Ariboflavinosis: A Case of Cheilosis

Case scenario

A 30-year old male patient got admitted to the medical ward complaining of chapping and fissuring of the lips (cheilosis) along with a red, sore tongue. He also acknowledged the presence of a scaly and oily rash in the scrotal region. Other than that, he had very vague symptoms of mild headache and fatigue.

What could be his medical condition? In reality, it was difficult to come to a diagnosis straight away. However, we made sure to keep some form of a nutritional deficiency on top of our clinical suspicions.

Differential Diagnosis we had in mind

• Anemia
• Migraine
• Malabsorption and nutritional deficiencies
• Oral candidiasis
• Eczema
• Malignancy
• Seborrheic dermatitis

Cheilosis along with dermatitis is often a common presentation in Riboflavin/vitamin B2 deficiency. Was it really riboflavin deficiency that our patient suffered from? What evidence would support such a diagnosis? Let’s go into details to find out.

What is Riboflavin deficiency or Ariboflavinosis?

Riboflavin or vitamin B2 is a water-soluble, heat-stable nutrient that is widely available in both plant and animal cells alike.

Good sources of riboflavin include leafy vegetables, dairy products, and offal. Since it is a heat-stable vitamin it does not get destroyed in the process of cooking. However, it can easily get destroyed, when exposed to the sunlight.

Riboflavin is absorbed in the small intestine and the excess is excreted via urine. Urinary excretion of riboflavin may reduce with age and stress.

The Importance of Riboflavin

Riboflavin acts as an essential component in many metabolic pathways in the body. At the intracellular level, riboflavin combines with phosphate molecules and undergoes phosphorylation, giving rise to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).

Both FMN and FAD act as important cofactors in enzymatic reactions metabolizing energy. They promote the activity of coenzymes that participate in several oxidative and reductive energy reactions at the cellular level.

When severe riboflavin deficiency reduces levels of FAD and FMN in the body, it can affect the metabolism of other nutrients, especially other B vitamins.

Scientific data indicate that riboflavin provides many health benefits and is an essential vitamin for multiple physiological functions inside the body.⁽¹⁾

Some of the benefits of riboflavin may include;

• Act as an antioxidant; reduce the activity of reactive oxygen species and minimize oxidative injuries
• Decrease the formation of cataract
• Boost immunity
• Provide anti-inflammatory and anti-nociceptive benefits
• Reduce migraine
• Control malaria infection
• Reduce osteoporosis
• For cancer therapy
• Decrease the risk of pre-menstrual syndrome

Who are at the most risk of developing Ariboflavinosis?

The following groups of individuals are at the most risk of developing riboflavin deficiency.⁽²⁾

• Athletes who are vegetarians- Athletes who engage in a lot of physical exercises often need to maintain high levels of metabolism in the body. They require micronutrients like riboflavin to ensure the proper functioning of the metabolic pathways. Since vegetarian individuals tend to avoid animal food sources that are rich in riboflavin, they are more prone to develop signs of deficiency.
• Pregnant and nursing women- Since the physiological requirement for micronutrients rise during the periods of pregnancy and lactation, women who do not consume adequate amounts of vitamin sources may become deficient in vital nutrients.

However, it is important to ensure that such deficiencies do not arise during this period as studies indicate that pregnant mothers who have riboflavin deficiency are at the risk of developing pre-eclampsia like medical conditions.⁽³⁾

• Individuals who are vegan and do not consume dairy products– Meat and dairy products account for considerable amounts of riboflavin in the diet. Therefore, the lack of their consumption may contribute to developing riboflavin deficiency.
• Individuals with riboflavin transporter deficiency– In a rare neurological disorder called Brown-Vialetto-Van Laere or Fazio-Londe syndrome, individuals may develop riboflavin transporter deficiency that leads to impairment of absorption and transportation of the vitamin. This occurs due to a genetic mutation that impairs the encoding of riboflavin transporters.

Findings that we looked for in Clinical Examination

 The symptoms and signs of Riboflavin deficiency are diverse and can take many forms. Some of the manifestations of ariboflavinosis can be common to many avitaminosis and be non-specific. Furthermore, there is a chance that these manifestations could be due to a combination of overlapping nutritional deficiencies rather than just one.

The rest of the clinical presentations may be dermatologic, ocular, and developmental in nature. In more than half the cases of ariboflavinosis, ocular symptoms could precede all the others and can present in over 90 percent of the affected.⁽⁴⁾

Non-specific Clinical Manifestations of Ariboflavinosis

• Nervousness
• Irritability
• Anorexia
• Gastric discomfort
• Fatigue
• Dysphagia
• Sore throat

Dermatological Manifestations of Ariboflavinosis

• Cheilosis or chapping of the lips
• Maceration at the commissures of the lips
• Soreness of the lips and tongue
• Red tongue
• Mild seborrheic dermatitis in the nasolabial folds, on the alae nasi, and occasionally on the ears and eyelids.
• Pruritus of the vulva or scrotum
• Hair loss

Ocular Manifestations of Ariboflavinosis

• Circumcorneal congestion- One of the earliest signs
• Corneal vascularization
• Photophobia
• Ocular fatigue
• Opacification of the eye lens
• Dim vision
• Mydriasis (unusual dilatation of the pupils)
• Defects of accommodation
• Keratitis (inflammation of the cornea)
• Iritis (inflammation of the iris)

Developmental Abnormalities that may associate with Ariboflavinosis

• Deformities like the cleft lip and palate
• Growth Retardation in infants and children
• Congenital heart defects

How investigations could help us arrive at a diagnosis

Apart from the basic investigations to assess the overall health condition, there’s only a limited set of laboratory investigations that can be carried out to detect riboflavin deficiency. It is usually not a routine practice to measure levels of riboflavin in the body of healthy individuals.

However, specific investigations can be done in patients with symptoms suggestive of riboflavin deficiency. Such investigations may include;

1. Measuring the erythrocyte glutathione reductase coefficient

This test evaluates the ratio between erythrocyte glutathione reductase enzyme’s in vitro activity in the presence of FAD to that without added FAD.

A ratio of 1.2 or less is usually indicative of an adequate riboflavin status, while 1.2–1.4 of ratio would indicate marginal deficiency.  When the coefficient is greater than 1.4, it points towards riboflavin deficiency.⁽²⁾

However, this test cannot be done in patients with glucose-6-phosphate dehydrogenase deficiency, which represents about 10% of African Americans.

• Measuring the rate of urinary excretion of riboflavin

This test includes the fluorometric measurement of urinary excretion over 24 hours. Since the body stores only a small amount of riboflavin, the amount excreted via urine can be taken as an indicator for the dietary intake of the nutrient.

The total riboflavin excretion in healthy, riboflavin-replete adults is approximately about 120 mcg/day. If a person has an excretion rate of riboflavin less than 40 mcg/day, it indicates the presence of riboflavin deficiency.

The investigation findings of our patient came back suggesting that he was truly having riboflavin deficiency. How can we proceed from here onwards? What kind of management plan can be adopted?

Treating a patient with Ariboflavinosis

The best way to treat riboflavin deficiency is to replenish its deficit. This replenishment can be achieved via diet or supplementation.

Therapeutic Riboflavin Replenishment

Usually, a dose of riboflavin 5mg daily along with vitamin B complex can be given for treating common manifestations of Ariboflavinosis.⁽⁵⁾ However, this dose may vary depending on the age and individual circumstances.

Some medications can impair the absorption of riboflavin into the body. Therefore, it is important to pay attention and adjust the dosage in such instances.

Some of the commonly used medications that may interfere with riboflavin absorption resulting in reduced levels include; anticholinergic, anticonvulsants, phenothiazines, and phenytoin.

On the other hand, riboflavin can also interfere with the action of other medications like tetracycline, which is an antibiotic, and doxorubicin, a chemotherapy drug.

The Recommended Dietary Intakes of Riboflavin

Riboflavin dietary supplementation can be a great way of overcoming riboflavin deficiency in susceptible populations.

 Riboflavin supplements are available in a range of 25 mg, 50 mg, and 100 mg tablets.

The National Institutes of Health has put forward recommended daily nutrient intakes of riboflavin that vary according to different ages and sex.

The recommended daily nutrient intakes of riboflavin are as follows⁽⁶⁾;

• 1.3mg for men
• 1.1mg for women
• 1.3 mg for male adolescents (age 14 to 18)
• 1.0 mg for female adolescents (age 14 to 18)
• 1.4mg for pregnant women
• 1.6mg for lactating mothers
• 0.3mg for infants-age of 0 to 6 months old
• 0.4mg for 7 to 12 months old
• 0.5mg for 1 to 3 years old
• 0.6mg for 4 to 8 years old
• 0.9mg for 9 to 13 years old

Riboflavin supplements should be taken with meals as absorption levels tend to rise with food consumption.  

Riboflavin in the diet

It is important to consume food items rich in Riboflavin such as milk, eggs, lean meat, organ meat, green vegetables, and grains in the diet as much as possible. A majority of food sources contain riboflavin in the form of FAD except for eggs and milk that contain free riboflavin.

About 95% of riboflavin (in the form of FAD or FMN) from food sources we consume is bioavailable. This accounts for nearly 27 mg of riboflavin per meal or dose. However, sometimes only 15% of riboflavin will be absorbed into the body.

Since riboflavin is a water-soluble vitamin, a portion is already lost in preparation before consumption. A significant amount of the riboflavin content is lost in cooking water when foods are boiled and also when steamed or put in the microwave.

It is also important to limit the intakes of alcohol, food items and beverages higher in added sugars, saturated fat, and sodium as they would d interfere with the absorption process of riboflavin.

Can Riboflavin deficiency be completely reversed?

With adequate riboflavin supplementation and replenishment, the early clinical manifestations of ariboflavinosis can be easily reversed.

However, if riboflavin deficiency has already resulted in anatomical changes like the cataract formation, it will not be possible to reverse such conditions with mere vitamin supplementation and may require further therapeutic measures.

Conclusion

Despite being rare, Riboflavin deficiency or Ariboflavinosis does exist in the modern world, especially among individuals who consume meals with less nutritional value. However, on a positive note with early detection and timely intervention, this condition can be completely cured or at least minimized in severity with less or no long-term effects.

But it is crucial to keep in mind that riboflavin deficiency often may accompany other nutritional deficits as well, particularly that of the vitamin B complex. It is important to make sure that the entire nutritional status of the patient is clinically assessed and addressed where relevant, without focusing on just one nutritional component only.

References

1.         Suwannasom N, Kao I, Pruß A, Georgieva R, Bäumler H. Riboflavin: The health benefits of a forgotten natural vitamin [Internet]. Vol. 21, International Journal of Molecular Sciences. MDPI AG; 2020 [cited 2021 Apr 24].

2.         Riboflavin – Health Professional Fact Sheet [Internet]. [cited 2021 Apr 25]. Available from: https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/

3.         Wacker J, Frühauf J, Schulz M, Chiwora FM, Volz J, Becker K. Riboflavin deficiency and preeclampsia. Obstet Gynecol [Internet]. 2000 Jul [cited 2021 Apr 25];96(1):38–44. Available from: https://pubmed.ncbi.nlm.nih.gov/10862839/

4.         Sydenstricker VP. Clinical Manifestations of Ariboflavinosis*. 1941.

5.         Kumar and Clark’s Clinical Medicine – 9th Edition [Internet]. [cited 2021 Feb 13]. Available from: https://www.elsevier.com/books/kumar-and-clarks-clinical-medicine/kumar/978-0-7020-6601-6

6.         Fox IS. Riboflavin deficiency [Internet]. Vol. 2, British Medical Journal. StatPearls Publishing; 1942 [cited 2021 Apr 25]. p. 678. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470460/