What is Primary Hyperoxaluria?
Primary hyperoxaluria (PH) is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate, a natural chemical in the body that is normally eliminated as waste through the kidneys. In patients with PH, the kidneys primarily excrete all oxalate, which is produced in the liver. However, there is such a buildup of oxalate in the urine, that a damage mechanism is activated leading to kidney failure. Then, the kidneys are no longer able to eliminate the large amount of oxalate that is produced, which accumulates not only in the kidneys, but everywhere in the body.
The three known types of PH (types 1, 2, and 3) each result from a mutation in a specific gene; “no mutation detected” (NMD) PH or idiopathic PH (IPH) is when doctors cannot determine the identity of the gene responsible for the disease. The three genetically known types of PH are:1,2
- PH1, which is caused by a mutation in the AGXT gene, leading to a deficiency of the enzyme alanine:glyoxylate-aminotransferase (AGT)
- PH2, which is caused by a mutation in the GRHPR gene, resulting in a deficiency of the enzyme glyoxylate/hydroxypyruvate reductase (GR/HPR)
- PH3, which is caused by a mutation in the HOGA1 gene, causing a deficiency of the enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA)
Download the PH Infographic to learn more about PH, including signs and symptoms, progression of PH, and current treatment options.
Signs and Symptoms
Hyperoxaluria occurs when you have too much oxalate in your urine. Oxalate is a natural chemical in your body, and it’s also found in certain types of food. But too much oxalate in your urine can cause serious problems. Patients with decreased renal function may also experience oxalosis, which involves a build-up of oxalate in other organs, such as the bone, skin, heart, and retina, possibly causing other concomitant, happening at the same time, debilitating complications.
The three types of PH differ in terms of symptoms. To the right is a list of potential signs and symptoms of PH, which can have varying levels of severity depending on the type. Patients with PH may not experience all of the symptoms listed to the right.
Often, the first sign of hyperoxaluria is a kidney stone. Symptoms of a kidney stone can include:
- Severe or sudden back pain
- Pain in the area below the ribs on the back (flank) that doesn’t go away
- Blood in the urine
- Frequent urge to urinate
- Pain when urinating
- Chills or fever
- Kidney damage
- End-stage renal disease and injury to other organs
- Blood in urine
- Urinary tract infections
- Retinal calcifications, resulting in vision problems
- Cardiac failure
- Bone fractures
- Skin calcifications, resulting in painful skin nodules and necrosis
Unmet Medical Need
Currently, there is no approved specific therapy for the treatment of PH, so that patients are currently treated with hyper-hydration and medication to attempt to increase solubility of oxalate in urine. However, PH can eventually damage your kidneys. Oxalosis in its late stages can cause a variety of complications outside the kidney known as systemic oxalosis, including bone disease leading to fractures, anemia (lack of red blood cells in your blood, causing tiredness, weakness, and other symptoms), skin ulcers or sores, heart and eye problems, and in children, a failure to develop and grow normally.
Patients with severe PH sometimes must undergo both liver and kidney transplants, which are major surgical procedures, and subsequently must take immunosuppressant drugs for the rest of their lives.
Incidence and Prevalence
- PH has a prevalence of 1-3 cases per million individuals and an incidence of 1 in 120,000 live births1
- The estimated genetic prevalence for each type of PH is:1
- PH1: in 151,887
- PH2: in 310,055
- PH3: in 135,866
- The median age at the first appearance of PH1 symptoms is 5.8 years2
- The median age at diagnosis of PH1 is between 4.2 and 11.5 years, depending on whether nephrocalcinosis (calcification [hardening of tissues within the body] in the renal parenchyma [the functional part of the kidney]) is present3
- Fifty percent of patients with PH1 reach end-stage renal disease (ESRD) by their mid-30s4
- PH1 is too often missed in patients with recurrent stone disease or in siblings with PH1, and may consequently lead to a high rate of diagnosis at an adult age among individuals with end-stage renal disease (ESRD)2
- The first symptoms of PH2 generally appear at a similar age as in patients with PH15,6
- Nephrocalcinosis occurs in 12 percent of patients with PH2, and is less common than in those with PH16-8
- PH3 accounts for approximately 10 percent of genetically characterized cases of PH1
- Approximately 50 percent of individuals with PH3 develop a kidney stone prior to the age of 5 years9,10 and experience multiple stone removals before receiving a PH diagnosis
- Kidney function in patients with PH3 appears to be better preserved in individuals with PH3, compared to those with PH1 or PH21, though long-term follow-up is currently being done to assess the development of chronic kidney disease
Progression of PH11
Note: PH can have varying levels of severity depending on the type
- Hopp K, Cogal A, Bergstralh E, et al. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. Journal of the American Society of Nephrology 2015; 26(10):2559-2570.
- van der Hoeven SM, van Woerden CS, Groothoff JW. Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. Nephrology, Dialysis, Transplantation 2012; 27(10):3855-3862.
- Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney International 2015; 87:623-631.
- Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010. Available at: http://www.rarekidneystones.org/hyperoxaluria/physicians.html. Accessed March 13, 2019.
- Cochat P, Rumsby G. Primary hyperoxaluria. New England Journal of Medicine 2013; 369:649-658.
- Rumsby G, Hulton SA. Primary hyperoxaluria type 2. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle, WA, University of Washington, 2008. Updated 2017. Available at: https://www.ncbi.nlm.nih.gov/books/NBK2692/. Accessed March 13, 2019.
- Hoppe B. An update on primary hyperoxaluria. Nature Reviews Nephrology 2012; 8:467-475.
- Leumann E, Hoppe B. The primary hyperoxalurias. Journal of the American Society of Nephrology 2001; 12:1986-1993.
- Milliner DS, Harris PC, Lieske JC. Primary hyperoxaluria type 3. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle, WA, University of Washington, 2015. Available at: https://www.ncbi.nlm.nih.gov/books/NBK316514/. Accessed March 13, 2019.
- Monico CG, Rossetti S, Belostotsky R, et al. Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clinical Journal of American Society of Nephrology 2011; 6:2289-2295.
- NIH. Primary hyperoxaluria. 2018 Available at: https://ghr.nlm.nih.gov/condition/primary-hyperoxaluria#. Accessed April 13, 2018.