Primary Hyperoxaluria Type 1 (PH1)
While kidney stones are the most common sign of primary hyperoxaluria type 1 (PH1), they do not occur in all patients.

Primary hyperoxaluria type 1 (PH1) is an extremely rare hereditary condition that is characterized by excessive oxalate formation—a waste product usually removed by the kidneys and discharged in the urine. Excess oxalate production can result in the accumulation of calcium oxalate crystals in the kidneys and urinary tract, which can lead to painful and recurring kidney stones, nephrocalcinosis, kidney failure, and systemic organ dysfunction. One to three people per million in the United States are diagnosed with PH1.

  • PH1 affects oxalate metabolism. Normally, oxalate is filtered by the kidneys and excreted in the urine. A genetic mutation in PH1 causes the liver to produce excess oxalate that accumulates in the kidneys and urinary system.
  • Excess oxalate in the tissues interacts with calcium to build poisonous calcium oxalate crystals. These crystals can form kidney stones, impeding kidney function over time. 
  • If neglected, this can progress to end-stage renal disease. Excess oxalate crystals may be accumulated throughout the body, including the eyes, bones, and joints (known as systemic oxalosis). 
  • Systemic oxalosis can trigger severe debilitating problems and impair growth and development.

PH1 can substantially affect the quality of life of individuals with this condition, as well as their families and caregivers. Depending on a patient’s kidney function, standard treatment may include supportive measures, dialysis, and a liver-kidney transplant.

What is the difference between PH1 and PH2 (PH1 vs. PH2)?

There are two types of hyperoxaluria: primary and secondary. Hyperoxaluria is a condition in which the urine contains an excessive amount of oxalate. Large amounts of oxalate in the body can cause serious health problems.

Primary hyperoxaluria (PH)

  • An uncommon hereditary (inherited) liver condition in which the liver either does not manufacture enough enzymes to avoid oxalate overproduction or the enzymes do not function effectively. 
  • There are three forms of PH, each involving a genetic deficiency in a different enzyme in the liver, and all of which contribute to oxalate overproduction.

Secondary hyperoxaluria

  • A disorder in which excessive oxalate is absorbed into the gastrointestinal (GI) tract and excreted in the urine. 
  • Consuming oxalate-rich foods or having medical conditions that allow the GI tract to absorb more oxalate (such as Crohn's disease, inflammatory bowel disease, gastric bypass, and other illnesses in which nutrients are not effectively absorbed) might induce higher absorption.

3 types of PH

  1. Primary hyperoxaluria type 1 (PH1)
    • Accounts for 85 percent of disease
    • Most severe form; overall, more than 70 percent of patients with PH1 develop end-stage kidney disease over time
    • Caused by mutations in the AGXT gene, causing dysfunction of the liver-specific peroxisomal enzyme—alanine glyoxylate aminotransferase
  2. PH2
    • Accounts for 8 to 10 percent of disease
    • Has a more benign course; no infantile oxalosis has been described, and end-stage kidney disease occurs at a relatively late age in about 20 percent of patients
    • Caused by mutations in the GHRPR gene, causing dysfunction of the cytosolic enzyme—glyoxylate/hydroxypyruvate reductase
  3. PH3
    • Accounts for 3.5 to 7 percent of disease
    • Most benign type with so far only a few reports of renal impairment and no end-stage kidney disease
    • Caused by mutations in the HOGA1 gene, causing dysfunction of the mitochondrial enzyme—4-hydroxy-2-oxoglutarate aldolase

SLIDESHOW

Kidney Stones: Symptoms, Causes, and Treatment See Slideshow

What are the symptoms of primary hyperoxaluria type 1 (PH1)?

Although kidney stones are the most common and sometimes the earliest sign of primary hyperoxaluria type 1 (PH1), they do not occur in all patients with PH1. Even if patients do not have stones, PH1 still puts the patient’s kidneys at risk.

Common signs and symptoms of PH1 include:

Symptoms of a kidney stone possibly due to PH1 may include:

Symptoms of PH1 that progresses from childhood to adulthood include:

  • Recurrent kidney stones
  • Progressive kidney disease (including kidney failure)
  • Multi-organ dysfunction

End-stage renal disease can develop as early as childhood and affects 50 percent of all children at the time of diagnosis. End-stage renal disease often affects people aged 25 to 40 years. When end-stage renal disease arises, additional symptoms may be noted including:

Symptoms and severity of PH1 might vary from patient to patient. The onset of symptoms spans from birth to the sixth decade of life (although there are exceptions). About 19 percent of patients with PH1 have a severe, extremely early-onset variant that manifests itself within a few months after birth. Some patients with PH1 are asymptomatic for almost 40 or 50 years. The average age of onset is about five to six years.

What causes primary hyperoxaluria type 1 (PH1)?

Primary hyperoxaluria (PH) is a genetic condition. In other words, people with PH diseases are born with mutations, or incorrect codes, in certain genes. As a result, they lack enzymes that keep their oxalate levels stable.

AGXT gene mutation

  • Mutations in the AGXT gene lead to primary hyperoxaluria type 1 (PH1). This gene instructs the body to produce an enzyme known as alanine-glyoxylate aminotransferase, which is present in liver cells (peroxisomes). It converts a compound known as glyoxylate into the amino acid glycine.
  • Mutations in the AGXT gene result in a reduction in the amount or activity of the enzyme, which prevents the breakdown of glyoxylate. Because of this, glyoxylate builds up and becomes oxalate rather than glycine. When too much oxalate is not eliminated from the body, it can combine with calcium to form calcium oxalate, which harms the kidneys and other organs, leading to life-threatening symptoms and conditions. 

Inherited

  • PH1 is an inherited condition, which means it is passed down through families. PH1 can affect members of the same family in various ways, including how the disease manifests and/or progresses. 

PH1 can occur in individuals of all ethnicities. Having a relative who is a carrier or who is affected can increase an individual’s risk of being a carrier.

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How is primary hyperoxaluria type 1 (PH1) diagnosed?

The first step to diagnosing primary hyperoxaluria type 1 (PH1) is to be aware of the signs and symptoms. Because of the similarities in presentation to other disease states, PH1 is frequently misdiagnosed or underdiagnosed.

If PH1 is suspected, there are a few ways that might aid in the diagnosis, which include:

24-hour urine test

  • Because of the nature of the condition, a urine test can be used to detect high oxalate levels. This test is beneficial in patients who have not reached the final stage of their renal disease.
  • Although a urine test cannot confirm the diagnosis of PH1, it can assist in further investigations.

Genetic testing

  • A genetic test is performed to find mutations to validate a PH1 diagnosis. If PH1 runs in the family, prenatal genetic testing can be used to make a diagnosis.

Other tests

Further examination is dependent on the baseline renal function at the time of diagnosis and the evaluations conducted as part of the diagnosis. Other tests that may be ordered by a physician include:

  • A glomerular filtration rate test to assess baseline renal function
  • Renal ultrasound and fundoscopic eye examination to check for oxalate deposition
  • Urinalysis
  • Measurement of plasma oxalate
  • Bone X-rays or bone marrow examination
  • Thyroid function testing
  • ECG, ultrasound, and/or CT scan of the heart and viscera
  • Blood tests to evaluate for anemia

Finding a diagnosis for a hereditary or rare disease is challenging. To determine a diagnosis, clinicians analyze a person's medical and family history and symptoms and perform a physical exam, as well as blood and urine testing. If no mutation is detected through genetic testing, clinicians may perform a liver biopsy. Because liver cells contain the enzyme required to avoid oxalate buildup, if no enzyme or not enough of it is present, this can aid in the diagnosis.

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How primary hyperoxaluria type 1 (PH1) might change over time?

Primary hyperoxaluria type 1 (PH1) is a severe, progressive, and potentially fatal condition. PH1 can cause significant renal problems. Hard oxalate crystals can migrate to other regions of the body when the kidneys fail. They can accumulate in the:

  • Bones
  • Skin
  • Eyes
  • Heart
  • Blood vessels
  • Central nervous system

The organs harmed by oxalate accumulation determine the subsequent phases of PH1. A person may experience significant, unpleasant, or life-threatening issues, such as:

  • Broken bones
  • Irregular heartbeat
  • Eye disease
  • Stroke
  • Enlarged liver
  • Peripheral neuropathy (a painful type of nerve damage)

People can develop symptoms of the condition at any age, from infancy to middle age. Patients might have the gene mutation for years and never notice any symptoms. They might not know they have PH1 until they are tested because someone else in their family has it.

Severe infantile form

  • Approximately 10 percent of patients with PH1 have symptoms in infancy or early childhood when they have severe calcium oxalate accumulation in their kidneys. 

Childhood or adolescent form

  • The majority of individuals with PH1 have their first symptoms in their childhood or early teen years.

Adult form

  • Some people do not realize they have the condition until they are adults, sometimes as late as their 50s. They may only find out if they continue to have kidney stone problems. Despite this, up to half of the adults with PH1 have severe renal disease.

Regardless of when a patient receives a PH1 diagnosis, they must work with their physician and begin treatment as soon as possible to avoid complications.

What are the treatment options for primary hyperoxaluria type 1 (PH1)?

Treatment of primary hyperoxaluria type 1 (PH1) aims to reduce calcium oxalate accumulation while maintaining renal function. Early detection and treatment are crucial for preserving kidney function for as long as feasible.

General treatment guidelines for PH1 patients

  • Stay optimally hydrated
  • Take potassium citrate orally
  • Take thiazides and other calcium-lowering medications
  • Limit the consumption of foods and drinks that are rich in vitamin C or D (they promote stone formation)
  • Take Dietary calcium supplementation depending on calcium levels

Treatment of kidney stones

Pyridoxine (Vitamin B6)

  • Used to reduce the formation of oxalate in the body. Although only 10 to 30 percent of patients with PH1 respond to pyridoxine treatment, it is recommended that all patients with PH1 receive a minimum three-month trial of pyridoxine.

Dialysis

  • There are some restrictions to dialysis for patients with PH1 to remove oxalate, but it may be necessary in some cases.

Organ transplantation

The ideal transplantation approach for patients with PH1 has been the subject of extensive debate among experts. Options may include:

  • Sequential liver-kidney transplant
  • Combined liver-kidney transplant
  • Isolated kidney transplant
  • Isolated liver transplant

FDA-approved drug

  • The FDA has approved the medication lumasiran for the treatment of PH1 to reduce oxalate levels in both children and adults.

Potential treatment options in the future

  • Oxalate degraders
  • RNA interference therapy
  • The adeno-associated viral vector of serotype 5 containing the human alanine-glyoxylate aminotransferase gene or cell therapy may be available for the treatment of PH in the future.

Coping with PH1

  • Living with a chronic disorder, such as PH1, can be stressful. Stress management is vital for physical and emotional well-being. Stress is a natural part of life, but too much stress can be harmful to one's health. A positive emotional outlook may help a person live longer and feel better. Maintain a positive attitude and continue to do things you enjoy. 

Finding support

  • Having people to lean on for support can be extremely beneficial when dealing with kidney disease, such as PH1. Don't be afraid to express feelings to others and seek help and support when necessary. Set up your support system or speak with a doctor about possible counseling sessions or support centers in nearby areas.

The treatment of choice for patients with PH1 is hyperhydration and intensive dialysis with or without organ transplantation and supportive/symptomatic care. Other significant organs that can be affected by calcium oxalate deposits should be routinely monitored in people with PH1.

Is primary hyperoxaluria type 1 (PH1) a curable condition?

The only method for curing patients with primary hyperoxaluria type 1 (PH1) is an organ transplant. However, it is not recommended for everyone. To try and slow the disease's progression, supportive measures can be implemented.

Patients with PH1 should be aware of the need to avoid specific things in addition to their treatment to avoid further complications. To protect their kidneys, patients should avoid dehydration.

Additionally, they should consult a doctor before taking excessive amounts of vitamin C, vitamin D, loop diuretics, nonsteroidal anti-inflammatory drugs, or any other drugs that could impair kidney function.

What is the prognosis of patients with primary hyperoxaluria type 1 (PH1)?

Primary hyperoxaluria type 1 (PH1) has varying rates of severity and outcome. The responsible gene (AGXT) may have particular mutations that are correlated with certain symptoms, disease progression and therapeutic response. 

Some people with PH1 respond to vitamin B6 (pyridoxine) treatment, whereas others do not. According to some research, specific mutations in the AGXT gene are linked to later-onset end-stage renal failure.

An early and accurate diagnosis, followed by aggressive supportive treatment, plays a significant role in both short- and long-term outcomes. 

Due to the variability in symptoms and age of onset, the prognosis of people with PH1 is less predictable, and it can quite often be poor, especially for those who experience symptoms early in their life. New therapies may improve the prognosis in the future.

What is the life expectancy of patients with primary hyperoxaluria type 1 (PH1)?

The life expectancy is extremely poor if primary hyperoxaluria type 1 (PH1) is not treated. PH1 causes progressive kidney failure without treatment, which results in death. 

End-stage kidney disease typically manifests in patients between the third and fifth decade of life. However, by the age of three years, end-stage kidney disease will be diagnosed in about 80 percent of patients with early onset. 

By the age of 15 years, 50 percent of people with childhood onset will have advanced kidney disease. Those with early-onset diseases run the risk of death within the first 10 years of life.

Some people with PH1 have lived normal or nearly normal life spans after organ transplant. Although combined liver-kidney transplantation can cure people with PH1, they must then confront the hurdles of lifelong immunosuppressive drugs and other organ transplant complications.

Patients with PH1 have a significant clinical burden, including kidney stones, urinary tract infections, fatigue/weakness and pain, and require repeated kidney stone operations, hospitalizations and emergency visits at various stages of renal disease. These complications underscore the severe morbidity and burden experienced by patients with PH1.

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Medically Reviewed on 10/28/2022
References
Image Source: iStock image

Primary Hyperoxaluria Type 1: https://www.ncbi.nlm.nih.gov/books/NBK1283/

Primary hyperoxaluria type 1: https://rarediseases.info.nih.gov/diseases/2835/primary-hyperoxaluria-type-1/

Primary Hyperoxaluria: https://rarediseases.org/rare-diseases/primary-hyperoxaluria/

Primary Hyperoxaluria Type 1: https://www.kidney.org/atoz/primary-hyperoxaluria

Primary hyperoxaluria: https://radiopaedia.org/articles/primary-hyperoxaluria