What Disease Causes Low Folate? Understanding the Root Causes

While dietary insufficiency is a common cause of low folate, many medical conditions can impair absorption, utilization, or increase the body's demand for this vital B vitamin. These underlying diseases can lead to a deficiency, even with adequate dietary intake, and can result in complications like anemia and fatigue.

Quick Summary

Several diseases can cause low folate levels, including malabsorption disorders like celiac and Crohn's disease, genetic mutations affecting metabolism, and chronic conditions such as liver or kidney disease. Certain medications can also interfere with folate absorption or function.

Key Points

• Malabsorption is a major cause: Digestive disorders like celiac disease and Crohn's disease prevent the small intestine from properly absorbing folate from food.

• Genetic factors can interfere: Mutations in the MTHFR gene can reduce the body's ability to convert folate into its active, usable form, even with adequate intake.

• Certain medical conditions increase demand: Chronic conditions like hemolytic anemia, kidney dialysis, liver disease, and some cancers raise the body's need for folate, leading to deficiency.

• Medications can disrupt folate levels: Certain drugs, including some anticonvulsants and chemotherapy agents, can block the absorption or utilization of folate.

• Alcoholism is a significant risk factor: Excessive alcohol use interferes with folate absorption in the gut and impairs the liver's ability to store it.

• Proper diagnosis is crucial: Since multiple diseases can cause low folate, a blood test and evaluation by a healthcare provider are necessary to identify the specific underlying cause.

Malabsorption Disorders Affecting the Digestive System

Folate is primarily absorbed in the small intestine, so any disease that damages the lining of the digestive tract or interferes with its normal function can lead to impaired absorption. This results in a deficiency regardless of how much folate is consumed through diet.

Celiac Disease

Celiac disease is an autoimmune disorder in which the ingestion of gluten leads to damage in the small intestine. This damage, known as villous atrophy, flattens the villi that line the intestine and are responsible for absorbing nutrients, including folate. A meta-analysis has confirmed that patients with inflammatory bowel diseases (IBD), which includes celiac, present lower folic acid levels than healthy adults.

Inflammatory Bowel Disease (IBD)

Chronic inflammatory conditions of the intestines, such as Crohn's disease and ulcerative colitis, can lead to widespread inflammation of the digestive tract. This inflammation can impair nutrient absorption, including folate, and can increase the body's metabolic demand for the vitamin. Crohn's disease, in particular, can affect any part of the digestive tract, further increasing the risk of malabsorption.

Gastric Bypass Surgery

Bariatric procedures like gastric bypass reduce the size of the stomach and alter the path of food through the small intestine. These changes can disrupt the normal process of nutrient absorption, placing patients at a significant risk for folate deficiency. In some cases, increased bacterial growth following surgery can also interfere with folate absorption.

Genetic Conditions Impairing Folate Utilization

Some people have inherited genetic variations that affect how their bodies process and utilize folate, even if they absorb enough from their diet.

MTHFR Polymorphism

The methylenetetrahydrofolate reductase (MTHFR) gene provides instructions for making an enzyme that is crucial for converting dietary folate into its active, usable form (5-MTHF). A genetic mutation in this gene can lead to a less active MTHFR enzyme, resulting in a reduced ability to convert folate. This can cause low levels of active folate in the body, leading to elevated homocysteine levels and other health issues.

Hereditary Folate Malabsorption

This is a rare inherited disorder caused by mutations in the SLC46A1 gene, which provides instructions for the proton-coupled folate transporter (PCFT) protein. A defect in this gene impairs both the absorption of folate from the intestine and its transport into the central nervous system. Symptoms often appear in early infancy and can include megaloblastic anemia, developmental delays, and seizures.

Chronic Diseases Increasing Folate Needs

Certain health conditions can increase the body's overall demand for folate, depleting stores faster than they can be replenished through diet alone.

Chronic Hemolytic Anemia

This blood disorder causes red blood cells to be destroyed faster than they can be produced. Folate is essential for the production of red blood cells, and the body's heightened demand to replace destroyed cells can quickly lead to a deficiency.

Kidney Dialysis

Patients undergoing long-term kidney dialysis may lose folate from their blood during the treatment process. In one study, folate deficiency was found in a significant percentage of chronic kidney disease patients on dialysis, highlighting the need for regular monitoring and supplementation.

Chronic Liver Disease and Alcoholism

The liver is the primary storage site for folate in the body. Chronic liver diseases, including those caused by alcohol abuse, can interfere with the liver's ability to store and process folate effectively. Excessive alcohol use also directly interferes with folate absorption and increases its excretion.

Cancer

Some types of cancer can cause folate deficiency by increasing the body's metabolic demand or through treatment side effects. Additionally, certain chemotherapy drugs, known as folate antagonists, are designed to interfere with folate metabolism to target rapidly dividing cancer cells.

Other Contributing Factors and Medications

In addition to chronic diseases, specific medications can interfere with folate levels.

Medications Known to Interfere with Folate

• Methotrexate: Used for cancer and certain autoimmune diseases, this drug is a folate antagonist.
• Sulfasalazine: Used for ulcerative colitis, this drug can impair folate absorption.
• Anticonvulsants: Medications like phenytoin and primidone can interfere with folate absorption and metabolism.
• Trimethoprim-sulfamethoxazole: This antibiotic can also inhibit folate metabolism.

Comparison of Disease Types Causing Low Folate

Feature	Malabsorption Disorders	Genetic Conditions	Increased Demand Conditions
Mechanism	Impairs the body's ability to absorb folate from the small intestine.	Disrupts the metabolic pathway for converting folate into its active form.	Increases the body's overall need for folate, depleting stores quickly.
Examples	Celiac disease, Crohn's disease, gastric bypass surgery.	MTHFR gene polymorphism, hereditary folate malabsorption.	Chronic hemolytic anemia, kidney dialysis, certain cancers.
Symptom Onset	Often gradual, alongside other digestive and nutritional issues.	Can be present from birth or develop later in life, sometimes with neurological symptoms.	Can be sudden or gradual, depending on the underlying condition.
Diagnosis	Often involves imaging, endoscopy, and blood tests for specific markers.	Genetic testing to identify gene mutations.	Monitoring blood counts, serum folate, and evaluating the underlying disease state.
Treatment	Managing the underlying digestive condition and supplementation.	Supplementation with the active form of folate (methylfolate).	Treating the primary condition and high-dose supplementation.

Conclusion

While a poor diet is a straightforward cause, many underlying diseases and genetic factors play a significant role in causing low folate levels. Conditions ranging from digestive disorders like celiac and Crohn's disease to genetic mutations like MTHFR can impair absorption or utilization. Furthermore, chronic illnesses such as hemolytic anemia, liver disease, and kidney disease requiring dialysis increase the body's demand for folate, making deficiency a real risk. Given the complexity of these causes, anyone experiencing persistent symptoms of folate deficiency should consult a healthcare professional for a proper diagnosis and tailored treatment plan. Addressing the root cause is essential for effective and lasting resolution. For more information, the NIH's Office of Dietary Supplements provides a comprehensive overview of folate [https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/].

Frequently Asked Questions

What is the primary medical reason for low folate levels?

The most common medical reasons for low folate include malabsorption issues stemming from digestive diseases like Celiac disease and Crohn's disease, and certain genetic mutations that affect how the body processes folate.

Can Crohn's disease or celiac disease cause folate deficiency?

Yes, both Crohn's disease and celiac disease can cause folate deficiency by damaging the intestinal lining, which prevents the proper absorption of nutrients like folate from food.

What role does the MTHFR gene play in folate deficiency?

A polymorphism in the MTHFR gene can make it difficult for the body to convert inactive folate into its active form, 5-MTHF, potentially leading to low levels of usable folate in the body.

Do kidney or liver diseases affect folate levels?

Yes, severe kidney problems requiring dialysis can cause folate loss during treatment, while chronic liver disease can reduce the liver's ability to store folate effectively.

Are there specific medications that cause low folate?

Several medications can interfere with folate, including the chemotherapy drug methotrexate, the antibiotic trimethoprim-sulfamethoxazole, and some anti-seizure medications like phenytoin.

What is hereditary folate malabsorption?

Hereditary folate malabsorption is a rare genetic disorder where mutations in the SLC46A1 gene impair both the intestinal absorption of folate and its transport into the central nervous system.

What are the common symptoms of low folate?

Symptoms can include fatigue, weakness, mouth sores, a red and sore tongue, irritability, and in severe cases, megaloblastic anemia.

How is folate deficiency treated when caused by an underlying disease?

Treatment involves addressing the underlying medical condition and typically includes high-dose folic acid supplementation. For genetic conditions like MTHFR polymorphism, a supplement with the active form (methylfolate) may be necessary.