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Hyperoxaluria, Primary, Type 1
Monday, 24 May 2004
Monday, 29 November 2004
Primary hyperoxaluria (excessive urinary oxalate), type 1 (PH1) is a rare metabolic disorder resulting from overproduction of oxalic acid. Oxalic acid, an organic acid, is a waste product produced by the body. In PH1, it accumulates in body organs, such as the kidney and can lead to kidney stones and progressive kidney failure. It was first identified in 1925.
PH1 is an autosomal recessive disease, an inherited genetic disorder where two defective genes are necessary. One in 100,000 children has PH1. Many children with PH1 may not have a family history of the disorder. However, if both parents are carriers of the defective gene, each pregnancy carries a 25% risk of that child developing the disease. Any race or ethnicity can be affected.
Signs and Symptoms
One-half of patients have symptoms by the age of 5 years. In PH1, excess oxalic acid binds to calcium, forming crystals. The crystals are deposited in every organ, except the liver. They are especially worrisome in the kidney, where oxalate is excreted, and forms kidney stones. Children may present with abdominal or back pain and blood in the urine with the passage of stones. They may also have urinary tract infections. High levels of oxalate and calcium oxalate crystals are also directly toxic to the cells of the kidney and result in progressive kidney dysfunction. Bones are another site for crystal deposition and this can cause bone pain, spontaneous fractures, and anemia. Other problems that the oxalate can cause include deposits in the blood vessels leading to mottling of the skin or, in severe cases, gangrene. Deposits can also cause irregular heart rhythms, and thyroid problems.
In a severe form of PH1 (infantile PH1), symptoms manifest in infants, around 4 months old. Patients with infantile PH1 do not have kidney stones, but instead have rapidly progressing renal failure. These babies often have anemia and poor growth due to their kidney disease.
In PH1, oxalic acid and another chemical, called glycolate, build up in the body because the enzyme necessary for their breakdown/metabolism is not working. This enzyme is found in liver cells and is called alanine/glyoxylate aminotransferease (AGT). The gene for AGT is located on chromosome 2. One-half of children with PH1 do not make this enzyme, whereas in the other half, it is present but does not function well. More than 30 mutations, or defects in the AGT gene, have been identified. However, the severity of the disease cannot be predicted by the type of mutation or degree of residual function of the enzyme. Some patients may be completely without symptoms.
Children with PH1 will have recurrent kidney stones. Analysis of the kidney stones will show large amounts of calcium oxalate crystals, which are only found in PH1. The diagnosis of PH1 is made by finding elevated levels of oxalate in the urine and blood. Glycolate levels are also elevated in 2/3 of patients. Definitive diagnosis can be made by performing a liver biopsy to check AGT activity. As there are numerous possible mutations, DNA analysis is not used for diagnosis. However, in a family where the disease is present, a pregnant mother may undergo chorionic villous sampling (placental tissue biopsy) to determine if the fetus has the same gene mutation.
Intake of plenty of fluids is important to decrease formation of calcium oxalate crystals which are more likely to form during dehydration. Supplementation with orthophosphate, potassium citrate, and magnesium may reduce kidney stone formation and calcium oxalate deposition in the body. These agents enhance the solubility of calcium oxalate. Avoiding foods with very high oxalate content, such as beet root, spinach, rhubarb, and ice tea is recommended. Animal products do not contain any oxalate. However, avoiding foods rich in oxalate has only a minimal effect on the amount of oxalate produced because patients with PH1 make such large amount of the chemical in their body. Protein restriction and vitamin C supplementation have not been shown to improve the disease.
One-third of patients with PH1, especially those with residual AGT activity, respond to treatment with pyridoxine. Pyridoxine (vitamin B6) is an important cofactor for AGT. A trial of at least 3mo will determine if the patient will respond to pyridoxine.
Patients in end-stage renal failure (ESRF) require dialysis. However, dialysis does not reduce the body oxalate burden. Oxalate will continue to accumulate in organs and form kidney stones.
In the past, kidney transplantation was performed. However, it was found that in majority of patients, the kidney disease reoccurred. Since the primary problem is in the liver, the transplanted kidney also becomes deposited with calcium oxalate crystals and gradually fails. Currently, combined liver/kidney transplantation is performed once the patient is in mild-moderate renal failure. Not all patients will require this. Liver transplantation replaces the AGT enzyme. After transplantation, the patient may have to continue to take potassium citrate to slowly clear accumulated body stores of calcium oxalate. In the future, gene therapy may afford replacement of the defective AGT gene without liver transplantation.
In patients who do not develop ESRF, prognosis is quite good. Approximately 20% of PH1 patients will develop ESRF by the age of 15 years and 50% of patients by the age of 25 years. Prognosis is worse in infantile PH1, where 50% of patients will have ESRF at diagnosis and 80% by the age of 3 yo. After combined liver/kidney transplantation, the five-year survival rates are about 80%.
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The Oxalosis and Hyperoxaluria Foundation
This is a well-constructed parent s foundation website with information, resources, advocacy.
Information about the disease provided by the Mayo Clinic s hyperoxaluria clinic.