A 45 –year-old male, a known alcoholic from the previous 10 years reported to the physician for consultation. He complained of burning of eyes and a sore tongue. There was history of reduced appetite and mild abdominal discomfort.
The examination revealed cracks on the lips and in the corners of the mouth. The tongue was red, fissured and inflamed. The hair was dull , skin was oily and nails were split.
What is the probable cause for all these manifestations?
What type of investigations should be carried out to know the cause of the disease?
The patient is most probably suffering from Vitamin B2 Deficiency (Riboflavin deficiency).
Vitamin B2 deficiency is frequent in chronic alcoholics. It can also occur in patients with chronic liver diseases, and in hospitalized patients who receive total parenteral nutrition (TPN) with inadequate riboflavin supplementation. Riboflavin is essential for healthy skin, nails, hair growth and general good health, including regulating thyroid activity. Riboflavin supports energy production by aiding in the metabolism of fats, carbohydrates, and proteins. Characteristic symptoms of riboflavin deficiency include lesions of the skin, especially in the corners of the mouth, and a red, sore tongue. Assessment of Riboflavin Status can be done by Erythrocyte glutathione reductase activity.
Basic concept- The term “flavin” originates from the Latin word “flavus” referring to the yellow colour of vitamin B2- Riboflavin. This fluorescent riboflavin is a part of the vitamin B-complex. In the body, riboflavin occurs primarily as an integral component of the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).These coenzymes participate in a large majority of the reactions in the body.
Figure –1- showing structure of riboflavin. It contains D- ribitol, Isoalloxazine ring( Flavin Nucleus), 1 carbon is attached to 9 position of Iso- alloxazine nucleus.
Functions- Flavin coenzymes perform the following functions in the body-
A) Role in redox reactions- Flavin coenzymes are essential for energy production via the respiratory chain, as they act as catalysts in the transfer of electrons in numerous essential oxidation-reduction reactions (redox reactions).
B) Metabolic reactions-They participate in many metabolic reactions of carbohydrates, fats and proteins. Some of the important reactions are as follows-
1) Oxidative decarboxylation of pyruvate and α-ketoglutarate.
2) Succinic dehydrogenase removes electrons from Succinate to form fumarate
3) Fatty acyl CoA dehydrogenase require FAD in fatty acid oxidation
4) As a coenzyme for Xanthine oxidase, FAD transfers electrons directly to oxygen
a) The enzyme contains FAD, Fe, and Mo
b) It converts Hypo Xanthine to Xanthine and then to uric acid
5) Aldehyde oxidase uses FAD to oxidize aldehyde
a) Pyridoxal (vitamin B6) is converted to pyridoxic acid (excreted)
b) Retinal (vitamin A) is converted to retinoic acid
6) Pyridoxine phosphate oxidase which converts Pyridoxamine phosphate and pyridoxine phosphate to Pyridoxal phosphate (primary coenzyme form of vitamin B6 is dependent on FMN
7) Enzymes for choline catabolism require FAD
a) Choline dehydrogenase
b) Dimethyl glycine dehydrogenase
8) Metabolism of some amines requires FAD-dependent monoamine oxidase
9) Reduction of GSSG to GSH is dependent on FAD-dependent glutathione reductase
10) FAD is required by Glycine oxidase enzyme.
11) FAD is a cofactor for methyltetrahydrofolate reductase and therefore modulates homocysteine metabolism. Synthesis of an active form of folate, N5 methyl Tetrahydrofolate, requires FADH2
12) Mitochondrial Glycerol-3- p dehydrogenase requires FAD
13) Oxidative Deamination of amino acids require flavoproteins
14) The vitamin also plays a role in drug and steroid metabolism, including detoxification reactions.
C) Biosynthetic role- Vitamin B2 also promotes normal growth and assists in the synthesis of steroids, red blood cells, and glycogen. Furthermore, it helps to maintain the integrity of mucous membranes, skin, eyes and the nervous system, and is involved in the production of adrenaline by the adrenal glands.
D) Antioxidant role-Riboflavin is also important for the antioxidant status within cell systems, both by itself and as part of the glutathione reductase and Xanthine oxidase system. This defense system may also help defend against bacterial infections and tumor cells.
Water-soluble riboflavin is not stored in ample amounts; minute reserves are stored in the liver, kidneys, and heart. A constant supply is needed. Deficiency in this vitamin is usually part of a multiple-nutrient deficiency and does not occur in isolation.
Milk and other dairy products make the greatest contributions of riboflavin in western diets. Other common dietary sources include cereals, meats, and dark green vegetables (spinach, asparagus, and broccoli). Deficiency can occur with a diet deficient in these riboflavin-rich foods. Deficiency is uncommon in the United States with fortification of many food including grains and cereals. Daily consumption of breakfast cereal and milk would be expected to maintain an adequate intake of riboflavin. Riboflavin is extremely sensitive to light, and milk should be stored in containers that protect against photo degradation.
Additional risk factors
The condition is more commonly seen in persons with such risk factors as pregnancy,lactation, phototherapy for hyperbilirubinemia (in premature infants), advanced age,low-income, and/or depression. Riboflavin is absorbed in the proximal small intestine. Malabsorption from such conditions as celiac sprue, malignancies, and alcoholism can also promote deficiency of riboflavin. Riboflavin is transported in the bloodstream as a flavin-protein complex, which means that nonavailability of the carrier protein also leads to apparent riboflavin deficiency. Similarly, it is possible for antagonists to interfere with absorption and/or transport and thus create an apparent deficiency at receptor sites.
Riboflavin deficiency may also occur as a result of:
- trauma, including burns and surgery
- chronic disorders (e.g. rheumatic fever, tuberculosis, sub acute bacterial endocarditis, diabetes, hypothyroidism, liver cirrhosis)
- chronic medication (tranquillizers, oral-contraceptives, thyroid hormones, fiber-based laxatives, antibiotics)
- high physical activity
Riboflavin deficiency is usually associated with other vitamin B complex deficiencies, and isolated deficiency is rare.However, it has been associated with multiple clinical manifestations.
Riboflavin deficiency most commonly associated with dermatologic conditions, such as the following:
1) Cheilosis, or chapping and fissuring of the lips.
Figure –2- showing cheilosis.
2) A sore, red tongue (Glossitis)
Figure –3- showing glossitis
3) Oily, scaly skin rashes on the scrotum, vulva and philtrum
4) Deficiency can be associated with some developmental abnormalities, such as the following:
a) Cleft lip and palate deformities
b) Growth retardation in infants and children
c) Congenital heart defects
5) Other associations of deficiency include the following:
- Red, itchy eyes
- Night blindness
- Peripheral neuropathy
- Mild anemia (secondary to interference with iron absorption)
- Malignancy (esophageal and cervical dysplasia)
- Measurement of RBC glutathione reductase activity may help in the detection of riboflavin deficiency. An increase in the stimulation of this enzymatic reaction confirms a low-level of riboflavin.
- Measurement of red blood cell or urinary riboflavin concentrations can also help in diagnosis.
- Direct methods include the determination of FAD and FMN in whole blood by HPLC (High Performance Liquid Chromatography).
- Treatment for riboflavin deficiency consists of riboflavin replenishment, with care taken not to overlook coexisting B-complex deficiencies.
- The recommended nutrient intake (RNI) of riboflavin is 0.6 mg/5000 kJ daily.
- The daily RNI ranges are 0.3-0.6 mg for infants, 0.7-1.1 mg for children, 1.1-1.4 mg for adolescents, and 1-1.6 mg for adults.
- Recommended increased requirements for pregnant and lactating women are as follows:
- Additional 0.1 mg/d in the first trimester
- Additional 0.3 mg/d in the second and third trimesters
- Additional 0.4 mg/d during lactation
- Oral riboflavin doses of 1-4 mg daily are usually considered sufficient as a nutritional supplement in patients with normal GI absorption. These doses should be present in the normal diet. Doses for deficiency treatment are slightly higher.
- Because the capacity of the gastrointestinal tract to absorb riboflavin is limited (~20 mg if given in one oral dose), riboflavin toxicity has not been described.