in decreased production or activity of the proteins they make, which stops the normal breakdown of glyoxylate. While mutation in genes causing PH3 results in its overactivity, resulting in excess conversion of hydroxyproline to glyoxylate.[1]

Treatment

Increased water intake and alkalinization of urine is advised to prevent oxalates precipitation in urinary tract. Vitamin B6 (pyridoxine) is used for primary hyperoxaluria type1 as alanine glyoxylate transaminase require pyridoxine as cofactor. A restriction in oxalate intake is of limited use as the main source of oxalate is endogenous.[2]

Lumasiran is indicated for the treatment of primary hyperoxaluria type 1 (PH1) in adults and children of all ages and is available under the UK Early Access to Medicines Scheme (EAMS).[3] Lumasiran was approved for medical use in the European Union and in the United States in November 2020.[4][5]

See also

References
  1. Belostotsky R, Seboun E, Idelson GH, et al. (September 2010). "Mutations in DHDPSL are responsible for primary hyperoxaluria type III". Am. J. Hum. Genet. 87 (3): 392–9. doi:10.1016/j.ajhg.2010.07.023. PMC 2933339. PMID 20797690.
  2. https://iris.unito.it/retrieve/handle/2318/104759/16020/2012_Cochat_post-print.pdf
  3. "Lumasiran: Public Assessment Report (PAR)" (PDF). Medicines and Healthcare products Regulatory Agency (MHRA). Retrieved 17 October 2020. Contains public sector information licensed under the Open Government Licence v3.0.
  4. "Oxlumo EPAR". European Medicines Agency (EMA). Retrieved 26 December 2020.
  5. "FDA Approves First Drug to Treat Rare Metabolic Disorder". U.S. Food and Drug Administration (FDA) (Press release). 23 November 2020. Retrieved 23 November 2020. This article incorporates text from this source, which is in the public domain.
Classification
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